KR20180125330A - Co-crystals of Aripiprazole and methods of preparing thereof - Google Patents

Abstract

The present invention provides a co-crystal of novel aripiprazole and a preparing method thereof. The co-crystal of novel aripiprazole has excellent solubility and dissolution rate compared to conventional aripiprazole and can maximize a therapeutic effect of aripiprazole. The co-crystal including aripiprazole and aromatic polyhydric alcohol is represented by chemical formula 1.

Description

[0002] Co-crystals of aripiprazole and methods of preparing < RTI ID = 0.0 >

The present invention relates to a novel process for preparing aripiprazole containing aripiprazole and an aromatic polyhydric alcohol and a process for preparing the same. The novel co-crystals of the aripiprazole of the present invention have improved solubility and exhibit improved stability by a high melting point.

The chemical name of aripiprazole is 7-4- [4- (2,3-dichlorophenyl) -1-piperazinyl] -butoxy-3,4-dihydrocarbostyril and is represented by the following formula (I).

(I)

 Aripiprazole is a dopaminergic neurotransmitter antagonist which is used as an atypical antipsychotic agent used in the treatment of schizophrenia, bipolar disorder, clinical depression, etc. and a carbostyril derivative (carbostyril derivatives). A typical commercially available therapeutic agent is 'avilipia', which is in the form of tablets, injectable preparations and oral disintegrating agents, and tablets are available in 5 mg, 10 mg, 15 mg, 20 mg and 30 mg.

However, aripiprazole exhibiting such excellent efficacy is very low in solubility and is not easy to exhibit its efficacy effectively. Studies on a polymorph of aripiprazole have been actively conducted to improve the solubility, Research reports are very limited.

The known co-crystals of aripiprazole are known as aripiprazole co-crystals using various organic acids such as salicylic acid and co-crystals of aripiprazole using catechol, resorcinol, hydroquinone, pyrogallol and phloroglucinol.

Accordingly, the present inventors have developed a novel co-crystal of aripiprazole through various methods such as pulverization and evaporation, and confirmed the structure of the crystal by analyzing the apparatus such as single crystal X-ray diffraction analysis.

It has been found that the crystallization according to the present invention has improved solubility and excellent stability compared to the aripiprazole co-crystals already reported in the literature.

Korean Patent Laid-Open Publication No. 10-2014-0000848

J. Med. Chem., (1998), 4, 658-667

It is an object of the present invention to provide novel aripiprazole co-crystals with improved solubility and dissolution properties.

It is another object of the present invention to provide a process for the preparation of the novel co-crystals of aripiprazole.

It is another object of the present invention to provide a pharmaceutical composition for the treatment of a mental illness comprising the co-crystallization of a novel aripiprazole.

The present invention provides a novel co-crystal of aripiprazole comprising aripiprazole (B polymorph, anhydride, Neuland Laboratories, Ltd) and an aromatic polyhydric alcohol represented by the formula (I)

[Chemical Formula 1]

In the present invention, the co-crystallization of aripiprazole and aromatic polyhydric alcohol exhibits excellent solubility and dissolution characteristics as compared to conventional aripiprazole or aripiprazole crystal polymorphs.

According to the "Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals" published by the US Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) in April 2013, A crystal is defined as a crystalline solid material composed of two or more molecules in the same lattice. Thus, the crystallization is distinct from the solid phase polymorph of the drug (API). Generally speaking, unlike polymorphisms that contain only drug molecules in a crystal lattice, the co-crystals consist of a coformer component that is neutral to the drug in the crystal lattice. Similarly, unlike the salts in which the components in the crystal lattice are in the ionized state, the co-crystal components are present in a neutral state and thus are defined as nonionic interactions.

The Guidance for Industry on Regulatory Classification of Pharmaceutical Co-Crystals published by the US Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) , Pharmaceutical co-crystals are typically defined as crystalline materials in which the drug and co-crystal former (coformant) are composed of two or more different molecules in the same crystal lattice.

In the present invention, the aromatic polyhydric alcohol functions as a porogen. The aromatic polyhydric alcohol is an aromatic polyhydric alcohol which is in a solid state at room temperature.

In one embodiment of the present invention, the aromatic polyhydric alcohol may be benzenediol, methyl benzenediol, or benzenetriol. Specifically, the aromatic polyhydric alcohol may be selected from the group consisting of: .

In one embodiment of the present invention, the co-crystal may include aripiprazole and an aromatic polyhydric alcohol in a molar ratio of 2: 1 to 1: 2, and more specifically, a mixture of aripiprazole and an aromatic polyhydric alcohol in a molar ratio of 1: 1 can do.

In one embodiment of the present invention, there is provided a novel co-crystal of aripiprazole comprising aripiprazole and orcinol represented by the above formula (I). In the present invention, the orcinol functions as a coformant in the co-crystals of aripiprazole and orcinol.

The co-crystals of aripiprazole and orcinol may exhibit improved solubility and dissolution rate as compared to conventional aripiprazole co-crystal polymorphs and conventional aripiprazole. For example, the co-crystals of aripiprazole and orcinol exhibit an improved solubility of about 1.5 to 2.5 times compared to a crystalline form of aripiprazole of the prior art and exhibit an improved solubility of about 4- to 5-fold compared to conventional aripiprazole.

In the present invention, the co-crystals of aripiprazole and orcinol may include aripiprazole and orcinol in a molar ratio of 2: 1 to 1: 2, and preferably in a molar ratio of 1: 1.

In the present invention, the aripiprazole and the balls determine the ohreusi glow powder XRD rotation pattern is ^{6.39 o, 9.916 o, 10.966 o} , 18.747 o, 19.606 o, 19.952 o, 20.544 o and 25.1 ^o diffraction angle 2θ (± 0.2 ^o of ) ≪ / RTI > value.

In the present invention, the aripiprazole and the balls determine the ohreusi glow powder XRD rotation pattern is ^{6.39 o, 9.916 o, 10.966 o} , 18.747 o, 19.606 o, 19.952 o, 20.544 o and 25.1 ^o diffraction angle 2θ (± 0.2 ^o of ) ≪ / RTI > value.

In the present invention, the powder XRD rotation pattern of co-crystals of aripiprazole and orcinol is shown in FIG.

In the present invention, the co-crystals of aripiprazole and orcinol exhibit one differential scanning calorimetry (DSC) endothermic peak at 181.3 ° C. to 184.5 ° C. at a heating rate of 10 ° C./min, preferably one And shows a differential scanning calorimetry (DSC) endothermic peak.

The present invention provides a process for preparing a novel co-crystal of aripiprazole comprising an aripiprazole represented by the above formula (I) and an aromatic polyhydric alcohol. The aripiprazole and the aromatic polyhydric alcohol are the same as described above.

In one embodiment of the present invention, the co-crystallization of the aripiprazole and the aromatic polyhydric alcohol may comprise pulverizing aripiprazole and an aromatic polyhydric alcohol.

In one embodiment of the present invention, the step of pulverizing the aripiprazole and the aromatic polyhydric alcohol may be carried out by dry pulverization or wet pulverization. Specifically, the pulverization of the aripiprazole and the aromatic polyhydric alcohol can be carried out by dry pulverization in which aripiprazole and orcinol are introduced into the trigger without an organic solvent and mixed and pulverized, or wet pulverization in which aripiprazole and orcynol are added to the trigger and pulverized in the presence of an organic solvent Or by grinding.

In the present invention, in the case of the wet grinding in which the pulverizing step is carried out in the presence of an organic solvent, the organic solvent may be an aprotic solvent, a linear or branched C1-C5 alcohol, a C3-C10 ester, Of one or more organic solvents selected from the group consisting of ketones. Specifically, the organic solvent may be one or more organic solvents selected from the group consisting of acetonitrile, dimethyl sulfoxide, methanol, ethanol, propanol, isopropanol, methyl acetate, ethyl acetate, acetone and methyl ethyl ketone.

In another embodiment of the present invention, the co-crystallization of the aripiprazole and the aromatic polyhydric alcohol may be prepared by a liquid phase method comprising dissolving aripiprazole and an aromatic polyhydric alcohol in a co-solvent.

Specifically, a production method according to an embodiment of the present invention is a method for producing a compound represented by the general formula (I), which comprises reacting a compound represented by the following general formula (I) with chloroform, dichloromethane, a straight chain or branched C1-C5 alcohol, Preparing a cosolvent by mixing two organic solvents selected from the group consisting of

Dissolving aripiprazole and an aromatic polyhydric alcohol in the cosolvent to prepare a mixture; And

And removing the co-solvent from the mixture.

In one embodiment of the invention, the co-solvent is a first solvent which is chloroform or dichloromethane; And a second solvent which is methanol, ethanol, propanol, isopropanol, methyl acetate, ethyl acetate, diethyl ether, methyl-tert-butyl ether, tetrahydrofuran, acetone or methyl ethyl ketone.

In one embodiment of the invention, the co-solvent is chloroform and ethanol.

In one embodiment of the present invention, the co-solvent comprises the first solvent and the second solvent in a volume ratio of 4: 1 to 1: 4.

In the present invention, the step of removing the co-solvent may be to evaporate the co-solvent. For example, the step of removing the cosolvent may be performed by allowing the solution to stand at room temperature or at room temperature in consideration of the drying time to evaporate the cosolvent, or by using a conventionally known drying method such as reduced-pressure drying, . ≪ / RTI >

The present invention also provides a pharmaceutical composition comprising the novel co-crystals of aripiprazole. Specifically, the present invention includes a pharmaceutical composition for the treatment of a mental disorder comprising as an active ingredient a co-crystal comprising an aripiprazole represented by the above formula (I) and an aromatic polyhydric alcohol.

The aripiprazole and the aromatic polyhydric alcohol are the same as described above.

The mental illness refers to a neurological disease, a neuropsychiatric disorder, a neurodegenerative disease, for example, schizophrenia, bipolar disorder, autism, attention deficit hyperactivity disorder, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, . ≪ / RTI >

The pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and may be formulated for oral or parenteral administration for human or veterinary use. When the pharmaceutical composition of the present invention is formulated, diluents or excipients such as a filler, a weight agent, a binder, a wetting agent, a disintegrating agent and a surfactant may be used.

Solid formulations for oral administration include tablets, pills, powders, granules and capsules, which may be prepared by mixing a pharmaceutical composition comprising the novel aripiprazole co-crystals of the present invention with at least one excipient, Starch, calcium carbonate, sucrose or lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium, styrene, and talc may be used.

Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups. Various excipients such as wetting agents, sweetening agents, fragrances and preservatives may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of non-aqueous solvents and suspensions may include injectable esters such as ethyl alcohol in vegetable oils such as propylene glycol, polyethylene glycol and olive oil. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The pharmaceutical composition of the present invention may be administered orally or parenterally in accordance with the desired method, and may be administered orally, parenterally or intraperitoneally, rectally, subcutaneously, intravenously, intramuscularly, You can choose the injection method.

The pharmaceutical composition of the present invention may further contain at least one active ingredient exhibiting the same or similar pharmaceutical activity besides the co-crystals comprising the aripiprazole and the aromatic polyhydric alcohol.

The present invention provides a method of treating a mental illness comprising administering a therapeutically effective amount of a co-crystal comprising aripiprazole and an aromatic polyhydric alcohol.

The present invention also provides the use of the aripiprazole and the aromatic polyhydric alcohol for the manufacture of a medicament for the treatment of mental disorders. The co-crystals comprising the aripiprazole and the aromatic polyhydric alcohol for the preparation of a medicament may be mixed with an acceptable adjuvant, diluent, carrier or the like, and may be prepared as a combined preparation together with other active agents to have synergistic action of the active ingredients .

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term, pharmaceutically effective amount, as used herein, means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dosage level will vary with the weight, sex, age, , The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. May be administered singly or multiply.

The dosage of the pharmaceutical composition according to the present invention should be a pharmaceutically effective amount. A " pharmaceutically effective amount " means an amount sufficient to prevent or treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level will vary depending on factors such as the formulation method, the condition and weight of the patient, The severity of the disease, the mode of administration, the route and time of administration, the rate of excretion, the responsiveness, and the like. Effective amounts may vary depending on the route of treatment, the use of excipients, and the likelihood of use with other agents, as will be appreciated by those skilled in the art.

The matters mentioned in the use, composition and treatment method of the present invention are applied equally unless they are mutually contradictory.

The co-crystals of aripiprazole of the present invention are superior in solubility and dissolution rate as compared with conventional aripiprazole and can maximize the therapeutic effect of aripiprazole.

Figure 1 is a powder X-ray diffraction (XRD) pattern of a novel aripiprazole-ornithinol co-crystal prepared by dry milling according to the present invention (Example 1).
Figure 2 is a powder X-ray diffraction (XRD) pattern of the novel aripiprazole-ornithinol co-crystal prepared by wet milling according to the invention (Example 2).
3 is a powder X-ray diffraction (XRD) pattern of aripiprazole-orcinolic co-crystal prepared by the liquid phase method (Example 3) according to the present invention.
Figure 4 is a powder X-ray diffraction (XRD) pattern of a conventional aripiprazole.
Figure 5 is a powder X-ray diffraction (XRD) pattern of orcinol.
Figure 6 is a graph of differential scanning calorimetry (DSC) of a novel aripiprazole-ornithinol co-crystal prepared by dry milling according to the present invention (Example 1).
Figure 7 is a graph of differential scanning calorimetry (DSC) of a novel aripiprazole-ornithinol co-crystal prepared by wet grinding according to the present invention (Example 2).
Figure 8 is a graph of differential scanning calorimetry (DSC) of a novel aripiprazole-ornithinol co-crystal prepared by the liquid phase method (Example 3) according to the present invention.
9 is a graph of differential scanning calorimetry (DSC) of a conventional aripiprazole.
10 is a graph of differential scanning calorimetry (DSC) of orcinol.
11 is a thermogravimetric analysis (TGA) result of a novel aripiprazole-orcinolic crystal according to the present invention.
Figure 12 shows a three-dimensional crystal structure through single crystal X-ray diffraction (SC-XRD) of a novel aripiprazole-orcinolic co-crystal according to the present invention.
Figure 13 shows the solubility of the novel aripiprazole-ornithinol co-crystals according to the present invention and conventional aripiprazole and conventional aripiprazole co-crystals.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Example 1 Preparation of aripiprazole-orcinolic crystal by neat grinding

89.6 mg of aripiprazole (B polymorph, anhydride, Neuland Laboratories, Ltd) and 24 mg of orcinol (≥97%, Sigma-Aldrich, St. Louis, Mo., USA) were weighed into an agate mortar After pulverization with a pestle for 30 minutes, the powder was recovered and then dried at 40 DEG C for 24 hours to obtain aripiprazole-orcinolic crystal.

< Example  2> Through liquid-assisted grinding Aripiprazole - Orcinol Ball decision  Manufacturing method

89.6 mg of aripiprazole (B polymorph, anhydride, Neuland Laboratories, Ltd) and 24 mg of orcinol (≥97%, Sigma-Aldrich, St. Louis, Mo., USA) were weighed into an agate mortar 20 [mu] l of methanol was added. After pulverization with a pestle for 30 minutes, the powder was recovered and dried at 40 DEG C for 24 hours to obtain aripiprazole-orcinolic crystal.

Example 3 Preparation of aripiprazole-orcinolic crystal by evaporation

448.39 mg of aripiprazole (type B polymorph, anhydride, Neuland Laboratories, Ltd) and 124.14 mg of orcinol (≥97%, Sigma-Aldrich, St. Louis, Mo., USA) were weighed into a 100 mL beaker. A co-solvent was prepared by mixing chloroform and ethanol in a volume ratio of 4: 1. The co-solvent prepared was added to a beaker, the beaker was capped, and aripiprazole and orcinol were sufficiently dissolved while stirring at room temperature for 30 minutes. After that, the lid of the beaker containing the solution was removed and evaporated in a hood using a hot plate at 70 ° C. When the solvent was sufficiently dried, the solid remaining in the beaker was recovered and dried under reduced pressure for 24 hours to obtain the aripiprazole-orcinolic crystal of the present invention.

<Experimental Example 1> Powder X-ray diffraction (XRD) pattern analysis

Powder X-ray diffraction (XRD) pattern analysis was performed on the aripiprazole-orcinolic co-crystals obtained in Examples 1-3.

The powder X-ray diffraction (XRD) pattern was obtained by generating a Cu-Kα X-ray having a wavelength of 0.154 nm at 40 kV / 40 mA using a Rigaku Miniflex 600 X-ray diffraction analyzer.

20 mg of each specimen powder was weighed into a pre-prepared silica mount to have a flat surface and the Bragg angle (2θ) in the range of 5 to 35 ^° was measured at a goniometer speed of 3 seconds per step size of 0.05 ^° Respectively.

Powder X-ray diffraction (XRD) pattern analysis results of the aripiprazole-ornithinol co-crystals obtained in Examples 1 to 3 are shown in Figs.

Powder X-ray diffraction (XRD) of aripiprazole (B polymorph, anhydrate, Neuland Laboratories, Ltd) and orcinol (≥97%, Sigma-Aldrich, St. Louis, Mo., USA) The pattern analysis results are shown in Figs. 4 and 5.

1 to 5, the horizontal axis is 2? (Bragg angle, ^o ), and the vertical axis is the intensity (cps) of X-rays.

All of the co-crystals according to FIGS. 1 to 3 exhibit the same powder X-ray diffraction (XRD) patterns and are characterized by powder X-ray diffraction (XRD) patterns (FIG. 4) of conventional aripiprazole and powder X- ) Pattern (FIG. 5).

Thus, Figures 1 to 3 show that a novel aripiprazole-orcinolic co-crystal has been formed.

<Experimental Example 2> Analysis of differential scanning calorimetry (DSC)

The endothermic properties of aripiprazole-orcinolic co-crystals, aripiprazole and orcinol obtained in Examples 1 to 3 were measured using a DSC-60 (Shimadzu, Japan) analysis equipment.

Approximately 1.5 mg of each sample powder was placed in an aluminum container and the DSC value was measured with an empty aluminum container as a reference. The DSC measurement was carried out at a temperature raising rate of 10 占 폚 / min under a nitrogen atmosphere at a temperature range of 30 to 300 占 폚.

The results of DSC measurement of the aripiprazole-orcinolic co-crystals obtained in Examples 1 to 3 are shown in Figs.

DSC measurement results of aripiprazole (B polymorph, anhydride, Neuland Laboratories, Ltd) and orcinol (≥97%, Sigma-Aldrich, St. Louis, MO, USA) 10.

6 to 10, the horizontal axis represents the temperature (占 폚), and the vertical axis represents the heat flux (mW).

As can be seen from the above DSC measurement results, the DSC graph (FIG. 9) of the conventional aripiprazole shows a distinct endothermic peak at 139 ° C., and the differential scanning calorimetry 10 shows the endothermic peak at 110 DEG C, whereas the aripiprazole-ornithine co-crystal has a new endothermic peak at about 181 to 184 DEG C as shown in Figs. 6 to 8, and a new aripiprazole - It can be seen that orcinol crystal was formed.

Experimental Example 3 Thermogravimetric analysis (TGA)

Aripiprazole-ornithin co-crystals, aripiprazole and orcinol obtained in Example 3 were measured using a TGA-1000N (Scinco, Korea) analyzer.

The results of TGA measurement of aripiprazole-orcinolic co-crystals, aripiprazole and orcinol are shown in FIG.

As can be seen from the above TGA measurement results, the aripiprazole-ornithinol co-crystal synthesized in Example 3 of the present invention had a first heat of weight reduction of 19.38% at 143-142 ° C and a second heat of weight of 75.89 %. The existing aripiprazole started to heat at around 220 ℃ and decreased by more than 99% from 489.0 ℃. Orsinol decreased more than 99% from 122 to 24 ℃.

Thus, it can be seen that the aripiprazole-orcinolic co-crystals are prepared in a 1: 1 ratio.

Experimental Example 4 Single crystal X-ray diffraction (SC-XRD) analysis

In order to analyze the three-dimensional crystal structure of the novel aripiprazole-orinositol co-crystal of the present invention, aripiprazole and orcinol co-crystals were dissolved in a co-solvent to obtain a co-crystal of monocrystal through a very slow evaporation method .

The results obtained by the single crystal X-ray diffraction analysis are shown in Fig.

As a result of the above single crystal X-ray diffraction analysis, it was confirmed that the amine group of aripiprazole and the hydroxy group of orcinol form a three-dimensional crystal structure through hydrogen bonding.

Experimental Example 5 Determination of Solvent Solubility by Mixing Acetonitrile and Water

Orcinol co-crystal powder obtained in Example 3 in an amount of 200 ml (acetonitrile: water = 1: 9 (v / v)) sufficiently to the extent that an undissolved powder was present, After stirring for 24 hours in a constant-temperature water bath, the concentration of the dissolved aripiprazole in the solution was measured using HPLC (Shimadzu, Japan).

The results of measurement of the solubility of aripiprazole-ornithin co-crystal obtained in Example 3 and acetonitrile mixed with water are shown in FIG. 13-A. The solubility measurement results of the conventional aripiprazole crystal form (polymorph B) 13-B.

In FIG. 13, the abscissa represents time (minute), and the ordinate represents concentration (mg / L) of aripiprazole.

As can be seen from the above solubility measurement results, the solubility of the aripiprazole-orcinolic co-crystals synthesized in Example 3 of the present invention in the cosolvent mixed with acetonitrile and water was measured at a maximum of 6 mg / L, It was found that the solubility of the conventional aripiprazole crystal (type B polymorph) in acetonitrile mixed with water was improved by about 2 to 3 times as compared with the solubility of 2.50 mg / L in the co-solvent.

Therefore, the co-crystals of aripiprazole-orcinol produced in the examples of the present invention exhibit improved solubility and thus are expected to be significantly superior in drug administration through improved absorption.

Claims (18)

A co-crystal comprising an aripiprazole of formula (I) and an aromatic polyhydric alcohol.
(I)

The co-crystal according to claim 1, wherein the aromatic polyhydric alcohol is in a solid state at room temperature. The process according to claim 1, wherein the aromatic polyhydric alcohol is benzenediol, methyl benzenediol or benzene triol. The co-crystal of claim 1, wherein the aromatic polyhydric alcohol is orcinol. The co-crystal of claim 1, wherein the co-crystal comprises aripiprazole and an aromatic polyhydric alcohol in a molar ratio of 2: 1 to 1: 2. The co-crystal of claim 1, wherein the co-crystal comprises aripiprazole and an aromatic polyhydric alcohol in a molar ratio of 1: 1. 5. The method of claim 4, wherein the co-crystal is characterized in that the powder XRD rotational pattern has a diffraction angle of 6.39, 9.916, 10.966, 18.747, 19.606, 19.952, 20.544 and 25.1 And a value of 2 &amp;thetas; (+/- 0.2 DEG). 5. The co-crystallite according to claim 4, wherein the co-crystal exhibits a differential scanning calorimetry (DSC) endothermic peak at 181.53 캜 to 184.52 캜 at a heating rate of 10 캜 / min. A process for preparing a co-crystal comprising aripiprazole and an aromatic polyhydric alcohol, which process comprises pulverizing an aripiprazole represented by the following formula (I) and an aromatic polyhydric alcohol.
(I)

10. The method of claim 9, wherein the grinding is dry grinding or wet grinding. 11. The method of claim 10, wherein the wet grinding is performed in the presence of an organic solvent. 12. The method according to claim 11, wherein the organic solvent is at least one selected from the group consisting of an aprotic solvent, a linear or branched C1-C5 alcohol, a C3-C10 ester, and a C3-C10 ketone . 12. The method according to claim 11, wherein the organic solvent is at least one selected from the group consisting of acetonitrile, dimethyl sulfoxide, methanol, ethanol, propanol, isopropanol, methyl acetate, ethyl acetate, acetone and methyl ethyl ketone . Two organic solvents selected from the group consisting of chloroform, dichloromethane, linear or branched C1-C5 alcohols, C3-C10 esters, C2-C10 ethers and C3-C10 ketones or acetone are mixed to form a co- Producing;
Dissolving aripiprazole and an aromatic polyhydric alcohol in the cosolvent to prepare a mixture; And
Lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; aromatic polyhydric alcohol. 15. The method of claim 14, wherein the co-
A first solvent that is chloroform or dichloromethane; And
Wherein the second solvent comprises a second solvent which is methanol, ethanol, propanol, isopropanol, methyl acetate, ethyl acetate diethyl ether, methyl-tert-butyl ether, tetrahydrofuran, acetone or methyl ethyl ketone. 15. The method of claim 14, wherein the co-solvent comprises chloroform and ethanol. 16. The method of claim 15, wherein the co-solvent comprises the first solvent and the second solvent in a volume ratio of 4: 1 to 1: 4. 9. A pharmaceutical composition for the treatment of a psychotic disorder comprising the co-crystals according to any one of claims 1 to 8 as an active ingredient.

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