CN117903050B - Aripiprazole co-crystal and pharmaceutical composition and application thereof - Google Patents

Aripiprazole co-crystal and pharmaceutical composition and application thereof Download PDF

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CN117903050B
CN117903050B CN202410295172.XA CN202410295172A CN117903050B CN 117903050 B CN117903050 B CN 117903050B CN 202410295172 A CN202410295172 A CN 202410295172A CN 117903050 B CN117903050 B CN 117903050B
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aripiprazole
acid
crystal
eutectic
behenic
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CN117903050A (en
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蔡挺
陈安
郭敏珊
彭亚运
翟豪
蔡佩杉
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China Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
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    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

The invention discloses an aripiprazole eutectic and a pharmaceutical composition and application thereof, and the eutectic and a micro-nano preparation thereof can accurately regulate and control the release behavior of a drug in vivo and in vitro by reasonably designing the alkane chain length and the particle size of fatty acid, thereby providing a novel regulation strategy. Compared with the original grinding aripiprazole monohydrate nano-preparation, the blood concentration in a short period is better, and the defect that the existing clinical medicine needs additional oral medicine is avoided; and the bioavailability and the sustained-release effect are nearly the same as those of the original preparation, and the preparation is safe and effective. In addition, the eutectic crystal form is stable, no crystal transformation occurs in the preparation process, and the physical stability of the preparation is good, thereby being beneficial to realizing industrial production.

Description

Aripiprazole co-crystal and pharmaceutical composition and application thereof
Technical Field
The invention relates to an aripiprazole co-crystal and a pharmaceutical composition and application thereof, in particular to an aripiprazole co-crystal with the property of regulating drug release behavior, and a pharmaceutical composition and application thereof.
Background
Mental diseases are diseases which are clinically manifested by abnormal conditions in aspects of cognition, emotion, will, behavior and the like caused by brain dysfunction under the influence of biological, psychological and social environmental factors. Because of the complex pathogenesis of mental diseases and high recurrence rate, the mental diseases are generally difficult to cure, and most mental disease patients need to take medicines for a long time or even for a whole life to maintain normal working, living and learning states. Poor medication compliance presents a significant challenge for the treatment of psychotic disorders.
Aripiprazole is a dihydroquinolone antipsychotic, and is mainly used for treating schizophrenia, bipolar disorder, major depression, autism of children and the like clinically. The main action target of the aripiprazole is a 5-HT2A receptor, and the aripiprazole also has partial agonism on dopamine D2 and 5-HT1A receptors, and has less side effects and adverse reactions compared with other atypical antipsychotics. In view of the poor clinical patient compliance, a number of long-acting formulations of aripiprazole have been developed.
The micrometer suspensions Abilify Maintena ® and Abilify Asimtufii ® are long-acting preparations which are injected once a month or two, and the active ingredients of the micrometer suspensions are aripiprazole monohydrate. The micro-suspension Aristada ® and the nano-suspension Aristada Initio ® are also long-acting preparations which are injected once a month or two, and the active ingredients of the micro-suspension Aristada ® and the nano-suspension are the Gui Xiana aripiprazole. However, in clinical use, the four types of aripiprazole long-acting injection preparations all need to be taken for a period of time (4-21 days) to maintain effective blood concentration, which is contrary to the design of long-acting injection preparations. In addition, the aripiprazole monohydrate long-acting preparation has the risk of dehydration and crystal transformation of the raw material medicine in the preparation production process, and the synthesis of the raw material medicine of the aripiprazole long-acting preparation in the month Gui Xiana involves organic chemical reaction, which all increase the cost, quality and safety risks of the industrialized production of the pharmaceutical preparation.
Disclosure of Invention
The invention aims to: the first object of the invention is to provide a novel aripiprazole fatty acid eutectic, the second object is to provide a micro-nano preparation taking the aripiprazole fatty acid eutectic as an active ingredient, and the third object is to provide a pharmaceutical application of the aripiprazole fatty acid eutectic and the micro-nano preparation thereof.
The technical scheme is as follows: the aripiprazole eutectic is formed by aripiprazole and a fatty acid ligand, wherein the fatty acid has a structural general formula of C nH2nO2, wherein n is selected from integers of 18-24, more preferably even numbers of 18-24, and even more preferably 18, 20, 22 and 24. The melting points y and n of the aripiprazole co-crystal satisfy the following equation: y=0.96 n+ 72.47, whose intrinsic dissolution rates IDR and n satisfy the following equation: idr= -0.17n+7.93.
Preferably, the molar ratio of aripiprazole to fatty acid is 1:1; the fatty acid is selected from stearic acid, arachidic acid, behenic acid or lignoceric acid.
Pharmaceutical co-crystals refer to solid, single-phase substances in which the pharmaceutically active ingredient and the ligand are linked by weak interactions in a specific chemical ratio, which substances have no charge transfer, nor are solvates. Compared with other strategies for regulating and controlling active ingredients of the medicine, the medicine co-crystallization strategy can effectively regulate the physical and chemical properties of the medicine such as release rate and the like on the premise of not influencing the pharmacodynamic activity, and is more beneficial to the design of a medicine slow-release preparation. Saturated fatty acids are one of the essential substances for organisms to maintain normal physiological activities, and are widely found in nature. Because of its good biocompatibility, safety and low water solubility, it has been widely used in the design of drug sustained release formulations. The pharmaceutical co-crystal strategy is combined with the fatty acid, and the series of fatty acids are used for pharmaceutical co-crystal design, so that the in-vivo and in-vitro release behaviors of the medicine can be precisely regulated and controlled, and the preparation meeting the expected release behaviors is obtained.
The invention combines a drug co-crystallization strategy and a micro-nano strategy to construct the antipsychotic drug aripiprazole and fatty acid into the aripiprazole fatty acid co-crystallization micro-nano suspension, thereby providing a preparation which is beneficial to patent medicine and has obvious slow release effect. Through inherent dissolution rate measurement and pharmacokinetics research, the aripiprazole fatty acid eutectic and the micro-nano preparation thereof can delay the release of the aripiprazole in vivo and in vitro, and the release behavior has obvious dependence on the chain length of fatty acid alkane. The longer the alkane chain, the slower the drug eutectic formed by the fatty acid and the aripiprazole and the inherent dissolution rate of the micro-nano preparation, and the lower the peak concentration of the drug.
Specifically, the invention designs a series of brand-new aripiprazole sustained release preparations, the drug substitution parameters of which can be adjusted by the chain length of fatty acid alkane and the particle size, and the invention has the advantages of single design strategy and insufficient administration mode of the aripiprazole long-acting preparation.
The aripiprazole stearic acid eutectic is a triclinic system,A space group; the unit cell parameters are a= 7.6166 (10) a, b= 10.7494 (11) a, c= 26.631 (4) a, α= 79.412 (4) °, β= 88.984 (5) °, γ= 75.058 (4) °; further, the co-crystal has at least one characteristic diffraction peak at 6.76 °、9.92 °、10.14 °、13.52 °、16.90 °、17.26 °、17.82 °、18.38 °、18.60 °、20.42 °、21.08 °、21.88 °、23.28 °、23.56 °、23.96 °、24.18 °、26.80 °、27.00 °, expressed as diffraction angle 2θ±0.2°; still further, the co-crystal has at least one characteristic diffraction peak at 6.76 °、8.68 °、9.92 °、10.14 °、11.92 °、12.38 °、12.92 °、13.52 °、13.96 °、15.48 °、16.48 °、16.90 °、17.26 °、17.82 °、18.38 °、18.60 °、19.58 °、19.92 °、20.42 °、21.08 °、21.88 °、22.60 °、23.28 °、23.56 °、23.96 °、24.18 °、24.88 °、25.26 °、25.52 °、25.70 °、26.00 °、26.48 °、26.80 °、27.00 °、29.22 °, expressed as diffraction angle 2θ±0.2°; still further, the co-crystal had a characteristic melting peak at 89.5±0.3 ℃.
The aripiprazole eicosanoic acid eutectic is expressed by a diffraction angle 2 theta plus or minus 0.2 degrees, and at least has one characteristic diffraction peak at 9.64 °、13.16 °、16.10 °、16.88 °、17.26 °、18.40 °、18.54 °、19.30 °、20.98 °、21.9 °、22.28 °、23.24 °、23.48 °、24.08 °、25.30 °; further, the co-crystal has at least one characteristic diffraction peak at 6.42 °、8.7 °、9.64 °、9.96 °、11.40 °、12.80 °、13.16 °、16.10 °、16.88 °、17.26 °、18.40 °、18.54 °、19.30 °、20.00 °、20.52 °、20.98 °、21.9 °、22.28 °、22.62 °、22.94 °、23.24 °、23.48 °、23.70 °、24.08 °、24.54 °、25.30 °、25.84 °、26.64 °、27.76 °、28.46 °, expressed as diffraction angle 2θ±0.2°; still further, the co-crystal has a characteristic melting peak at 92.4±0.4 ℃.
The aripiprazole behenic acid eutectic is expressed by diffraction angle 2 theta plus or minus 0.2 degrees, and at least one characteristic diffraction peak is arranged at 5.5 °、9.16 °、11.04 °、14.38 °、16.6 °、17.74 °、19.36 °、19.52 °、20.38 °、21.56 °、22.1 °、23.40 °、24.14 °、24.98 °、26.66 °; further, the co-crystal has at least one characteristic diffraction peak at 5.5 °、5.8 °、7.2 °、7.32 °、8.26 °、8.74 °、8.90 °、9.16 °、9.58 °、10.84 °、11.04 °、11.66 °、11.82 °、12.06 °、12.82 °、14.38 °、14.96 °、15.50 °、15.82 °、16.34 °、16.6 °、16.96 °、17.74 °、17.90 °、18.64 °、19.36 °、19.52 °、19.64 °、19.72 °、20.38 °、21.20 °、21.32 °、21.56 °、22.1 °、22.4 °、22.64 °、22.72 °、22.96 °、23.04 °、23.40 °、23.74 °、24.14 °、24.98 °、25.94 °、26.66 °、27.14 °、27.44 °、27.94 °、28.30 °、28.80 °、29.62 °、30.16 °、31.54 °, expressed as diffraction angle 2θ±0.2°; still further, the co-crystal had a characteristic melting peak at 93.7±0.8 ℃.
The aripiprazole lignan acid eutectic is expressed by diffraction angles 2 theta plus or minus 0.2 degrees, and at least one characteristic diffraction peak is arranged at 18.44 degrees, 18.62 degrees, 20.98 degrees, 21.02 degrees, 21.50 degrees, 22.14 degrees, 22.64 degrees, 23.36 degrees, 23.7 degrees, 24.0 degrees, 24.76 degrees and 25.54 degrees; further, the co-crystal has at least one characteristic diffraction peak at 7.68 °、8.62 °、8.74 °、8.92 °、10.3 °、12.86 °、14.74 °、16.32 °、17.08 °、17.24 °、17.3 °、17.6 °、17.64 °、17.68 °、17.98 °、18.44 °、18.62 °、19.06 °、19.58 °、19.74 °、19.92 °、20.12 °、20.18 °、20.34 °、20.46 °、20.54 °、20.6 °、20.72 °、20.98 °、21.02 °、21.18 °、21.32 °、21.36 °、21.50 °、21.7 °、21.76 °、22.14 °、22.64 °、23.36 °、23.7 °、24.0 °、24.76 °、25.54 °、26.24 °, expressed as diffraction angle 2θ±0.2°; still further, the co-crystal has a characteristic melting peak at 95.5±0.1 ℃.
The preparation method of the aripiprazole eutectic provided by the invention is selected from any one of the following methods:
The method comprises the following steps: forming suspension of aripiprazole and fatty acid in solvent, stirring, and removing solvent to obtain the final product;
the second method is as follows: dissolving aripiprazole and fatty acid in solvent, filtering, removing solvent crystal to obtain the final product;
and a third method: dissolving aripiprazole and fatty acid in a solvent, mixing with water, and removing the solvent to obtain the final product;
The method four: heating and melting aripiprazole and fatty acid, and cooling to obtain the final product.
Preferably, in method one, the molar ratio of aripiprazole to fatty acid is 1:2 to 2:1, more preferably 1:1; the solvent is one or more selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, and N-methylpyrrolidone, preferably acetonitrile; the mass ratio of the aripiprazole to the solvent is 1:5-1:20, more preferably 1:8-1:15; the stirring temperature was room temperature and the solvent was removed by suction filtration.
Preferably, in method II, the molar ratio of aripiprazole to fatty acid is 1:2 to 2:1, more preferably 1:1; the solvent is one or more selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, and N-methylpyrrolidone, preferably acetonitrile; the mass ratio of the aripiprazole to the solvent is 1:100-1:500, more preferably 1:150-1:350; the dissolution method is heating or ultrasonic dissolution assisting, and the solvent removal method is standing evaporation or rotary evaporation.
Preferably, in method three, the molar ratio of aripiprazole to fatty acid is 1:2 to 2:1, more preferably 1:1; the solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, and N-methylpyrrolidone, and more preferably acetone or dimethyl sulfoxide; the mass ratio of the aripiprazole to the solvent is 1:50-1:200, more preferably 1:80-1:120; the mixing temperature is 0-10 ℃, and the solvent is removed by suction filtration.
Preferably, in method four, the molar ratio of aripiprazole to fatty acid is 1:2 to 2:1, more preferably 1:1; the temperature of the heating and melting is 120-150 ℃, more preferably 140+ -5 ℃.
The medicine composition of the invention takes the aripiprazole eutectic of the invention as an active ingredient; the particle size of the pharmaceutical composition is 0.1-5 mu m, and the specific dosage form is aripiprazole fatty acid eutectic micro-nano suspension. Wherein, the particle size of the nano suspension is less than 500nm, and the PDI is less than 0.3; the D 50 of the microsuspension is less than 5 μm. The pharmaceutical composition is administered orally or by injection, and has a tendency that the pharmacokinetic parameters in rats and the chain length of fatty acid change monotonically.
Preferably, the aripiprazole stearic acid eutectic micro-nano suspension has at least one characteristic diffraction peak at 6.76 °、8.68 °、9.92 °、10.14 °、11.92 °、12.38 °、12.92 °、13.52 °、13.96 °、15.48 °、16.48 °、16.90 °、17.26 °、17.82 °、18.38 °、18.60 °、19.58 °、19.92 °、20.42 °、21.08 °、21.88 °、22.60 °、23.28 °、23.56 °、23.96 °、24.18 °、24.88 °、25.26 °、25.52 °、25.70 °、26.00 °、26.48 °、26.80 °、27.00 °、29.22 °, expressed as diffraction angle 2θ±0.2°.
Preferably, the aripiprazole arachidic acid eutectic micro-nano suspension has at least one characteristic diffraction peak at 6.42 °、8.7 °、9.64 °、9.96 °、11.40 °、12.80 °、13.16 °、16.10 °、16.88 °、17.26 °、18.40 °、18.54 °、19.30 °、20.00 °、20.52 °、20.98 °、21.9 °、22.28 °、22.62 °、22.94 °、23.24 °、23.48 °、23.70 °、24.08 °、24.54 °、25.30 °、25.84 °、26.64 °、27.76 °、28.46 ° as expressed in diffraction angle 2θ±0.2°.
Preferably, the aripiprazole wood wax acid eutectic micro-nano suspension has at least one characteristic diffraction peak at 7.68 °、8.62 °、8.74 °、8.92 °、10.3 °、12.86 °、14.74 °、16.32 °、17.08 °、17.24 °、17.3 °、17.6 °、17.64 °、17.68 °、17.98 °、18.44 °、18.62 °、19.06 °、19.58 °、19.74 °、19.92 °、20.12 °、20.18 °、20.34 °、20.46 °、20.54 °、20.6 °、20.72 °、20.98 °、21.02 °、21.18 °、21.32 °、21.36 °、21.50 °、21.7 °、21.76 °、22.14 °、22.64 °、23.36 °、23.7 °、24.0 °、24.76 °、25.54 °、26.24 °, expressed as diffraction angle 2θ±0.2°.
Preferably, the aripiprazole fatty acid eutectic can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, syrup, suspending agents or injection, and the preparations can be added with common medicinal auxiliary materials such as perfume, sweetener, liquid/solid filler, diluent and the like.
The preparation method of the pharmaceutical composition is selected from any one of the following methods:
The method comprises the following steps: forming a suspension of the aripiprazole fatty acid eutectic in an aqueous solution containing an additive, and grinding to obtain the aripiprazole fatty acid eutectic;
The second method is as follows: preparing a solution containing aripiprazole and fatty acid, mixing with an aqueous solution containing an additive, stirring, and removing the solvent.
Preferably, the additive is selected from one or more of polysorbate, polyethylene glycol 1000 vitamin E succinate, poloxamer, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, and gelatin. Wherein the additive in method one is further preferably polysorbate, more preferably polysorbate 20; the additive in method two is further preferably polysorbate 80 or hydroxypropyl methylcellulose.
Further preferably, the dosage of the additive in the first method is 0.5% -2% of the water mass; the dosage of the aripiprazole fatty acid eutectic is 5% -20% of the water mass, more preferably 10%; the grinding speed is 600-1000 rpm, and the grinding time is 0-4 h.
Further preferably, the solvent in process two is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone, more preferably acetone or dimethyl sulfoxide; the dosage of the additive is 0.01% -2% of the water mass, more preferably 0.05% -0.1%; the raw material for preparing the solution containing the aripiprazole and the fatty acid is an aripiprazole fatty acid eutectic or a mixture of the aripiprazole and the fatty acid, and more preferably the aripiprazole fatty acid eutectic; the dosage of the aripiprazole fatty acid eutectic is 0.1% -2% of the water mass, more preferably 0.3% -0.6%; the mass ratio of the solvent to the water is 1:10-1:50, and more preferably 1:20; the stirring temperature is 0-10 ℃, and the method for removing the solvent is freeze-drying.
The aripiprazole eutectic or the pharmaceutical composition thereof disclosed by the invention maintains the biological activity of the aripiprazole, and can be applied to the preparation of medicines for preventing and/or treating mental diseases.
Preferably, the medicament is a medicament for preventing and/or treating schizophrenia, bipolar disorder, major depression, autism or tourette's syndrome.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
The aripiprazole fatty acid eutectic and the micro-nano preparation thereof designed by the invention can accurately regulate and control the release behavior of the medicine in vivo and in vitro by reasonably designing the alkane chain length and the particle size of fatty acid, and provide a new regulation strategy. Compared with the original grinding aripiprazole monohydrate nano preparation, the blood concentration in a short period is better, the defect that the existing clinical medicine needs additional oral medicine is avoided, the bioavailability and the sustained-release effect are nearly consistent, and the preparation is safe and effective. In addition, the eutectic crystal form is stable, no crystal transformation occurs in the preparation process, and the physical stability of the preparation is good, thereby being beneficial to realizing industrial production.
Drawings
FIG. 1 is a diagram showing the structure of a single crystal asymmetric unit of the eutectic aripiprazole stearic acid prepared in example 5;
FIG. 2 is a differential scanning calorimeter of the aripiprazole fatty acid co-crystals and aripiprazole crystal form III prepared in examples 1, 2, 3,4, 17;
FIG. 3 is a linear plot of melting point versus carbon number of fatty acids for the aripiprazole fatty acid co-crystals prepared in examples 1, 2,3, and 4;
FIG. 4 is a thermogravimetric analysis of the aripiprazole fatty acid co-crystals and aripiprazole crystal form III prepared in examples 1, 2,3, 4, 17;
FIG. 5 is an X-ray powder diffraction pattern of the co-crystals of aripiprazole fatty acids and aripiprazole crystal form III prepared in examples 1, 2,3, 4, 17;
FIG. 6 is a graph of the intrinsic dissolution rates of the preparation of the aripiprazole fatty acid co-crystals and aripiprazole crystal form III of examples 1, 2, 3, 4, 17;
FIG. 7 is a differential scanning calorimeter plot of micro-nano suspensions of aripiprazole fatty acid co-crystals and aripiprazole monohydrate prepared in examples 19, 20, 21, 23, 24;
FIG. 8 is an X-ray powder diffraction pattern of micro-nano suspensions of aripiprazole fatty acid co-crystals and aripiprazole monohydrate prepared in examples 19, 20, 21, 23, 24;
FIG. 9 is a graph showing the pharmacokinetics of micro-nano suspensions of aripiprazole fatty acid co-crystals and aripiprazole monohydrate prepared in examples 19, 20, 21, 24 in rats;
fig. 10 is a graph showing the pharmacokinetic profile of micro-nano suspensions of aripiprazole fatty acid co-crystals and aripiprazole monohydrate prepared in examples 19, 23, and 24 in rats.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
The instrument for solid state characterization of the pharmaceutical co-crystal in the invention is as follows:
the differential scanning calorimeter is TA Q2000, and the specific operation mode is that 3-5 mg of sample is weighed in a sealed aluminum crucible, the temperature is raised to 160 ℃ at the speed of 10 ℃ per minute, the instrument is calibrated by adopting metal indium, the inert gas is protected by high-purity nitrogen (more than 99.99%), the nitrogen flow rate is 50mL per minute, and the analysis software is TA Universal Analysis.
The model of the thermogravimetric analyzer is TA Q500, and the specific operation mode is that 5-15 mg of sample is placed in a platinum disk, and the temperature is raised to 400 ℃ at the speed of 20 ℃ per minute. The test environment was protected by high purity (99.99%) nitrogen, flow rate of nitrogen 40 mL/min.
The X-ray powder diffractometer has the instrument model number of Japanese science SmartLab SE; and (3) target: cu-ka radiation (λ=1.5406 a); tube voltage: copper palladium 40 kV; current flow: 40 mA;2 theta range: 5-40 degrees; scanning step length: 0.02 A degree; scanning rate: 10. degree/min.
Example 1
The crude drug of aripiprazole (2.24 g) and stearic acid (1.42 g) were weighed, 20 mL acetonitrile solution was added, suspension stirred at room temperature for 3 days, suction filtration, vacuum drying at 40 ℃ for 48 h, and solid state characterization was carried out to confirm that aripiprazole stearic acid co-crystal (APZ 18C) was obtained.
Example 2
The raw materials of the aripiprazole (2.24 g) and the arachidic acid (1.56 g) are weighed, 20 mL acetonitrile solution is added, suspension stirring is carried out for 3 days at room temperature, suction filtration is carried out, vacuum drying is carried out at 40 ℃ for 48 h, and the aripiprazole arachidic acid eutectic (APZ 20C) is obtained through solid state characterization.
Example 3
The crude drug of aripiprazole (2.24 g) and behenic acid (1.70 g) were weighed, 20 mL acetonitrile solution was added, suspension stirred at room temperature for 3 days, suction filtration, vacuum drying at 40 ℃ for 48 h, and solid state characterization was confirmed to obtain aripiprazole behenic acid co-crystal (APZ 22C).
Example 4
The crude drug of the aripiprazole (2.24 g) and the xylonic acid (1.84 g) are weighed, 20 mL acetonitrile solution is added, suspension stirring is carried out for 3 days at room temperature, suction filtration is carried out, vacuum drying is carried out at 40 ℃ for 48 h, and the aripiprazole xylonic acid eutectic (APZ 24C) is obtained through solid state characterization.
Example 5
And (3) weighing 448 mg aripiprazole crystal form III and 284 mg stearic acid, simultaneously adding 75 mL acetonitrile as a solvent, ultrasonically heating and dissolving, filtering into a beaker, placing the beaker in a fume hood to volatilize the solvent, drying the product, and performing solid state characterization and confirmation to obtain the aripiprazole stearic acid eutectic (APZ 18C).
Example 6
And (3) weighing 448 mg aripiprazole crystal form III and 312 mg arachidic acid, simultaneously adding 100 mL acetonitrile as a solvent, ultrasonically heating and dissolving, filtering into a beaker, placing the beaker in a fume hood to volatilize the solvent, drying the product, and carrying out solid state characterization and confirmation to obtain the aripiprazole arachidic acid eutectic (APZ 20C).
Example 7
And (3) weighing 448 mg aripiprazole crystal form III and 340 mg behenic acid, simultaneously adding 120 mL acetonitrile as a solvent, ultrasonically heating and dissolving, filtering into a beaker, placing the beaker in a fume hood to volatilize the solvent, drying the product, and carrying out solid characterization and confirmation to obtain the aripiprazole behenic acid eutectic (APZ 22C).
Example 8
And weighing 448 mg aripiprazole crystal form III and 368 mg wood wax acid, simultaneously adding 150 mL acetonitrile as a solvent, ultrasonically heating and dissolving, filtering into a beaker, placing the beaker in a fume hood to volatilize the solvent, drying the product, and performing solid characterization and confirmation to obtain the aripiprazole wood wax acid eutectic (APZ 24C).
Example 9
And weighing 50 mg aripiprazole crystal form III and 32 mg stearic acid, simultaneously adding 5mL acetone for dissolution, slowly dripping into an aqueous solution under the stirring condition, carrying out suction filtration, drying the product, and carrying out solid state characterization and confirmation to obtain the aripiprazole stearic acid eutectic (APZ 18C).
Example 10
And weighing 50 mg aripiprazole crystal form III and 35 mg arachidic acid, simultaneously adding 5mL acetone for dissolution, slowly dripping into an aqueous solution under the stirring condition, carrying out suction filtration, drying the product, and carrying out solid state characterization and confirmation to obtain the aripiprazole arachidic acid eutectic (APZ 20C).
Example 11
And weighing 50 mg aripiprazole crystal form III and 38 mg behenic acid, simultaneously adding 5mL acetone for dissolution, slowly dripping into an aqueous solution under the stirring condition, carrying out suction filtration, drying the product, and carrying out solid state characterization and confirmation to obtain the aripiprazole behenic acid eutectic (APZ 22C).
Example 12
And (3) weighing 50 mg aripiprazole crystal form III and 41 mg wood wax acid, simultaneously adding 5mL acetone for dissolution, slowly dripping into an aqueous solution under the stirring condition, carrying out suction filtration, drying the product, and carrying out solid state characterization and confirmation to obtain the aripiprazole wood wax acid eutectic crystal (APZ 24C).
Example 13
And weighing 448 mg aripiprazole crystal form III and 284 mg stearic acid, fully and uniformly mixing, heating and melting at a temperature of 140 ℃, taking out to an aluminum block for quenching, and then placing at 60 ℃ for reheating until the amorphous crystallization is complete. The solid state characterization proves that the aripiprazole stearic acid eutectic (APZ 18C) is obtained.
Example 14
And weighing 448 mg aripiprazole crystal form III and 312 mg arachidic acid, fully and uniformly mixing, heating and melting at a temperature of 140 ℃, taking out to an aluminum block for quenching, and then placing at 60 ℃ for reheating until the amorphous crystallization is complete. The solid state characterization proves that the aripiprazole eicosanoid eutectic (APZ 20C) is obtained.
Example 15
And weighing 448 mg aripiprazole crystal form III and 340 mg behenic acid, fully and uniformly mixing, heating and melting at a temperature of 140 ℃, taking out to quench on an aluminum block, and then heating again at 60 ℃ until the amorphous crystallization is complete. The Aripiprazole behenic acid eutectic (APZ 22C) is obtained through solid state characterization.
Example 16
And weighing 448 mg aripiprazole crystal form III and 368 mg wood wax acid, fully and uniformly mixing, heating and melting at a temperature of 140 ℃, taking out to quench on an aluminum block, and then placing at a temperature of 60 ℃ for reheating until the amorphous crystallization is complete. Solid state characterization proves that the aripiprazole lignan acid eutectic (APZ 24C) is obtained.
Example 17
The crude drug of 10 g aripiprazole is weighed, a mixed solvent of 200 mL ethanol and water (4:1) is added, reflux is carried out at 70 ℃ for 2h, the temperature is slowly reduced to room temperature, suction filtration is carried out, vacuum drying is carried out at 40 ℃ for 48 h, and aripiprazole monohydrate (APZMH) is confirmed to be obtained through solid state characterization. The aripiprazole monohydrate is placed in a flat state on a 100 ℃ hot stage heated for 30min, and the aripiprazole crystal form III (APZF) is confirmed by solid state characterization.
A single crystal of aripiprazole stearic acid co-crystal was prepared from example 5, whose asymmetric units in the crystal structure consisted of one molecule of aripiprazole and one molecule of stearic acid (FIG. 1). The difference in the distance between the two carbon-oxygen bonds in the carboxylic acid in the eutectic structure of aripiprazole stearic acid (Δd （C-O）) was determined to be 0.106 a. The multicomponent single phase solid synthesized from aripiprazole and stearic acid is considered to be a co-crystal rather than a salt according to the carboxylic acid rule (Δd （C-O） in neutral carboxyl is greater than 0.08 a and Δd （C-O） in carboxylate anion is less than 0.03 a) that distinguishes co-crystals from salts.
Solid state characterization results of the aripiprazole fatty acid co-crystals and aripiprazole crystal form III are shown in fig. 2, fig. 4 and fig. 5. From the characterization results, it can be seen that the basic physicochemical properties of the whole fatty acid co-crystal are substantially uniform, i.e. the melting point of the fatty acid co-crystal is between that of the fatty acid and that of aripiprazole crystal form III, despite the different chain lengths of the fatty acid alkanes in the fatty acid co-crystal. The X-ray powder diffraction patterns are substantially consistent, suggesting similar molecular structure packing, and the single-phase materials of each component prepared are eutectic rather than salt. Counting the melting points, the melting point of the aripiprazole fatty acid co-crystal was found to increase with increasing fatty acid chain length, and the co-crystal melting point y and fatty acid carbon number n satisfied the following equation: y=0.96 n+ 72.47 (fig. 3). The results indicate that the fatty acid eutectic strategy can be used for regulating basic physicochemical properties of the drug, and the eutectic with expected physicochemical properties can be obtained for subsequent formulation development through reasonable design of fatty acid chain length.
Example 18: intrinsic dissolution Rate experiment
1. Sample source
Aripiprazole crude drug is purchased from Jiangsu ai Kang Shengwu pharmaceutical research and development Co., ltd, and fatty acid is purchased from Shanghai Ala Biochemical technology Co., ltd; the aripiprazole crystal form III is purified from aripiprazole bulk drug substance.
2. Experimental method
The powder of aripiprazole crystal form III and aripiprazole fatty acid co-crystals of 50 mg were separately weighed through an 80 mesh sieve, placed in an intrinsic dissolution die having a diameter of 4mm, and pressed at a pressure of 200 kg for 1 min. After the compression was completed, the mold was removed and one side of the tablets was exposed to 550 mL dissolution medium (0.25% aqueous Sodium Dodecyl Sulfate (SDS)), dissolution was performed at 37 ℃ at a rotational speed of 50 rpm, 4 mL sample solutions were sampled at different time points (30, 60, 90, 120, 150, 180 min) while supplementing the same amount of thermostatically controlled blank medium, the sample solutions were centrifuged at 13000 rpm for 5 min, and the supernatant was HPLC-sampled.
High performance liquid chromatography determination experimental conditions:
instrument: the Shimadzu LC-20AT high performance liquid chromatograph;
chromatographic ultraviolet detector model: island body fluid SPD-20A;
Chromatographic quaternary pump model: shimadzu LC-20AT;
chromatographic column: agilent Zorbax SB C-18 (4.6X1250 mm,5 μm);
Mobile phase: acetonitrile 0.1% formic acid-0.1% aqueous ammonia (v/v, 60:40);
column temperature: 40. c°;
flow rate: 1 mL/min;
sample injection amount: 50. mu L;
detection wavelength: 254 nm.
3. Experimental results
The results of the intrinsic dissolution profile of the aripiprazole fatty acid co-crystals for form III of the aripiprazole oral formulation are shown in fig. 6. The calculated intrinsic dissolution rates are shown in table 1.
TABLE 1 intrinsic dissolution rate of aripiprazole fatty acid co-crystals in 0.25% SDS for oral formulations of aripiprazole form III
The results show that the inherent dissolution rate of the aripiprazole fatty acid eutectic designed by the invention is slower than that of the aripiprazole crystal form III, and the inherent dissolution rate of the aripiprazole fatty acid eutectic with different chain lengths is reduced along with the increase of the chain length of the fatty acid, and the inherent dissolution rate IDR and the fatty acid carbon number n meet the following equation: idr= -0.17n+7.93. Indicating that the formation of the fatty acid eutectic of the aripiprazole delays the dissolution of the aripiprazole, and is beneficial to realizing the slow release of the medicine. The correlation characteristic between the inherent dissolution rate and the chain length shows that the fatty acid eutectic strategy can be used for regulating the release behavior of the drug in vitro, and indirectly indicates that the fatty acid eutectic strategy has great potential for regulating the release of the drug in vivo.
Example 19
308.1 Mg of the aripiprazole stearic acid eutectic which is prepared in example 1 and passes through a 80-mesh sieve is weighed, 3mL of aqueous solution containing 30 mg Tween 20 is added, 4g of zirconia grinding beads with the diameter of 1mm are added, 2h of the grinding beads are ground at the rotating speed of 800 rpm at room temperature, an appropriate amount of sodium chloride, sodium citrate, sodium dihydrogen phosphate and disodium hydrogen phosphate are added to adjust the osmotic pressure and the pH value of the preparation, and the aripiprazole stearic acid eutectic nano suspension (NAPZ C) with the particle size of 304.47 +/-7.04 nm and the PDI of 0.18+/-0.15 is obtained, and the preparation is stored at the temperature of 4 ℃ for standby.
Example 20
319.8 Mg of the 80 mesh sieve-passing Aripiprazole eicosanoid eutectic prepared in example 2 was weighed, 3 mL of an aqueous solution containing 30 mg Tween 20 was added, 3g zirconia grinding beads with a diameter of 1mm were added, 2h was ground at a rotation speed of 700 rpm at room temperature, an appropriate amount of sodium chloride, sodium citrate, sodium dihydrogen phosphate and disodium hydrogen phosphate were added to adjust the osmotic pressure and pH of the preparation, and Aripiprazole eicosanoid eutectic nanosuspension (NAPZ C) with a particle size of 307.13.+ -. 0.04 nm and a PDI of 0.26.+ -. 0.01 was obtained and stored at 4 ℃ for later use.
Example 21
The 80 mesh sieve-passing Aripiprazole wood cerotic acid eutectic prepared in example 4 of 343.5 mg was weighed, 3mL aqueous solution containing 30 mg Tween 20 and 4g zirconia grinding beads with a diameter of 1mm were added, 2h was ground at a rotation speed of 700 rpm at room temperature, an appropriate amount of sodium chloride, sodium citrate, sodium dihydrogen phosphate and disodium hydrogen phosphate were added to adjust the osmotic pressure and pH of the preparation, and Aripiprazole wood cerotic acid eutectic nanosuspension (NAPZ C) with a particle size of 252.1.+ -. 0.66 nm and a PDI of 0.19.+ -. 0.02 was prepared and stored at 4 ℃ for later use.
Example 22
188 Mg Aripiprazole stearic acid eutectic prepared in example 1 is weighed, added with 2 mL dimethyl sulfoxide for dissolution, slowly added dropwise into 40 mL aqueous solution containing 28 mg Tween 80 under ice water bath environment, stirred while dropwise adding, and after the dropwise adding is finished, the product is characterized by ultrasonic 30min with 70W power, the particle size is 375.47 +/-6.97 nm, and the PDI is 0.136+/-0.092.
Example 23
308.1 Mg of the aripiprazole stearic acid eutectic which is prepared in example 1 and passes through a 80-mesh sieve is weighed, 3 mL of water solution containing 30mg Tween 20 is added, 4g zirconia grinding beads with the diameter of 1mm are added, 8 min of the grinding beads are ground at the rotating speed of 800 rpm at room temperature, a proper amount of sodium chloride, sodium citrate, sodium dihydrogen phosphate and disodium hydrogen phosphate are added to adjust the osmotic pressure and the pH value of the preparation, and thus the aripiprazole stearic acid eutectic micron suspension (MAPZ C) with the D 50 of 2.77+/-0.01 mu m is obtained, and the suspension is placed at the temperature of 4 ℃ for standby.
Example 24
196.2 Mg of 80 mesh sieve aripiprazole monohydrate prepared in example 5 was weighed, 3mL of aqueous solution containing 30 mg Tween 20 and 6g zirconia grinding beads with a diameter of 1mm were added, 2.5 h was ground at a rotation speed of 1000 rpm at room temperature, an appropriate amount of sodium chloride, sodium citrate, sodium dihydrogen phosphate and disodium hydrogen phosphate were added to adjust the osmotic pressure and pH of the preparation, and aripiprazole monohydrate Nanosuspension (NAPZMH) with a particle size of 286.6.+ -. 0.03 nm and a PDI of 0.17.+ -. 0.01 was prepared and stored at 4 ℃ for later use.
The particle size characterization of all the prepared aripiprazole fatty acid eutectic and aripiprazole monohydrate micro-nano suspension shows that the particle size of the four nano preparations is less than 500 nm, the PDI is less than 0.3, the D 50 of the aripiprazole stearic acid eutectic micro-suspension is less than 5 mu m, and the aripiprazole fatty acid eutectic and aripiprazole monohydrate micro-nano suspension has proper particle size and good stability. The formulation was freeze-dried and then solid state characterized, as shown in fig. 7 and 8, with a slight decrease in melting point of the fatty acid co-crystals after formulation, which may be related to interactions between the drug and excipients in the formulation. And the X-ray powder diffraction pattern after preparation is basically consistent with that before preparation, which indicates that the preparation process does not generate crystal form transformation.
Example 25: pharmacokinetic studies of aripiprazole fatty acid nanoformulations
1. Experimental materials
Male SD rats (weight 180-220 g, purchased from Shanghai Bikeside Biotechnology Co., ltd., production license number SCXK (Shanghai) 2018-0006), aripiprazole stearic acid eutectic nanosuspension (prepared in example 19), aripiprazole arachidic acid eutectic nanosuspension (prepared in example 20), aripiprazole lignoceric acid eutectic nanosuspension (prepared in example 21), aripiprazole stearic acid eutectic microsuspension (prepared in example 23), aripiprazole monohydrate nanosuspension (prepared in example 24).
2. Experimental method
30 Male SD rats were randomly divided into 5 groups (6 per group) and each group was labeled individually with an ear tag for unique identification as A, B, C, D, E groups, with free water during the test. Wherein, the A, B, C, D groups of SD rats are subjected to single intramuscular injection of the aripiprazole stearic acid eutectic nanosuspension, the aripiprazole arachidic acid eutectic nanosuspension and the aripiprazole lignoceric acid eutectic nanosuspension according to the dosage of 100 mg/kg (calculated by aripiprazole), and the aripiprazole stearic acid eutectic microsuspension; group E SD rats were single intramuscular injected with aripiprazole monohydrate nanosuspension at a dose of 100 mg/kg (calculated as aripiprazole); at various time points (0, 2h, 4h, 8h, 1 d, 2 d, 3d, 5 d, 7 d, 10 d, 14 d, 19 d, 25 d, 30 d, 35 d, 40 d, 50 d) orbital bleeding was performed for 0.5 mL into heparin sodium wetted 2 mL centrifuge tubes, 4000 rpm centrifuged for 15 min, and the upper plasma was placed in a-80 ℃ refrigerator until LC-MS detection.
Liquid phase mass spectrometry conditions:
Instrument: shimadzu LCMS 8045 triple four-stage rod liquid chromatography-mass spectrometer;
Chromatographic column: water C18 (150X 4.6 mm,5 μm);
Mobile phase: 0.05% ammonia water-0.05% formic acid water: acetonitrile (v/v, 15:85);
column temperature: 38. c°;
Flow rate: 0.5 mL/min;
Sample injection volume: 5. mu L;
Ion source: +esi;
interface temperature: 300. c°;
Interface voltage: 4000 V, V;
heating block temperature: 400. c°;
Ion pair: aripiprazole (parent ion 448.3, product ion 285.2);
Carbamazepine (parent ion 237.2, product ion 194.2).
3. Experimental results
TABLE 2 pharmacokinetic parameters of nanosuspensions of aripiprazole fatty acid co-crystals and aripiprazole monohydrate
The effect of different aripiprazole fatty acid co-crystal nanosuspensions on the pharmacokinetics of aripiprazole in rats was examined by controlling the chain length of fatty acids in the co-crystals, and the experimental results are shown in fig. 9 and table 2.
The aripiprazole fatty acid co-crystal nanosuspension shows significant pharmacokinetic advantages from the aripiprazole plasma concentration-time profile in rats. After intramuscular injection, the in vivo aripiprazole blood level of the aripiprazole fatty acid co-crystal nanosuspension was rapidly elevated within the first 24 h, and both were high for the Yu Ali piprazole monohydrate nanosuspension group. Wherein, the highest blood concentration (C max) is related to the chain length of fatty acid in the eutectic and is consistent with the in vitro dissolution trend. After 24 h, the aripiprazole blood concentration of each preparation in the rat tends to be consistent, which indicates that the preparation has the same slow release period and slow release effect. The area under the curve (AUC) of each preparation in the rat body is not significantly different in the whole, which indicates that the bioavailability is not significantly different.
Therefore, on the premise of ensuring medication safety and treating blood concentration, the aripiprazole fatty acid eutectic nanometer suspension with proper fatty acid chain length can quickly reach the blood concentration of drug treatment without oral administration of drugs, improves the medication compliance of patients, and has the same slow release period and slow release effect as the original development agent. The drug release regulation strategy for rapidly increasing the blood concentration in the body in a short period is consistent with the aim of the conventional aripiprazole long-acting injection preparation matched with the administration strategy of oral drugs, and can be used as an alternative drug preparation scheme.
TABLE 3 pharmacokinetic parameters of aripiprazole stearic acid co-crystal micro-nano suspension and aripiprazole monohydrate nano suspension
Further taking the aripiprazole stearic acid eutectic as a model, the influence of the aripiprazole stearic acid eutectic micro-nano suspension on the pharmacokinetics of the aripiprazole in rats is examined by regulating the particle size of the particles, and the experimental results are shown in fig. 10 and table 3.
From the in-rat aripiprazole blood concentration-time curve, the aripiprazole stearic acid eutectic micro-nano suspension all showed significant pharmacokinetic advantages. After intramuscular injection, in the front 24h, the in-vivo aripiprazole blood concentration level of the aripiprazole stearic acid eutectic micro-nano suspension is rapidly increased, and the aripiprazole monohydrate nano suspension is high Yu Ali. Wherein, the highest blood concentration (C max) of the aripiprazole stearic acid eutectic nanosuspension is 4 times of the highest blood concentration (C max) of the aripiprazole stearic acid eutectic micron suspension. The aripiprazole blood levels of each formulation tended to be consistent in rats after 24 h. The area under the curve (AUC) of each preparation in the rat body is not significantly different in the whole, which indicates that the bioavailability is not significantly different. Thus, it has similar effects to the aforementioned fatty acid chain length regulation strategy.
In conclusion, the fatty acid chain length and the particle size can be regulated, so that the in-vivo drug concentration can be quickly increased to the drug treatment concentration level in a short period, the defect that the original long-acting preparation can reach the drug treatment concentration level only by matching with oral drugs is overcome, and the compliance of the patient in drug administration is improved, and the long-acting slow release effect is achieved.

Claims (12)

1. A eutectic crystal of aripiprazole stearic acid is characterized in that the eutectic crystal is a triclinic system,A space group; the unit cell parameters are a= 7.6166 (10) a, b= 10.7494 (11) a, c= 26.631 (4) a, α= 79.412 (4) °, β= 88.984 (5) °, γ= 75.058 (4) °; wherein the molar ratio of aripiprazole to stearic acid is 1:1.
2. The aripiprazole stearic acid co-crystal according to claim 1, characterized by a characteristic diffraction peak at 6.76 °、8.68 °、9.92 °、10.14 °、11.92 °、12.38 °、12.92 °、13.52 °、13.96 °、15.48 °、16.48 °、16.90 °、17.26 °、17.82 °、18.38 °、18.60 °、19.58 °、19.92 °、20.42 °、21.08 °、21.88 °、22.60 °、23.28 °、23.56 °、23.96 °、24.18 °、24.88 °、25.26 °、25.52 °、25.70 °、26.00 °、26.48 °、26.80 °、27.00 °、29.22 °, expressed as diffraction angle 2Θ ± 0.2 °.
3. The aripiprazole stearic acid co-crystal according to claim 1, having a characteristic melting peak at 89.5 ± 0.3 ℃.
4. An aripiprazole eicosanoid co-crystal characterized by a characteristic diffraction peak at 6.42 °、8.7 °、9.64 °、9.96 °、11.40 °、12.80 °、13.16 °、16.10 °、16.88 °、17.26 °、18.40 °、18.54 °、19.30 °、20.00 °、20.52 °、20.98 °、21.9 °、22.28 °、22.62 °、22.94 °、23.24 °、23.48 °、23.70 °、24.08 °、24.54 °、25.30 °、25.84 °、26.64 °、27.76 °、28.46 °, expressed as diffraction angle 2θ±0.2°; wherein the molar ratio of the aripiprazole to the eicosane is 1:1.
5. The aripiprazole eicosanoic acid co-crystal of claim 4, having a characteristic melting peak at 92.4±0.4 ℃.
6. An aripiprazole behenic acid co-crystal characterized by having a characteristic diffraction peak at 5.5 °、5.8 °、7.2 °、7.32 °、8.26 °、8.74 °、8.90 °、9.16 °、9.58 °、10.84 °、11.04 °、11.66 °、11.82 °、12.06 °、12.82 °、14.38 °、14.96 °、15.50 °、15.82 °、16.34 °、16.6 °、16.96 °、17.74 °、17.90 °、18.64 °、19.36 °、19.52 °、19.64 °、19.72 °、20.38 °、21.20 °、21.32 °、21.56 °、22.1 °、22.4 °、22.64 °、22.72 °、22.96 °、23.04 °、23.40 °、23.74 °、24.14 °、24.98 °、25.94 °、26.66 °、27.14 °、27.44 °、27.94 °、28.30 °、28.80 °、29.62 °、30.16 °、31.54 °, expressed as diffraction angle 2θ±0.2°; wherein the molar ratio of aripiprazole to behenic acid is 1:1.
7. The aripiprazole behenic acid co-crystal according to claim 6, characterized by a characteristic melting peak at 93.7 ± 0.8 ℃.
8. An aripiprazole wood-wax acid co-crystal characterized by a characteristic diffraction peak at 7.68 °、8.62 °、8.74 °、8.92 °、10.3 °、12.86 °、14.74 °、16.32 °、17.08 °、17.24 °、17.3 °、17.6 °、17.64 °、17.68 °、17.98 °、18.44 °、18.62 °、19.06 °、19.58 °、19.74 °、19.92 °、20.12 °、20.18 °、20.34 °、20.46 °、20.54 °、20.6 °、20.72 °、20.98 °、21.02 °、21.18 °、21.32 °、21.36 °、21.50 °、21.7 °、21.76 °、22.14 °、22.64 °、23.36 °、23.7 °、24.0 °、24.76 °、25.54 °、26.24 °, expressed as diffraction angle 2θ±0.2°; wherein the molar ratio of aripiprazole to the pyroligneous acid is 1:1.
9. The aripiprazole wood-wax acid co-crystal of claim 8 having a characteristic melting peak at 95.5±0.1 ℃.
10. A process for preparing the co-crystal of aripiprazole stearic acid, the co-crystal of aripiprazole arachidic acid, the co-crystal of aripiprazole behenic acid, or the co-crystal of aripiprazole lignoceric acid, the co-crystal of aripiprazole cerotic acid, the co-crystal of aripiprazole stearic acid, the co-crystal of aripiprazole arachidic acid, the co-crystal of aripiprazole behenic acid, the co-crystal of aripiprant, the co-crystal of aripiprazole cerotic acid, the co-crystal of aripiprant acid of aripipae, the co-acid of aripipae wax acid, the co-crystal of:
the method comprises the following steps: respectively mixing aripiprazole with stearic acid, arachidic acid, behenic acid or lignoceric acid in solvent to form suspension, stirring, and removing solvent to obtain the final product;
the second method is as follows: dissolving aripiprazole and stearic acid, arachidic acid, behenic acid or lignoceric acid in solvent respectively, filtering, removing solvent crystallization to obtain the final product;
And a third method: dissolving aripiprazole in stearic acid, arachidic acid, behenic acid or lignoceric acid respectively, mixing with water, and removing solvent to obtain the final product;
The method four: heating and melting aripiprazole with stearic acid, arachidic acid, behenic acid or cerotic acid respectively, and cooling to obtain the final product;
In the method I, the molar ratio of the aripiprazole to the stearic acid, the arachidic acid, the behenic acid or the lignoceric acid is 1:1, the adopted solvent is acetonitrile, and the stirring temperature is room temperature;
in the second method, the molar ratio of the aripiprazole to the stearic acid, the arachidic acid, the behenic acid or the lignoceric acid is 1:1, and the adopted solvent is acetonitrile;
in the method III, the molar ratio of the aripiprazole to the stearic acid, the arachidic acid, the behenic acid or the lignoceric acid is 1:1, and the adopted solvent is acetone;
In method four, the molar ratio of aripiprazole to stearic acid, arachidic acid, behenic acid or lignoceric acid is 1:1.
11. A pharmaceutical composition comprising as an active ingredient the co-crystal of aripiprazole stearic acid according to claim 1, the co-crystal of aripiprazole arachidic acid according to claim 4, the co-crystal of aripiprazole behenic acid according to claim 6 or the co-crystal of aripiprazole lignoceric acid according to claim 8; the particle size of the pharmaceutical composition is 0.1-5 mu m.
12. Use of the co-crystal of aripiprazole stearic acid according to claim 1, the co-crystal of aripiprazole arachidic acid according to claim 4, the co-crystal of aripiprazole behenic acid according to claim 6, the co-crystal of aripiprazole lignoceric acid according to claim 8 or the pharmaceutical composition according to claim 11 for the preparation of a medicament for the prevention and/or treatment of schizophrenia, bipolar disorder, major depression, autism or tourette's syndrome.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101791287A (en) * 2007-05-28 2010-08-04 重庆医药工业研究院有限责任公司 Solid oral drug composite containing aripiprazole microcrystalline
CN103923154A (en) * 2013-01-16 2014-07-16 杭州容立医药科技有限公司 Eutectic of ulipristal acetate and preparation method thereof
KR20180125330A (en) * 2017-05-15 2018-11-23 순천향대학교 산학협력단 Co-crystals of Aripiprazole and methods of preparing thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090054455A1 (en) * 2006-02-03 2009-02-26 Dr. Reddy's Laboratories Ltd. Aripiprazole co-crystals
US20060223820A1 (en) * 2006-03-21 2006-10-05 Chemagis Ltd. Crystalline aripiprazole salts and processes for preparation and purification thereof
US11369579B2 (en) * 2016-10-24 2022-06-28 Syneurx International (Taiwan) Corp. Polymorphic forms of sodium benzoate and uses thereof
TW202140466A (en) * 2020-03-19 2021-11-01 瑞士商赫孚孟拉羅股份公司 Salts and crystalline forms of a taar1 agonist
WO2023170547A1 (en) * 2022-03-07 2023-09-14 Janssen Pharmaceuticals, Inc. Pure forms of crystalline aticaprant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101791287A (en) * 2007-05-28 2010-08-04 重庆医药工业研究院有限责任公司 Solid oral drug composite containing aripiprazole microcrystalline
CN103923154A (en) * 2013-01-16 2014-07-16 杭州容立医药科技有限公司 Eutectic of ulipristal acetate and preparation method thereof
KR20180125330A (en) * 2017-05-15 2018-11-23 순천향대학교 산학협력단 Co-crystals of Aripiprazole and methods of preparing thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
抗精神病药阿立哌唑的药理、毒理和临床评价;石奇龙;上海医药;20041210(12);第537-541页 *

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