CN117903050A - Aripiprazole cocrystal and its pharmaceutical composition and application - Google Patents

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 cocrystal and its pharmaceutical composition and application

Technical Field

The present invention relates to an aripiprazole cocrystal and a pharmaceutical composition and application thereof, and in particular to an aripiprazole cocrystal with the characteristic of regulating drug release behavior and a pharmaceutical composition and application thereof.

Background technique

Mental illness is a disorder of brain function under the influence of biological, psychological and social environmental factors, which leads to abnormal clinical manifestations in cognition, emotion, will and behavior. Due to the complex pathogenesis and high recurrence rate of mental illness, it is usually difficult to cure. Most patients with mental illness need to take medication for a long time or even for life to maintain normal work, life and study. Poor medication compliance has brought great challenges to the treatment of mental illness.

Aripiprazole is a dihydroquinolone antipsychotic drug, which is mainly used in the clinical treatment of schizophrenia, bipolar disorder, major depression, autism, childhood autism, etc. The main target of aripiprazole is the 5-HT2A receptor, and it also has a partial agonist effect on dopamine D2 and 5-HT1A receptors. Compared with other atypical antipsychotic drugs, it has fewer side effects and adverse reactions. Considering the poor medication compliance of patients in clinical practice, a number of long-acting preparations of aripiprazole have been developed.

Micron suspensions Abilify Maintena ^® and Abilify Asimtufii ^® are long-acting preparations that are injected once a month or two months, and the active ingredient of both is aripiprazole monohydrate. Micron suspensions Aristada ^® and nanosuspensions Aristada Initio ^® are also long-acting preparations that are injected once a month or two months, and the active ingredient of both is aripiprazole lauroxil. However, when the above four aripiprazole long-acting injection preparations are used clinically, they all require aripiprazole oral preparations to be taken for a period of time (4 to 21 days) to maintain effective blood drug concentrations, which runs counter to the original design of long-acting injection preparations. In addition, there is a risk of dehydration and crystallization of the raw material of aripiprazole monohydrate long-acting preparations during the preparation production process, and the raw material synthesis of aripiprazole lauroxil long-acting preparations involves organic chemical reactions, all of which increase the cost, quality and safety risks of industrial production of pharmaceutical preparations.

Summary of the invention

Objectives of the invention: The first objective of the present invention is to provide a novel aripiprazole fatty acid co-crystal, the second objective is to provide a micro-nano preparation with the aripiprazole fatty acid co-crystal as an active ingredient, and the third objective is to provide a pharmaceutical application of the aripiprazole fatty acid co-crystal and its micro-nano preparation.

Technical solution: The aripiprazole cocrystal of the present invention is formed by aripiprazole and a fatty acid ligand, wherein the fatty acid has a general structural formula of C _n H _2n O ₂ , wherein n is selected from an integer of 18 to 24, more preferably an even number of 18 to 24, and more preferably 18, 20, 22, 24. The melting point y and n of the aripiprazole cocrystal satisfy the following equation: y = 0.96n + 72.47, and the intrinsic dissolution rate IDR and n satisfy the following equation: IDR = -0.17n + 7.93.

Preferably, the molar ratio of aripiprazole to fatty acid is 1:1; and the fatty acid is selected from stearic acid, arachidic acid, behenic acid or lignoceric acid.

Drug cocrystal refers to a solid single-phase substance in which the active ingredient of a drug is connected to a ligand through weak interactions in a specific chemical ratio. The substance has no charge transfer and is not a solvate. Compared with other strategies for regulating the active ingredients of a drug, the drug cocrystal strategy can effectively regulate the physicochemical properties of the drug, such as the release rate, without affecting the pharmacodynamic activity, and is more conducive to the design of sustained-release drug preparations. Saturated fatty acids are one of the essential substances for organisms to maintain normal physiological activities and are widely present in nature. Due to their good biocompatibility, safety and low water solubility, they have been widely used in the design of sustained-release drug preparations. Combining the drug cocrystal strategy with fatty acids, the use of a series of fatty acids in the design of drug cocrystals is expected to accurately regulate the in vitro and in vivo release behavior of the drug, thereby obtaining preparations that meet the expected release behavior.

The present invention combines the drug co-crystallization strategy with the micro-nano strategy to construct an aripiprazole fatty acid co-crystal micro-nano suspension of the antipsychotic drug aripiprazole and fatty acids, providing a preparation that is easy to prepare and has a significant sustained-release effect. According to the intrinsic dissolution rate determination and pharmacokinetic study, the aripiprazole fatty acid co-crystal and its micro-nano preparation can delay the release of aripiprazole in vivo and in vitro, and the release behavior has a significant dependence on the length of the fatty acid alkane chain. The longer the alkane chain of the fatty acid, the slower the intrinsic dissolution rate of the drug co-crystal and its micro-nano preparation formed by the aripiprazole, and the lower the peak concentration of the drug.

Specifically, the present invention designs a series of novel sustained-release aripiprazole preparations, the pharmacokinetic parameters of which can be adjusted by the fatty acid alkane chain length and particle size, which has the advantages of improving the single design strategy and insufficient administration methods of aripiprazole long-acting preparations.

The aripiprazole stearic acid eutectic of the present invention is a triclinic system. space group; unit cell parameters are a = 7.6166(10) Å, b = 10.7494(11) Å, c = 26.631(4) Å, α = 79.412(4) °, β = 88.984(5) °, γ = 75.058(4) °; further, expressed as diffraction angle 2θ ± 0.2 °, the eutectic has diffraction angles of 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 ° has at least one characteristic diffraction peak at 2θ ± 0.2 °; further, expressed by a diffraction angle of 2θ ± 0.2 °, the eutectic is 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 The eutectic has at least one characteristic diffraction peak at 26.80 °, 27.00 °, and 29.22 °; further, the eutectic has a characteristic melting peak at 89.5 ± 0.3 °C.

The aripiprazole eicosanoid cocrystal of the present invention has at least 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°, and 25.30°, expressed as a diffraction angle of 2θ±0.2°; further, the cocrystal 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°, 20.98°, 21.9°, 22.28°, 23.24°, 23.48°, 24.08°, and 25.30°, expressed as a diffraction angle of 2θ±0.2°. The eutectic has at least one characteristic diffraction peak at 20.4°, 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°, and 28.46°; further, the eutectic has a characteristic melting peak at 92.4±0.4°C.

The aripiprazole behenic acid cocrystal of the present invention has at least one characteristic diffraction peak 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°, and 26.66°, expressed as a diffraction angle of 2θ±0.2°; further, the cocrystal 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 The eutectic has at least one characteristic diffraction peak at 30.16 °, 31.54 °, and further, the eutectic has a characteristic melting peak at 93.7 ± 0.8 °C.

The aripiprazole lignoceric acid cocrystal of the present invention has at least one characteristic diffraction peak at 18.44°, 18.62°, 20.98°, 21.02°, 21.50°, 22.14°, 22.64°, 23.36°, 23.7°, 24.0°, 24.76°, and 25.54°, expressed as a diffraction angle of 2θ±0.2°; further, the cocrystal 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 The eutectic has at least one characteristic diffraction peak at 95.5 ± 0.1 °C, 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 °, and 26.24 °; further, the eutectic has a characteristic melting peak at 95.5 ± 0.1 °C.

The method for preparing the aripiprazole cocrystal of the present invention is selected from any of the following methods:

Method 1: Aripiprazole and fatty acid are suspended in a solvent, stirred, and the solvent is removed to obtain;

Method 2: Dissolve aripiprazole and fatty acid in a solvent, filter, remove the solvent and crystallize to obtain;

Method 3: dissolving aripiprazole and fatty acid in a solvent, mixing with water, and removing the solvent to obtain;

Method 4: Heat and melt aripiprazole and fatty acid, and cool to obtain the product.

Preferably, in method one, the molar ratio of aripiprazole to fatty acid is 1:2-2:1, more preferably 1:1; the solvent used is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone, more preferably acetonitrile; the mass ratio of aripiprazole to solvent is 1:5-1:20, more preferably 1:8-1:15; the stirring temperature is room temperature, and the method for removing the solvent is suction filtration.

Preferably, in method 2, the molar ratio of aripiprazole to fatty acid is 1:2-2:1, more preferably 1:1; the solvent used is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone, more preferably acetonitrile; the mass ratio of aripiprazole to solvent is 1:100-1:500, more preferably 1:150-1:350; the dissolution method is heating or ultrasonic dissolution, and the method for removing the solvent is standing volatilization or rotary evaporation.

Preferably, in method three, the molar ratio of aripiprazole to fatty acid is 1:2-2:1, more preferably 1:1; the solvent used is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone, more preferably acetone or dimethyl sulfoxide; the mass ratio of aripiprazole to solvent is 1:50-1:200, more preferably 1:80-1:120; the mixing temperature is 0-10 °C, and the method for removing the solvent is suction filtration.

Preferably, in method 4, the molar ratio of aripiprazole to fatty acid is 1:2 to 2:1, more preferably 1:1; the heating and melting temperature is 120 to 150 °C, more preferably 140 ± 5 °C.

The pharmaceutical composition of the present invention uses the aripiprazole cocrystal of the present invention as an active ingredient; the particle size of the pharmaceutical composition is 0.1-5 μm, and the specific dosage form is aripiprazole fatty acid cocrystal micro-nano suspension. Among them, the particle size of the nanosuspension is less than 500 nm, the PDI is less than 0.3; the D ₅₀ of the micron suspension is less than 5 μm. The pharmaceutical composition is administered orally or by injection, and its pharmacokinetic parameters in rats show a monotonic change trend with the chain length of the fatty acid.

Preferably, expressed as a diffraction angle 2θ ± 0.2°, the aripiprazole stearic acid eutectic micro-nano suspension has a diffraction angle of 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°, There is at least one characteristic diffraction peak at 26.48°, 26.80°, 27.00°, and 29.22°.

Preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole eicosanoid acid cocrystal micronano 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°, and 28.46°.

Preferably, expressed as a diffraction angle 2θ ± 0.2°, the aripiprazole lignoceric acid eutectic micro-nano suspension has a diffraction angle of 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°, There is at least one characteristic diffraction peak at 21.36 °, 21.50 °, 21.7 °, 21.76 °, 22.14 °, 22.64 °, 23.36 °, 23.7 °, 24.0 °, 24.76 °, 25.54 °, and 26.24 °.

Preferably, the aripiprazole fatty acid cocrystal of the present invention can be added with a pharmaceutically acceptable carrier to prepare a common pharmaceutical preparation, such as tablets, capsules, syrups, suspensions or injections. The preparation can be added with common pharmaceutical excipients such as flavors, sweeteners, liquid/solid fillers, diluents, etc.

The preparation method of the pharmaceutical composition of the present invention is selected from any of the following methods:

Method 1: Aripiprazole fatty acid cocrystal is suspended in an aqueous solution containing an additive, and then ground to obtain the suspension;

Method 2: Prepare a solution containing aripiprazole and fatty acid, mix it with an aqueous solution containing additives, stir it, and remove the solvent to obtain the product.

Preferably, the additive is selected from one or more of polysorbate, polyethylene glycol, polyethylene glycol 1000 vitamin E succinate, poloxamer, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and gelatin. Among them, the additive in method one is more preferably polysorbate, more preferably polysorbate 20; the additive in method two is more preferably polysorbate 80 or hydroxypropyl methylcellulose.

Further preferably, the amount of the additive in method one is 0.5% to 2% of the mass of water; the amount of aripiprazole fatty acid cocrystal is 5% to 20% of the mass of water, more preferably 10%; the grinding speed is 600 to 1000 rpm, and the grinding time is 0 to 4 h.

Further preferably, the solvent in method 2 is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone, more preferably acetone or dimethyl sulfoxide; the amount of the additive is 0.01% to 2% of the mass of water, more preferably 0.05% to 0.1%; the raw material for preparing the solution containing aripiprazole and fatty acid is aripiprazole fatty acid eutectic or a mixture of aripiprazole and fatty acid, more preferably aripiprazole fatty acid eutectic; the amount of aripiprazole fatty acid eutectic is 0.1% to 2% of the mass of water, more preferably 0.3% to 0.6%; the mass ratio of the solvent to water is 1:10 to 1:50, more preferably 1:20; the stirring temperature is 0 to 10 ° C, and the method for removing the solvent is freeze-drying.

The aripiprazole cocrystal or the pharmaceutical composition thereof of the present invention retains the biological activity of aripiprazole and can be used in the preparation of drugs for preventing and/or treating mental illnesses.

Preferably, the drug is a drug for preventing and/or treating schizophrenia, bipolar disorder, major depressive disorder, autism or Tourette syndrome.

Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

The aripiprazole fatty acid cocrystal and its micro-nano preparation designed by the present invention can accurately control the release behavior of the drug in vivo and in vitro by rationally designing the alkane chain length of the fatty acid and the particle size, providing a new control strategy. Compared with the original aripiprazole monohydrate nano preparation, the blood drug concentration is better in the short term, avoiding the disadvantage of the need for additional oral drugs in existing clinical medication, and the bioavailability and sustained release effect are close to the same, safe and effective. In addition, the cocrystal has a stable crystal form, no crystal transformation occurs during the preparation process, and the preparation has good physical stability, which is conducive to industrial production.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a diagram showing the structure of a single crystal asymmetric unit of aripiprazole stearic acid cocrystal prepared in Example 5;

FIG2 is a differential scanning calorimetry graph of the aripiprazole fatty acid cocrystals and aripiprazole Form III prepared in Examples 1, 2, 3, 4, and 17;

FIG3 is a linear graph of melting point-fatty acid carbon number of aripiprazole fatty acid cocrystals prepared in Examples 1, 2, 3, and 4;

FIG4 is a thermogravimetric analysis of aripiprazole fatty acid cocrystals and aripiprazole Form III prepared in Examples 1, 2, 3, 4, and 17;

FIG5 is an X-ray powder diffraction pattern of aripiprazole fatty acid cocrystals and aripiprazole Form III prepared in Examples 1, 2, 3, 4, and 17;

FIG6 is a graph showing the intrinsic dissolution rates of aripiprazole fatty acid cocrystals and aripiprazole Form III prepared in Examples 1, 2, 3, 4, and 17;

FIG7 is a differential scanning calorimetry graph of the micro-nano suspensions of aripiprazole fatty acid cocrystals and aripiprazole monohydrate prepared in Examples 19, 20, 21, 23, and 24;

FIG8 is an X-ray powder diffraction pattern of the micro-nano suspensions of aripiprazole fatty acid cocrystals and aripiprazole monohydrate prepared in Examples 19, 20, 21, 23, and 24;

FIG9 is a graph showing the pharmacokinetic curves of the micro-nano suspensions of aripiprazole fatty acid cocrystals and aripiprazole monohydrate prepared in Examples 19, 20, 21, and 24 in rats;

FIG10 is a graph showing the pharmacokinetic curves of the micro-nano suspensions of aripiprazole fatty acid cocrystals and aripiprazole monohydrate prepared in Examples 19, 23, and 24 in rats.

Detailed ways

The technical solution of the present invention is further described below in conjunction with embodiments.

The instruments used for solid-state characterization of drug co-crystals in the present invention are as follows:

The model of the differential scanning calorimeter is TA Q2000. The specific operation method is to weigh 3-5 mg of sample into a sealed aluminum crucible and heat it to 160 °C at a rate of 10 °C/min. The instrument is calibrated with metal indium and protected by inert gas high-purity nitrogen (>99.99%) with a nitrogen flow rate of 50 mL/min. The analysis software is TA Universal Analysis.

The model of the thermogravimetric analyzer is TA Q500. The specific operation method is to place 5-15 mg of sample in a platinum pan and heat it to 400 °C at a rate of 20 °C/min. The test environment is protected by high-purity (99.99%) nitrogen gas with a nitrogen flow rate of 40 mL/min.

The instrument model of the X-ray powder diffractometer is Japan Rigaku SmartLab SE; target: Cu-Kα ray (λ =1.5406 Å); tube voltage: copper palladium 40 kV; current: 40 mA; 2θ range: 5~40°; scanning step: 0.02°; scanning rate: 10°/min.

Example 1

Aripiprazole (2.24 g) and stearic acid (1.42 g) raw materials were weighed, added into 20 mL of acetonitrile solution, suspended and stirred at room temperature for 3 days, filtered, and vacuum dried at 40 °C for 48 h. Solid-state characterization confirmed that aripiprazole stearic acid cocrystal (APZ18C) was obtained.

Example 2

Aripiprazole (2.24 g) and arachidic acid (1.56 g) raw materials were weighed, added into 20 mL of acetonitrile solution, suspended and stirred at room temperature for 3 days, filtered, and vacuum dried at 40 °C for 48 h. Solid-state characterization confirmed that aripiprazole arachidic acid cocrystal (APZ20C) was obtained.

Example 3

Aripiprazole (2.24 g) and behenic acid (1.70 g) raw materials were weighed, added with 20 mL of acetonitrile solution, suspended and stirred at room temperature for 3 days, filtered, and vacuum dried at 40 °C for 48 h. Solid-state characterization confirmed that aripiprazole behenic acid cocrystal (APZ22C) was obtained.

Example 4

Aripiprazole (2.24 g) and lignoceric acid (1.84 g) raw materials were weighed, added into 20 mL of acetonitrile solution, suspended and stirred at room temperature for 3 days, filtered, and vacuum dried at 40 °C for 48 h. Solid-state characterization confirmed that aripiprazole lignoceric acid cocrystal (APZ24C) was obtained.

Example 5

Weigh 448 mg of aripiprazole form III and 284 mg of stearic acid, add 75 mL of acetonitrile as solvent, dissolve by ultrasonic heating, filter into a beaker, place in a fume hood to evaporate the solvent, dry the product, and confirm by solid-state characterization that aripiprazole stearic acid cocrystal (APZ18C) is obtained.

Example 6

Weigh 448 mg of aripiprazole form III and 312 mg of arachidic acid, add 100 mL of acetonitrile as solvent, dissolve by ultrasonic heating, filter into a beaker, place in a fume hood to evaporate the solvent, dry the product, and confirm by solid-state characterization that aripiprazole arachidic acid cocrystal (APZ20C) is obtained.

Example 7

Weigh 448 mg of aripiprazole form III and 340 mg of behenic acid, add 120 mL of acetonitrile as solvent, dissolve by ultrasonic heating, filter into a beaker, place in a fume hood to evaporate the solvent, dry the product, and confirm by solid-state characterization that aripiprazole behenic acid cocrystal (APZ22C) is obtained.

Example 8

Weigh 448 mg of aripiprazole form III and 368 mg of lignoceric acid, add 150 mL of acetonitrile as solvent, dissolve by ultrasonic heating, filter into a beaker, place in a fume hood to evaporate the solvent, dry the product, and confirm by solid-state characterization that aripiprazole lignoceric acid cocrystal (APZ24C) is obtained.

Example 9

Weigh 50 mg of aripiprazole form III and 32 mg of stearic acid, add 5 mL of acetone to dissolve, slowly add dropwise to the aqueous solution under stirring, filter, and dry the product. Solid-state characterization confirms that aripiprazole stearic acid cocrystal (APZ18C) is obtained.

Example 10

Weigh 50 mg of aripiprazole form III and 35 mg of arachidic acid, add 5 mL of acetone to dissolve, slowly add dropwise to the aqueous solution under stirring, filter, and dry the product. Solid-state characterization confirms that aripiprazole arachidic acid cocrystal (APZ20C) is obtained.

Embodiment 11

Weigh 50 mg of aripiprazole form III and 38 mg of behenic acid, add 5 mL of acetone to dissolve, slowly add dropwise to the aqueous solution under stirring, filter, and dry the product. Solid-state characterization confirms that aripiprazole behenic acid cocrystal (APZ22C) is obtained.

Example 12

Weigh 50 mg of aripiprazole form III and 41 mg of lignoceric acid, add 5 mL of acetone to dissolve, slowly add dropwise to the aqueous solution under stirring, filter, and dry the product. Solid-state characterization confirms that aripiprazole lignoceric acid cocrystal (APZ24C) is obtained.

Example 13

Weigh 448 mg of aripiprazole crystal form III and 284 mg of stearic acid, mix them thoroughly, heat them on a 140 °C hot plate to melt, take them out and quench them on an aluminum block, and then heat them again at 60 °C until the amorphous crystal is complete. Solid-state characterization confirmed that aripiprazole stearic acid eutectic (APZ18C) was obtained.

Embodiment 14

Weigh 448 mg of aripiprazole form III and 312 mg of arachidic acid, mix them thoroughly, heat them on a 140 °C hot plate to melt, take them out and quench them on an aluminum block, and then heat them again at 60 °C until the amorphous crystal is complete. Solid-state characterization confirmed that aripiprazole arachidic acid cocrystal (APZ20C) was obtained.

Embodiment 15

Weigh 448 mg of aripiprazole form III and 340 mg of behenic acid, mix them thoroughly, heat them on a 140 °C hot plate to melt, take them out and quench them on an aluminum block, and then heat them again at 60 °C until the amorphous crystals are completely crystallized. Solid-state characterization confirmed that aripiprazole behenic acid cocrystal (APZ22C) was obtained.

Example 16

Weigh 448 mg of aripiprazole crystal form III and 368 mg of lignoceric acid, mix them thoroughly, heat them on a 140 °C hot plate to melt, take them out and quench them on an aluminum block, and then heat them again at 60 °C until the amorphous crystal is complete. Solid-state characterization confirmed that aripiprazole lignoceric acid cocrystal (APZ24C) was obtained.

Embodiment 17

Weigh 10 g of aripiprazole API, add 200 mL of a mixed solvent of ethanol and water (4:1), reflux at 70 °C for 2 h, slowly cool to room temperature, filter, vacuum dry at 40 °C for 48 h, and confirm that aripiprazole monohydrate (APZMH) is obtained by solid-state characterization. Spread aripiprazole monohydrate on a 100 °C hot plate and heat for 30 min. Confirm that aripiprazole crystal form III (APZF3) is obtained by solid-state characterization.

The single crystal of aripiprazole stearic acid cocrystal was prepared in Example 5, and the asymmetric unit in its crystal structure was composed of one molecule of aripiprazole and one molecule of stearic acid (Figure 1). The distance difference (Δd _(CO) ) between the two carbon oxygen bonds in the carboxylic acid in the aripiprazole stearic acid cocrystal structure was determined to be 0.106 Å. According to the carboxylic acid rule for distinguishing cocrystals from salts (Δd _(CO) in neutral carboxyl groups is greater than 0.08 Å, and Δd _(CO) of carboxylate anions is less than 0.03 Å), it is believed that the multi-component single-phase solid synthesized by aripiprazole and stearic acid is a cocrystal rather than a salt.

The solid-state characterization results of aripiprazole fatty acid cocrystal and aripiprazole crystal form III are shown in Figures 2, 4 and 5. From the characterization results, it can be seen that although the fatty acid alkane chain lengths in the fatty acid cocrystals are different, the basic physicochemical properties exhibited as a whole are basically the same, that is, the melting point of the fatty acid cocrystal is between the melting points of the fatty acid and aripiprazole crystal form III. The X-ray powder diffraction patterns are basically the same, indicating that they have similar molecular structure stacking, and the prepared single-phase materials of each component are all cocrystals rather than salts. Statistics of the melting points show that the melting point of aripiprazole fatty acid cocrystal increases with the increase of fatty acid chain length, and the cocrystal melting point y and the fatty acid carbon number n satisfy the following equation: y = 0.96n + 72.47 (Figure 3). This result shows that the fatty acid cocrystal strategy can be used to adjust the basic physicochemical properties of drugs. Through the rational design of the fatty acid chain length, cocrystals with desired physicochemical properties can be obtained for subsequent formulation development.

Example 18: Intrinsic dissolution rate experiment

1. Source of test samples

Aripiprazole API was purchased from Jiangsu Aikon Biopharmaceutical R&D Co., Ltd., and fatty acids were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Aripiprazole Form III was purified from aripiprazole API.

2. Experimental methods

50 mg of aripiprazole crystal form III and aripiprazole fatty acid cocrystal powders passed through an 80-mesh sieve were weighed separately and placed in an intrinsic dissolution mold with a diameter of 4 mm, and pressed at a pressure of 200 kg for 1 min. After the pressing was completed, the mold was removed to expose one side of the tablet to 550 mL of dissolution medium (0.25% sodium dodecyl sulfate aqueous solution (SDS)), and the tablet was dissolved at 37 °C at a speed of 50 rpm. At different time points (30, 60, 90, 120, 150, and 180 min), 4 mL of sample solution was sampled and supplemented with an equal amount of constant temperature blank medium. The sample solution was centrifuged at 13,000 rpm for 5 min, and the supernatant was taken for HPLC injection.

HPLC experimental conditions:

Instrument: Shimadzu LC-20AT high performance liquid chromatograph;

Chromatographic UV detector model: Shimadzu SPD-20A;

Chromatographic quaternary pump model: Shimadzu LC-20AT;

Chromatographic column: Agilent Zorbax SB C-18 (4.6 × 250 mm, 5 μm);

Mobile phase: acetonitrile:0.1% formic acid-0.1% ammonia aqueous solution (v/v, 60:40);

Column temperature: 40 °C;

Flow rate: 1 mL/min;

Injection volume: 50 μL;

Detection wavelength: 254 nm.

3. Experimental results

The intrinsic dissolution curves of Form III and aripiprazole fatty acid cocrystal for oral aripiprazole preparation are shown in Figure 6. The calculated intrinsic dissolution rates are shown in Table 1.

Table 1. Intrinsic dissolution rates of aripiprazole oral formulation Form III and aripiprazole fatty acid cocrystals in 0.25% SDS

The results show that the intrinsic dissolution rate of the aripiprazole fatty acid cocrystal designed by the present invention is slower than the intrinsic dissolution rate of aripiprazole crystal form III, and the intrinsic dissolution rate of aripiprazole fatty acid cocrystals with different chain lengths decreases with the increase of fatty acid chain length, and the intrinsic dissolution rate IDR and the carbon number n of the fatty acid satisfy the following equation: IDR = -0.17n + 7.93. It shows that the formation of aripiprazole fatty acid cocrystal delays the dissolution of aripiprazole, which is conducive to the sustained release of the drug. The correlation between the intrinsic dissolution rate and the chain length shows that the fatty acid cocrystal strategy can be used to regulate the release behavior of the drug in vitro, which indirectly indicates that the fatty acid cocrystal strategy has great potential for regulating the release of drugs in vivo.

Embodiment 19

308.1 mg of the aripiprazole stearic acid eutectic prepared in Example 1 and passed through an 80-mesh sieve was weighed, 3 mL of an aqueous solution containing 30 mg of Tween 20 was added, 4 g of zirconia grinding beads with a diameter of 1 mm were added, and the mixture was ground at 800 rpm for 2 h at room temperature. Appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate and sodium hydrogen phosphate were added to adjust the osmotic pressure and pH value of the preparation to obtain an aripiprazole stearic acid eutectic nanosuspension (NAPZ18C) with a particle size of 304.47 ± 7.04 nm and a PDI of 0.18 ± 0.15, which was stored at 4 °C for later use.

Embodiment 20

319.8 mg of the aripiprazole arachidic acid cocrystals prepared in Example 2 and passed through an 80-mesh sieve were weighed, 3 mL of an aqueous solution containing 30 mg of Tween 20 was added, 3 g of zirconia grinding beads with a diameter of 1 mm were added, and the mixture was ground at 700 rpm for 2 h at room temperature. Appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate and sodium hydrogen phosphate were added to adjust the osmotic pressure and pH value of the preparation to obtain an aripiprazole arachidic acid cocrystal nanosuspension (NAPZ20C) with a particle size of 307.13 ± 0.04 nm and a PDI of 0.26 ± 0.01, which was stored at 4 °C for later use.

Embodiment 21

343.5 mg of aripiprazole lignoceric acid eutectic prepared in Example 4 and passed through an 80-mesh sieve was weighed, 3 mL of an aqueous solution containing 30 mg of Tween 20 and 4 g of zirconium oxide grinding beads with a diameter of 1 mm were added, and the mixture was ground at 700 rpm for 2 h at room temperature. Appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate and sodium hydrogen phosphate were added to adjust the osmotic pressure and pH value of the preparation to obtain aripiprazole lignoceric acid eutectic nanosuspension (NAPZ24C) with a particle size of 252.1 ± 0.66 nm and a PDI of 0.19 ± 0.02, which was stored at 4 °C for later use.

Embodiment 22

188 mg of the aripiprazole stearic acid eutectic prepared in Example 1 was weighed, 2 mL of dimethyl sulfoxide was added to dissolve it, and the mixture was slowly added dropwise to 40 mL of an aqueous solution containing 28 mg of Tween 80 in an ice-water bath while stirring. After the addition was completed, the product was ultrasonically treated at a power of 70 W for 30 min. The product was characterized and had a particle size of 375.47 ± 6.97 nm and a PDI of 0.136 ± 0.092.

Embodiment 23

Weigh 308.1 mg of the aripiprazole stearic acid eutectic prepared in Example 1 and passed through an 80-mesh sieve, add 3 mL of an aqueous solution containing 30 mg of Tween 20, add 4 g of zirconium oxide grinding beads with a diameter of 1 mm, grind at 800 rpm for 8 min at room temperature, add appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate and sodium hydrogen phosphate to adjust the osmotic pressure and pH value of the preparation, and obtain an aripiprazole stearic acid eutectic microsuspension (MAPZ18C) with a _D50 of 2.77 ± 0.01 μm, which is stored at 4 °C for later use.

Embodiment 24

196.2 mg of the aripiprazole monohydrate prepared in Example 5 and passed through an 80-mesh sieve was weighed, 3 mL of an aqueous solution containing 30 mg of Tween 20 and 6 g of zirconium oxide grinding beads with a diameter of 1 mm were added, and the mixture was ground at a speed of 1000 rpm at room temperature for 2.5 h. Appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate and sodium hydrogen phosphate were added to adjust the osmotic pressure and pH value of the preparation to obtain an aripiprazole monohydrate nanosuspension (NAPZMH) with a particle size of 286.6 ± 0.03 nm and a PDI of 0.17 ± 0.01, which was stored at 4 °C for later use.

All prepared aripiprazole fatty acid cocrystals and aripiprazole monohydrate micro-nano suspensions were characterized for particle size. The results showed that the particle sizes of the four nanoformulations were all less than 500 nm, the PDI was less than 0.3, and the D ₅₀ of the aripiprazole stearic acid cocrystal microsuspension was less than 5 μm, which had a suitable particle size and good stability. The preparations were freeze-dried and then solid-state characterized. The results are shown in Figures 7 and 8. The melting point of the fatty acid cocrystal decreased slightly after preparation, which may be related to the interaction between the drug and excipients in the preparation. The X-ray powder diffraction pattern after preparation was basically the same as that before preparation, indicating that no crystal transformation occurred during the preparation process.

Example 25: Pharmacokinetic Study of Aripiprazole Fatty Acid Nanoformulation

1. Experimental Materials

Male SD rats (weighing 180-220 g, purchased from Shanghai Bikaikeyi 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), and aripiprazole monohydrate nanosuspension (prepared in Example 24).

2. Experimental methods

Thirty male SD rats were randomly divided into five groups (six rats in each group) and uniquely identified by ear tags as groups A, B, C, D, and E. The rats had free access to water during the experiment. Among them, SD rats in groups A, B, C, and D were given a single intramuscular injection of aripiprazole stearic acid cocrystal nanosuspension, aripiprazole arachidic acid cocrystal nanosuspension, aripiprazole lignoceric acid cocrystal nanosuspension, and aripiprazole stearic acid cocrystal microsuspension at a dose of 100 mg/kg (calculated as aripiprazole); SD rats in group E were given a single intramuscular injection of aripiprazole monohydrate nanosuspension at a dose of 100 mg/kg (calculated as aripiprazole). At different time points (0, 2 h, 4 h, 8 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 19 d, 25 d, 30 d, 35 d, 40 d, and 50 d), 0.5 mL of blood was collected from the orbits and transferred into 2 mL centrifuge tubes moistened with heparin sodium. The blood was centrifuged at 4000 rpm for 15 min, and the upper plasma was stored in a refrigerator at -80 °C until LC-MS detection.

HPLC-MS conditions:

Instrument: Shimadzu LCMS 8045 triple quadrupole liquid spectrometer;

Chromatographic column: Water C18 (150×4.6 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;

Injection volume: 5 μL;

Ion source: +ESI;

Interface temperature: 300 °C;

Interface voltage: 4000 V;

Heating block temperature: 400 °C;

Ion pair: Aripiprazole (precursor ion 448.3, product ion 285.2);

Carbamazepine (precursor ion 237.2, product ion 194.2).

3. Experimental results

Table 2. Pharmacokinetic parameters of nanosuspensions of aripiprazole fatty acid cocrystals and aripiprazole monohydrate

By regulating the fatty acid chain length in the cocrystal, the effects of different aripiprazole fatty acid cocrystal nanosuspensions on the pharmacokinetics of aripiprazole in rats were investigated. The experimental results are shown in Figure 9 and Table 2.

From the aripiprazole blood concentration-time curve in rats, aripiprazole fatty acid cocrystal nanosuspensions all showed significant pharmacokinetic advantages. After intramuscular injection, within the first 24 hours, the aripiprazole blood concentration level of aripiprazole fatty acid cocrystal nanosuspension in vivo increased rapidly, and was higher than that of aripiprazole monohydrate nanosuspension group. Among them, the maximum blood concentration (C _max ) was related to the chain length of fatty acids in the cocrystal and was consistent with the in vitro dissolution trend. After 24 hours, the aripiprazole blood concentration of each preparation in rats tended to be consistent, indicating that they had the same sustained release period and sustained release effect. Overall, there was no significant difference in the area under the drug-time curve (AUC) of each preparation in rats, indicating that there was no significant difference in bioavailability.

Therefore, under the premise of ensuring drug safety and therapeutic blood drug concentration, by using aripiprazole fatty acid cocrystal nanosuspension with appropriate fatty acid chain length, the blood drug concentration of drug therapy can be quickly achieved without oral medication, improving patient compliance with medication, and having a sustained release cycle and sustained release effect equivalent to the original formulation. This drug release regulation strategy that rapidly increases the blood drug concentration in the body in a short period of time is consistent with the goal of the existing aripiprazole long-acting injection preparation combined with oral medication, and can be used as an alternative drug formulation solution.

Table 3. Pharmacokinetic parameters of aripiprazole stearic acid cocrystal micro-nanosuspension and aripiprazole monohydrate nanosuspension

Further, using aripiprazole stearic acid cocrystal as a model, the effect of aripiprazole stearic acid cocrystal micro-nano suspension on the pharmacokinetics of aripiprazole in rats was investigated by regulating the particle size. The experimental results are shown in Figure 10 and Table 3.

From the aripiprazole blood concentration-time curve in rats, aripiprazole stearic acid cocrystal micro-nano suspensions all showed significant pharmacokinetic advantages. After intramuscular injection, within the first 24 hours, the aripiprazole blood concentration levels of aripiprazole stearic acid cocrystal micro-nano suspensions in vivo increased rapidly, and were all higher than aripiprazole monohydrate nanosuspension. Among them, the maximum blood concentration (C _max ) of aripiprazole stearic acid cocrystal nanosuspension was 4 times that of aripiprazole stearic acid cocrystal micro-suspension. After 24 hours, the aripiprazole blood concentrations of each preparation in rats tended to be consistent. Overall, there was no significant difference in the area under the drug-time curve ( _AUC ) of each preparation in rats, indicating that there was no significant difference in bioavailability. Therefore, it has a similar effect to the aforementioned fatty acid chain length regulation strategy.

In summary, whether regulating the fatty acid chain length or the particle size, the drug concentration in the body can be quickly increased to the therapeutic concentration level in a short period of time, which improves the deficiency of the original long-acting preparation that needs to be combined with oral medication to reach the therapeutic concentration level, improves the patient's medication compliance and has the effect of long-acting sustained release.

Claims (14)

1. The aripiprazole eutectic is characterized by being formed by aripiprazole and a fatty acid ligand, wherein the fatty acid has a structural general formula of C _nH_2nO₂, and n is an integer selected from 18-24; the melting points y and n of the aripiprazole co-crystal satisfy the following equation: y=0.96 n+ 72.47.

2. The aripiprazole co-crystal according to claim 1, wherein 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.

3. 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) °.

4. The aripiprazole stearic acid co-crystal according to claim 3, wherein 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 ° is expressed as diffraction angle 2Θ ± 0.2 °.

5. The aripiprazole stearic acid co-crystal according to claim 3, having a characteristic melting peak at 89.5 ± 0.3 ℃.

6. An aripiprazole eicosanoid co-crystal characterized by having at least 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 °, expressed as diffraction angle 2θ±0.2°.

7. The aripiprazole eicosanoic acid co-crystal of claim 6, having a characteristic melting peak at 92.4±0.4 ℃.

8. An aripiprazole behenic acid co-crystal characterized by having at least one characteristic diffraction peak 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 °, expressed as diffraction angle 2θ±0.2°.

9. The aripiprazole behenic acid co-crystal according to claim 8, characterized by a characteristic melting peak at 93.7±0.8 ℃.

10. An aripiprazole wood-wax acid co-crystal characterized by having at least one characteristic diffraction peak at 18.44 °, 18.62 °, 20.98 °, 21.02 °, 21.50 °, 22.14 °, 22.64 °, 23.36 °, 23.7 °, 24.0 °, 24.76 °, 25.54 ° as expressed by diffraction angle 2θ±0.2°.

11. The aripiprazole wood-wax acid co-crystal of claim 10 having a characteristic melting peak at 95.5±0.1 ℃.

12. A pharmaceutical composition characterized by comprising the co-crystal according to any one of claims 1 to 11 as an active ingredient; the particle size of the pharmaceutical composition is 0.1-5 mu m.

13. Use of the co-crystal according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 for the preparation of a medicament for the prevention and/or treatment of psychotic disorders.

14. The use according to claim 13, wherein the medicament is a medicament for the prevention and/or treatment of schizophrenia, bipolar disorder, major depression, autism or tourette's syndrome.