Quinolinone pharmaceutical co-crystal and preparation method therefor, pharmaceutical composition and use

Abstract

A quinolinone pharmaceutical co-crystal and a preparation method therefor, a pharmaceutical composition and a use. The pharmaceutical co-crystal relates to a pharmaceutical co-crystal series formed by aripiprazole and a fatty acid ligand. By rationally designing the alkane chain length of a fatty acid and the particle size of a pharmaceutical formulation of the fatty acid, the release behavior of a drug can be systematically and accurately regulated, and the physicochemical properties of the drug can be remarkably improved, thereby facilitating multi-dosage-form drug formation and multi-scene clinical applications. In addition, the preparation method for the pharmaceutical co-crystal is convenient and economical, and is conducive to industrial preparation.

Description

Quinolinone drug cocrystal and preparation method, pharmaceutical composition and application thereof Technical Field

[0001] The present invention relates to a quinolinone drug co-crystal and a preparation method, a pharmaceutical composition and applications thereof, and in particular to a quinolinone drug co-crystal having excellent physicochemical properties and capable of regulating drug release behavior and a preparation method, a pharmaceutical composition and applications thereof. Background Art

[0002] Aripiprazole is a dihydroquinolone antipsychotic drug, primarily used clinically to treat schizophrenia, bipolar disorder, major depressive disorder, autism, and childhood autism. Aripiprazole primarily targets the 5-HT2A receptor and also has partial agonist effects on dopamine D2 and 5-HT1A receptors. Compared with other atypical antipsychotics, it has fewer side effects and adverse reactions.

[0003] According to the BDDCS classification system, aripiprazole is a Class II drug with a solubility in water of only 0.045 mg / L at 25°C. The low solubility itself affects its absorption in the body. In addition, aripiprazole has poor physical stability and easily crystallizes to form aripiprazole monohydrate with even poorer water solubility, further affecting its metabolic kinetics in the body. Therefore, the clinical application of aripiprazole is restricted by the limitations of its physical and chemical properties.

[0004] To address the solubility issue, Structural insights into novel therapeutic deep eutectic systems with capric acid using 1D,2D NMR and DSC techniques with superior gut permeability (RSC Adv., 2024, 14, 14793-14806) employed a solution that formed a deep eutectic system with aripiprazole and decanoic acid. This solution allowed the drug to form weak interactions with decanoic acid through the amide group and the nitrogen atom adjacent to the benzene ring on the piperazine ring, respectively, to form a deep eutectic system. Although the drug's solubility was improved, the deep eutectic system had a lower melting point than the single-component substance and was a liquid or slurry with a certain viscosity at room temperature. Its physical form was not conducive to processing operations during the formulation process, such as grinding, mixing, tableting, and granulation. Therefore, it was difficult to formulate it into a drug formulation suitable for clinical application.

[0005] At the same time, due to the complex pathogenesis and high relapse 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. In order to solve the problem of poor medication compliance of patients, a number of long-acting preparations of aripiprazole have been developed. Among them, the micron suspension Abilify and Abilify Aripiprazole monohydrate long-acting formulation for monthly or bimonthly injection, micron suspension and nanosuspension Aristada These are long-acting formulations of aripiprazole lauroxil that are injected once every one or two months. However, in clinical use, these long-acting formulations all require concurrent administration of oral aripiprazole for a period of time (14 to 21 days) to maintain effective blood drug concentrations, which runs counter to the original design of long-acting injectable formulations. Furthermore, aripiprazole monohydrate carries the risk of dehydration during preparation, and aripiprazole lauroxil must be synthesized from aripiprazole via a chemical reaction. These factors increase the cost of industrial production of pharmaceutical formulations, as well as the risks of quality control and safety.

[0006] Summary of the Invention

[0007] Objectives of the invention: The first objective of the present invention is to provide a novel quinolinone drug co-crystal, the second objective is to provide a method for preparing the drug co-crystal, the third objective is to provide a pharmaceutical composition containing the drug co-crystal, and the fourth objective is to provide a pharmaceutical application of the drug co-crystal and its pharmaceutical composition.

[0008] Technical solution: The quinolinone drug co-crystal of the present invention is formed by aripiprazole and a saturated fatty acid ligand with 10 to 24 carbon atoms; in the drug co-crystal structure, the amide groups of two aripiprazole molecules self-assemble through NH…O hydrogen bonds to form a The homodimer is extended by an OH...N hydrogen bond formed by a hydroxyl group on the carboxyl end of the saturated fatty acid molecule and a nitrogen atom on the piperazine ring away from the benzene ring in the aripiprazole molecule.

[0009] Preferably, in the drug co-crystal structure, the CH…O hydrogen bond formed between the carbonyl group at the carboxyl end of the saturated fatty acid molecule and the alkane on the piperazine ring of the aripiprazole molecule, and the CH…O hydrogen bond formed between the hydroxyl group at the carboxyl end of the saturated fatty acid molecule and the benzene ring of the aripiprazole molecule also participate in the construction of the aripiprazole drug co-crystal of the present invention.

[0010] More preferably, the amide groups of the two aripiprazole molecules are bonded by NH…O hydrogen bonds (bond length ) self-assembled into The dimer is a homodimer formed by forming an OH...N hydrogen bond (bond length 10 ... ) extends, the C—H…O hydrogen bond (bond length ) and the CH…O hydrogen bond (bond length ) participated in the construction of the aripiprazole drug cocrystal of the present invention.

[0011] Preferably, the saturated fatty acid is selected from capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid, wherein the molar ratio of aripiprazole to the saturated fatty acid is 1-2:1-2.

[0012] More preferably, the molar ratio of aripiprazole to saturated fatty acid is 1:1.

[0013] A pharmaceutical cocrystal is a solid, single-phase substance in which a pharmaceutical active ingredient and a ligand are connected by weak interactions in a specific chemical ratio. This substance exhibits no charge transfer and is not a solvate. Compared to other strategies for regulating the in vitro and in vivo properties of pharmaceutical active ingredients, the pharmaceutical cocrystal strategy can effectively modulate the basic physicochemical properties and in vitro and in vivo release behavior of a drug without affecting its efficacy. Fatty acids are essential substances for maintaining normal physiological activities in organisms and are widely present in nature. Due to their excellent biocompatibility and safety, they have been widely used in the design of multi-component drugs (drug cocrystals, salts).

[0014] The present invention addresses the deficiencies in aripiprazole's physicochemical properties (solubility, stability, etc.), in vivo pharmacokinetic properties, and clinical application (drug compliance). By adopting a drug co-crystal strategy, fatty acids are combined with aripiprazole through non-covalent bonds. Without changing the drug's efficacy, the alkane chain length of the fatty acid in the co-crystal drug is systematically controlled, forming a strategy for precisely controlling the drug's physicochemical properties and drug release behavior.

[0015] On the one hand, aripiprazole-fatty acid cocrystals with appropriate alkane chain lengths can significantly improve solubility and bioavailability, accelerate intrinsic dissolution, and enhance stability. Furthermore, solubility, dissolution rate, and solution stability show a clear correlation with the length of the fatty acid alkane chain. Shorter alkane chains result in higher solubility and faster intrinsic dissolution rates for the drug cocrystals formed with aripiprazole. Longer alkane chains also result in higher solution stability in water.

[0016] On the other hand, aripiprazole-fatty acid cocrystals with appropriate alkane chain lengths can also delay the release of aripiprazole in vitro and in vivo, with the release behavior clearly dependent on the fatty acid alkane chain length. Longer alkane chain fatty acids with aripiprazole form drug cocrystals and their micro-nanoformulations with slower intrinsic dissolution rates and lower peak drug concentrations.

[0017] Quinolinone drug aripiprazole (APZ) and saturated fatty acids with 10 to 24 carbon atoms

[0018] On the other hand, the aripiprazole-fatty acid drug co-crystal designed by the present invention exists in a solid form at room temperature. Its physical form is suitable for various formulation processes, thereby being used for the development of different formulation forms. In particular, the improved liquid stability enables it to maintain an effective crystal form even in liquid formulations.

[0019] In addition, the drug and ligand in the aripiprazole-fatty acid cocrystal are connected by weak interactions at a specific chemical dosage ratio, have a clear crystal structure, and have a more obvious correspondence with the solid-state physicochemical properties, which gives them more advantages in quality evaluation and process control.

[0020] The aripiprazole-decanoic acid cocrystal of the present invention is a triclinic crystal system. Space group; unit cell parameters are α=81.285(4)°, β=82.440(5)°, γ=74.182(4)°.

[0021] In the above aripiprazole drug cocrystal structure, the amide groups of the two aripiprazole molecules are bonded by NH…O hydrogen bonds (N3-H3…O2, ) self-assembled into The further extension of the dimer is mainly through the OH…N(O3-H3B…N2, ) hydrogen bond. In addition, the carbonyl group at the carboxyl end of decanoic acid forms a CH…O(C9-H9A…O4, ) hydrogen bond and the CH…O(C3-H3A…O3, formed by the hydroxyl group at the carboxyl end of decanoic acid and the benzene ring of aripiprazole ) Hydrogen bonds also participate in the construction of aripiprazole-decanoic acid cocrystal.

[0022] Preferably, expressed as a diffraction angle of 2θ±0.2°, the aripiprazole-decanoic acid cocrystal has characteristic diffraction peaks at 4.14°, 8.32°, 16.72°, 19.74°, and 22.24°.

[0023] Further preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-decanoic acid cocrystal has characteristic diffraction peaks at 4.14°, 8.32°, 16.72°, 17.10°, 19.74°, 21.64°, 22.24°, 23.28°, and 25.16°.

[0024] More preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-decanoic acid cocrystal has characteristic diffraction peaks at 4.14°, 8.32°, 9.60°, 11.60°, 12.78°, 13.96°, 16.72°, 17.10°, 18.14°, 18.72°, 19.26°, 19.74°, 20.94°, 21.64°, 22.24°, 23.28°, 23.68°, 24.00°, 24.46°, 24.84°, 25.16°, and 26.24°.

[0025] Preferably, the aripiprazole-decanoic acid cocrystal has a characteristic melting peak at 75.3±0.5°C.

[0026] The aripiprazole-lauric acid cocrystal of the present invention is a triclinic crystal system. Space group; unit cell parameters are α=91.364(2)°, β=98.872(2)°, γ=106.0730(10)°.

[0027] In the above aripiprazole drug cocrystal structure, the amide groups of the two aripiprazole molecules are bonded by NH…O hydrogen bonds (N3-H3…O2, ) self-assembled into The further extension of the dimer is mainly through the OH...N(O4-H4A...N2, ) hydrogen bond. In addition, the carbonyl group at the carboxyl end of lauric acid forms a CH…O(C9-H9A…O3, ) hydrogen bond and the CH…O(C3-H3A…O4, formed by the hydroxyl group at the carboxyl end of lauric acid and the benzene ring of aripiprazole )Hydrogen bonds also participate in the construction of aripiprazole-lauric acid cocrystal.

[0028] Preferably, expressed as a diffraction angle of 2θ±0.2°, the aripiprazole-lauric acid cocrystal has characteristic diffraction peaks at 3.90°, 7.82°, 9.64°, 15.7°, 18.14°, 20.76°, 21.54°, 23.62°, and 24.44°.

[0029] Further preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-lauric acid cocrystal has characteristic diffraction peaks at 3.90°, 7.82°, 9.64°, 15.70°, 17.14°, 18.14°, 18.36°, 18.66°, 20.76°, 21.54°, 23.62°, 24.44°, and 28.24°.

[0030] More preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-lauric acid cocrystal has characteristic diffraction peaks at 3.90°, 7.82°, 9.64°, 11.06°, 13.00°, 13.40°, 15.70°, 17.14°, 18.14°, 18.36°, 18.66°, 19.18°, 19.38°, 20.76°, 21.24°, 21.54°, 22.20°, 23.62°, 24.44°, 27.60°, and 28.24°.

[0031] Preferably, the aripiprazole-lauric acid cocrystal has a characteristic melting peak at 80.5±0.4°C.

[0032] The aripiprazole-myristic acid cocrystal of the present invention is a triclinic crystal system. Space group; unit cell parameters are α=95.2340(10)°, β=93.7410(10)°, γ=106.2470(10)°.

[0033] In the above aripiprazole drug cocrystal structure, the amide groups of the two aripiprazole molecules are bonded by NH…O hydrogen bonds (N3-H3…O2, ) self-assembled into The further extension of the dimer is mainly through the OH…N(O3-H3B…N2, ) hydrogen bond. In addition, the carbonyl group at the carboxyl end of myristic acid forms a CH…O(C9-H9A…O4, ) hydrogen bond and the CH…O(C3-H3A…O3, formed by the hydroxyl group at the carboxyl end of myristic acid and the benzene ring of aripiprazole )Hydrogen bonds are also involved in the construction of aripiprazole-myristic acid cocrystal.

[0034] Preferably, expressed as a diffraction angle of 2θ±0.2°, the aripiprazole-myristic acid cocrystal has characteristic diffraction peaks at 3.72°, 7.43°, 14.90°, 17.18°, 18.22°, 18.67°, 23.10°, 26.52°, and 27.82°.

[0035] Further preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-myristic acid cocrystal has characteristic diffraction peaks at 3.72°, 7.43°, 14.90°, 17.18°, 18.22°, 18.67°, 19.54°, 20.12°, 21.20°, 21.7°, 22.45°, 23.10°, 23.28°, 26.52°, and 27.82°.

[0036] More preferably, expressed as a diffraction angle of 2θ±0.2°, the aripiprazole-myristic acid cocrystal has characteristic diffraction peaks at 3.72°, 7.43°, 9.78°, 10.54°, 11.18°, 12.76°, 12.96°, 13.18°, 14.90°, 17.18°, 18.22°, 18.67°, 19.54°, 20.12°, 21.20°, 21.7°, 22.45°, 23.10°, 23.28°, 23.7°, 24.24°, 24.44°, 26.00°, 26.24°, 26.52°, and 27.82°.

[0037] Preferably, the aripiprazole-myristic acid cocrystal has a characteristic melting peak at 85.3±0.3°C.

[0038] The aripiprazole-palmitic acid eutectic of the present invention is a triclinic crystal system. Space group; unit cell parameters are α=70.367(2)°, β=80.901(2)°, γ=78.615(2)°.

[0039] In the above aripiprazole drug cocrystal structure, the amide groups of the two aripiprazole molecules are bonded by NH…O hydrogen bonds (N6-H6…O5, N9-H9…O2, N3-H3…O10, ) self-assembled into The further extension of the dimer is mainly through the OH…N(O4-H4A…N2, O8-H8…N5, O12-H12…N8, ) hydrogen bond. In addition, the carbonyl group at the carboxyl end of palmitic acid forms a CH…O(C10-H10C…O11, C88-H88A…O7, C48-H48A…O3, ) hydrogen bond and the CH…O(C3-H3A…O4, formed by the hydroxyl group at the carboxyl end of palmitic acid and the benzene ring of aripiprazole C22-H22A…O5, C42-H42…O8, C81-H81…O12, )Hydrogen bonds also participate in the construction of aripiprazole-palmitic acid cocrystal.

[0040] Preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-palmitic acid cocrystal has characteristic diffraction peaks at 3.56°, 7.02°, 14.10°, 17.18°, 17.70°, 18.28°, 21.14°, 21.58°, 21.78°, 24.20°, and 24.92°.

[0041] Further preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-palmitic acid cocrystal has characteristic diffraction peaks at 3.56°, 7.02°, 9.78°, 10.54°, 14.10°, 17.18°, 17.70°, 18.28°, 18.34°, 18.88°, 21.14°, 21.58°, 21.78°, 24.20°, and 24.92°.

[0042] More preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-palmitic acid cocrystal has characteristic diffraction peaks at 3.56°, 7.02°, 8.52°, 9.78°, 10.08°, 10.54°, 12.44°, 12.80°, 14.10°, 16.26°, 17.18°, 17.70°, 18.28°, 18.34°, 18.88°, 19.34°, 19.96°, 21.14°, 21.58°, 21.78°, 22.56°, 22.88°, 23.24°, 24.20°, 24.92°, 27.38°, and 28.38°.

[0043] Preferably, the aripiprazole-palmitic acid cocrystal has a characteristic melting peak at 87.1±0.3°C.

[0044] The aripiprazole-stearic acid eutectic of the present invention is a triclinic crystal system. Space group; unit cell parameters are α=79.412(4)°, β=88.984(5)°, γ=75.058(4)°.

[0045] In the above aripiprazole drug cocrystal structure, the amide groups of the two aripiprazole molecules are bonded by NH…O hydrogen bonds (N3-H3…O2, ) self-assembled into The further extension of the dimer is mainly through the OH...N(O3-H3B...N2, ) hydrogen bond. In addition, the carbonyl group at the carboxyl end of stearic acid forms a CH…O(C10-H10B…O4, ) Hydrogen bonds also participate in the construction of aripiprazole-stearic acid cocrystal.

[0046] Preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-stearic acid cocrystal has characteristic diffraction peaks 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°, and 27.00°.

[0047] More preferably, the diffraction angle of the aripiprazole-stearic acid eutectic is expressed as 2θ±0.2° at 6.76°, 8.68°, 9.92°, There are characteristic diffraction peaks at 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°, and 29.22°.

[0048] More preferably, the aripiprazole-stearic acid eutectic has a characteristic melting peak at 89.5±0.3°C.

[0049] The aripiprazole-eicosanoic acid cocrystal of the present invention has characteristic diffraction peaks 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°.

[0050] Further preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-stearic acid cocrystal has characteristic diffraction peaks 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°.

[0051] More preferably, the aripiprazole-stearic acid eutectic has a characteristic melting peak at 92.4±0.4°C.

[0052] The aripiprazole-behenic acid cocrystal of the present invention has characteristic diffraction peaks 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°;

[0053] More preferably, the aripiprazole-behenic acid cocrystal has a diffraction angle of 2θ±0.2°, expressed as 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. There are characteristic diffraction peaks at 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°, and 31.54°.

[0054] More preferably, the aripiprazole-behenic acid cocrystal has a characteristic melting peak at 93.7±0.8°C.

[0055] The aripiprazole-lignoceric acid cocrystal of the present invention has characteristic diffraction peaks 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°.

[0056] More preferably, the aripiprazole-lignoceric acid cocrystal is expressed as a diffraction angle of 2θ±0.2° at 7.68°, 8.62°, 8.74°, 8.92°, 10.3°, 12.86°, 14.74°, 16.32°, 17.08°, 17.24°, 17.3°, 17.64°, 17.68°, 17.98°, 18.44°, 18.62°, 19.06°, 19.58°, 19.74°, 19. There are characteristic diffraction peaks at .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°.

[0057] More preferably, the aripiprazole-lignoceric acid eutectic has a characteristic melting peak at 95.5±0.1°C.

[0058] The method for preparing the aripiprazole drug cocrystal of the present invention is selected from any one of the following methods:

[0059] Method 1: preparing a suspension of aripiprazole and fatty acid, stirring, and removing the solvent to obtain the cocrystal;

[0060] Method 2: dissolving aripiprazole and fatty acid, filtering, removing the solvent from the filtrate, and crystallizing to obtain the co-crystal;

[0061] Method 3: dissolving aripiprazole and fatty acid, then mixing with the mixture, and removing the solvent to obtain the cocrystal;

[0062] Method 4: heating aripiprazole and fatty acid until melted and cooling to obtain the cocrystal;

[0063] Method 5: dissolving aripiprazole and fatty acid, cooling, and removing the solvent to obtain the cocrystal;

[0064] Method 6: Aripiprazole and fatty acid are mixed and ground to obtain the co-crystal.

[0065] Preferably, in method 1, the molar ratio of aripiprazole to fatty acid is 1:2 to 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-to-volume ratio of aripiprazole to solvent is 1:5 to 1:20, more preferably 1:8 to 1:15; the stirring temperature is room temperature, and the method for removing the solvent is filtration.

[0066] Preferably, in method 2, the molar ratio of aripiprazole to fatty acid is 1:2 to 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-to-volume ratio of aripiprazole to solvent is 1:100 to 1:500, more preferably 1:150 to 1:350; the dissolution method is heating or ultrasonic dissolution, and the solvent removal method is volatilization at normal pressure or evaporation at reduced pressure.

[0067] Preferably, in method three, the molar ratio of aripiprazole to fatty acid is 1:2 to 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 antisolvent used is selected from one or more of water, methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, and acetonitrile, more preferably water; the mass volume ratio of aripiprazole to solvent is 1:50 to 1:200, more preferably 1:80 to 1:120; the mixing temperature is 0 to 10° C., and the method for removing the solvent is filtration.

[0068] 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 135 to 145°C, further preferably 135°C, 136°C, 137°C, 138°C, 139°C, 140°C, 141°C, 142°C, 143°C, 144°C, 145°C, and most preferably 140±5°C.

[0069] Preferably, in method five, the molar ratio of aripiprazole to fatty acid is 1:2 to 2:1, more preferably 1:1; the solvent used for dissolution 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 volume ratio of aripiprazole to solvent is 1:100 to 1:500, more preferably 1:150 to 1:350; the dissolution method is heating or ultrasonic dissolution-assisted, and the cooling method is natural cooling or programmed cooling.

[0070] Preferably, in method six, the molar ratio of aripiprazole to fatty acid is 1:2 to 2:1, more preferably 1:1; a solvent is added or not during the grinding process, more preferably a solvent is added to assist the grinding, and the solvent 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 or acetone; the mass volume ratio of the mixed solid to the solvent is 1:10 to 1:100, more preferably 1:20.

[0071] The pharmaceutical composition of the present invention uses the aripiprazole-fatty acid cocrystal of the present invention as an active ingredient.

[0072] Preferably, the particle size of the pharmaceutical composition is 0.1 to 5 μm, and the specific dosage form is aripiprazole-fatty acid cocrystal micro-nano suspension. The particle size of the nanosuspension is less than 500 nm, the PDI is less than 0.3; the D 50 The pharmaceutical composition is administered orally or by injection, and its pharmacokinetic parameters in vivo show a monotonically changing trend with the chain length of the fatty acid.

[0073] Preferably, the aripiprazole-stearic acid eutectic micro-nano suspension has a diffraction angle of 2θ±0.2° 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°, 18.6 There are characteristic diffraction peaks at 0°, 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°, and 29.22°.

[0074] Preferably, expressed as a diffraction angle 2θ±0.2°, the aripiprazole-eicosanoic acid cocrystal micro-nano suspension has characteristic diffraction peaks 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°.

[0075] Preferably, the aripiprazole-lignoceric acid eutectic micro-nano suspension is expressed as a diffraction angle of 2θ±0.2° 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°, 1 There are characteristic diffraction peaks at 9.92°, 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°.

[0076] Preferably, the aripiprazole-fatty acid cocrystals of the present invention can be formulated into common pharmaceutical formulations by adding a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be an excipient widely used in the pharmaceutical production field. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They can also provide methods to ensure that the active ingredient dissolves at a desired rate after administration to a subject, or to promote effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients can be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipients can include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners, etc.

[0077] The pharmaceutical compositions of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0078] The pharmaceutical compositions of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical, or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention can also be in a controlled-release or sustained-release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powder formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and lozenges.

[0079] The preparation method of the pharmaceutical composition of the present invention is selected from any one of the following methods:

[0080] Method 1: Aripiprazole-fatty acid co-crystal is suspended in an aqueous solution containing an additive, and then ground to obtain the product;

[0081] Method 2: Prepare a solution containing aripiprazole and fatty acid, mix it with an aqueous solution containing additives, stir, and remove the solvent to obtain the product.

[0082] 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. In method one, the additive is preferably polysorbate, more preferably polysorbate 20; and in method two, the additive is preferably polysorbate 80 or hydroxypropyl methylcellulose.

[0083] Further preferably, the amount of the additive in method 1 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 hours.

[0084] 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% by mass of the 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% by mass of the 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.

[0085] The aripiprazole-fatty acid cocrystal or the pharmaceutical composition thereof of the present invention is used in the preparation of a medicament for preventing and / or treating central nervous system diseases or conditions related to the central nervous system.

[0086] Preferably, the drug is a drug for preventing and / or treating schizophrenia, mania, bipolar disorder, mixed episodes of bipolar disorder, depression, autism, autism, autism-related hypersensitivity, Tourette syndrome, Alzheimer's disease, dementia, epilepsy, anxiety, tic disorder, irritability associated with childhood autism, Tourette syndrome, alcoholism, trichotillomania, dermatitis, autism spectrum disorder, tumor, emergence delirium, attention deficit disorder with hyperactivity, metabolic syndrome, postpartum depression, developmental disorders, opioid dependence, cocaine addiction, Asperger syndrome, HIV infection, fragile X syndrome, post-traumatic stress disorder, and weight changes caused by mental disorders.

[0087] Preferably, the subjects of use of the drug include adults, teenagers, and children.

[0088] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0089] The aripiprazole-fatty acid cocrystal series and their micro-nanoformulations designed in this invention enable systematic and precise control of drug release behavior in vitro and in vivo by rationally designing the fatty acid alkane chain length and the particle size of the formulation, significantly improving the physicochemical properties of aripiprazole. This makes the drug cocrystals more stable in the liquid state, resulting in improved short-term blood drug concentrations. Furthermore, drug cocrystals with different alkane chain lengths can achieve rapid dissolution to enhance bioavailability or delayed dissolution for long-term sustained release, overall improving clinical efficacy and medication compliance. Furthermore, the drug cocrystals exhibit a stable crystal form, undergo no crystal transformation during the formulation process, and exhibit excellent physical stability, facilitating the development of multiple dosage forms and multi-scenario clinical applications. The preparation method is convenient and economical, making it easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] FIG1 is a single crystal asymmetric unit structure diagram and molecular stacking diagram of the aripiprazole-decanoic acid cocrystal prepared in Example 5;

[0091] FIG2 is a diagram showing the asymmetric unit structure of aripiprazole-lauric acid co-crystal prepared in Example 6;

[0092] FIG3 is a diagram showing the asymmetric unit structure of aripiprazole-myristic acid cocrystal prepared in Example 7;

[0093] FIG4 is a diagram showing the asymmetric unit structure of aripiprazole-palmitic acid cocrystal prepared in Example 8;

[0094] FIG5 is a diagram showing the single crystal asymmetric unit structure of the aripiprazole-stearic acid co-crystal prepared in Example 29;

[0095] FIG6 is a thermogravimetric analysis of aripiprazole-fatty acid co-crystals prepared in Examples 1 to 4 and 25 to 28 and aripiprazole Form III prepared in Example 41;

[0096] FIG7 is a differential scanning calorimetry graph of the aripiprazole-fatty acid co-crystals prepared in Examples 1 to 4 and 25 to 28 and the aripiprazole Form III prepared in Example 41;

[0097] FIG8 is an X-ray powder diffraction pattern of the aripiprazole-fatty acid co-crystals prepared in Examples 1 to 4 and 25 to 28 and the aripiprazole Form III prepared in Example 41;

[0098] FIG9 is a powder dissolution diagram of the aripiprazole-fatty acid co-crystals prepared in Examples 1 to 4 and the aripiprazole Form III prepared in Example 41;

[0099] FIG10 is a Raman image of the powder dissolution residue of the aripiprazole-fatty acid co-crystal prepared in Examples 1 to 4 and the aripiprazole Form III prepared in Example 41;

[0100] FIG11 is a graph showing the intrinsic dissolution time-concentration of the aripiprazole-fatty acid co-crystals prepared in Examples 1-4 and 25-28 and the aripiprazole Form III prepared in Example 41;

[0101] FIG12 is a graph showing the intrinsic dissolution rates of the aripiprazole-fatty acid co-crystals prepared in Examples 1 to 4 and the aripiprazole Form III prepared in Example 41;

[0102] FIG13 is a Raman image of the intrinsic dissolution residue of the aripiprazole-fatty acid co-crystals prepared in Examples 1 to 4 and the aripiprazole Form III prepared in Example 41;

[0103] FIG14 is a differential scanning calorimetry graph of the aripiprazole-fatty acid cocrystals prepared in Examples 25-26 and 28, the aripiprazole monohydrate prepared in Example 41, the aripiprazole-fatty acid cocrystal micro-nanosuspensions prepared in Examples 43-45 and 47, and the aripiprazole monohydrate nanosuspension prepared in Example 48;

[0104] FIG15 is an X-ray powder diffraction pattern of the aripiprazole-fatty acid cocrystals prepared in Examples 25-26 and 28, the aripiprazole monohydrate prepared in Example 41, the aripiprazole-fatty acid cocrystal micro-nanosuspensions prepared in Examples 43-45 and 47, and the aripiprazole monohydrate nanosuspension prepared in Example 48;

[0105] FIG16 shows the stability of the aripiprazole-fatty acid co-crystals prepared in Examples 1 to 4 under accelerated test conditions (40° C. / 75% RH);

[0106] FIG17 is a pharmacokinetic curve of the aripiprazole-fatty acid co-crystals prepared in Examples 2 to 4 and the aripiprazole Form III prepared in Example 41;

[0107] FIG18 is a pharmacokinetic curve of the aripiprazole-fatty acid cocrystal nanosuspensions prepared in Examples 43 to 45 and the aripiprazole monohydrate nanosuspension prepared in Example 48;

[0108] FIG19 shows the pharmacokinetic curves of the aripiprazole-stearic acid cocrystal micro-nanosuspensions prepared in Examples 43 and 47 and the aripiprazole monohydrate nanosuspension prepared in Example 48. DETAILED DESCRIPTION

[0109] The technical solution of the present invention will be further described below in conjunction with embodiments.

[0110] The instruments used for solid-state characterization of drug cocrystals in the present invention are as follows:

[0111] Thermogravimetric analysis was performed using a TA Q500 thermogravimetric analyzer. 5-15 mg of sample was placed in a platinum pan and heated to 400°C at a heating rate of 20°C / min. The heating environment was a high-purity (99.99%) nitrogen atmosphere with a nitrogen flow rate of 40 mL / min.

[0112] Differential scanning calorimetry (DSC) analysis was performed using a TA Q2000 differential scanning calorimeter. 3-5 mg of sample was weighed into a sealed aluminum crucible and heated to 160°C at a heating rate of 10°C / min. The instrument was regularly calibrated with metallic indium. The heating environment was a high-purity (99.99%) nitrogen atmosphere at a nitrogen flow rate of 50 mL / min.

[0113] The powder X-ray diffraction characterization instrument used was a Japanese Rigaku SmartLab SE powder X-ray diffractometer; target: Cu-Kα ray Tube voltage: 40 kV for copper palladium; current: 40 mA; 2θ range: 3-40°; scan step: 0.02°; scan rate: 10° / min.

[0114] The Raman spectrometer was a Thermo Fisher Scientific DXR instrument with a laser wavelength of 780 nm, a magnification of 10×, an exposure time of 1 s, 30 acquisitions, and a laser power of 15 mW.

[0115] Example 1

[0116] 2.24 g of aripiprazole and 0.86 g of capric acid were weighed and mixed, and 10 mL of acetonitrile solution was added to form a suspension. The mixture was stirred at room temperature for 3 days, filtered, and vacuum dried at 40°C for 48 h. PXRD, DSC, and TGA characterization confirmed the formation of aripiprazole-capric acid cocrystal (APZ10C).

[0117] Example 2

[0118] 2.24 g of aripiprazole and 1.00 g of lauric acid were weighed and mixed, and 10 mL of acetonitrile solution was added to form a suspension. The mixture was stirred at room temperature for 3 days, filtered, and dried under vacuum at 40°C for 48 h. PXRD, DSC, and TGA characterization confirmed the formation of aripiprazole-lauric acid cocrystal (APZ12C).

[0119] Example 3

[0120] 2.24 g of aripiprazole and 1.14 g of myristic acid were weighed and mixed, and 10 mL of acetonitrile solution was added to form a suspension. The mixture was stirred at room temperature for 3 days, filtered, and vacuum dried at 40°C for 48 h. PXRD, DSC, and TGA characterization confirmed the formation of aripiprazole-myristic acid cocrystal (APZ14C).

[0121] Example 4

[0122] 2.24 g of aripiprazole and 1.28 g of palmitic acid were weighed and mixed, and 10 mL of acetonitrile solution was added to form a suspension. The mixture was stirred at room temperature for 3 days, filtered, and vacuum dried at 40°C for 48 h. PXRD, DSC, and TGA characterization confirmed the formation of aripiprazole-palmitic acid cocrystal (APZ16C).

[0123] Example 5

[0124] Aripiprazole Form III (448 mg) and decanoic acid (172 mg) were weighed and mixed. 40 mL of acetonitrile was added and dissolved by ultrasonic heating. The mixture was filtered into a beaker and the solvent was slowly evaporated until crystals precipitated. The product was dried and characterized by PXRD, DSC, and TGA to confirm the preparation of aripiprazole-decanoic acid cocrystal (APZ10C).

[0125] Example 6

[0126] Aripiprazole Form III (448 mg) and lauric acid (200 mg) were weighed and mixed. 50 mL of acetonitrile was added and dissolved by ultrasonic heating. The mixture was filtered into a beaker and the solvent was slowly evaporated until crystals precipitated. The product was dried and characterized by PXRD, DSC, and TGA to confirm the preparation of aripiprazole-lauric acid cocrystal (APZ12C).

[0127] Example 7

[0128] Aripiprazole Form III (448 mg) and myristic acid (228 mg) were weighed and mixed. 50 mL of acetonitrile was added and dissolved by ultrasonic heating. The mixture was filtered into a beaker and the solvent was slowly evaporated until crystals precipitated. The product was dried and characterized by PXRD, DSC, and TGA to confirm the preparation of aripiprazole-myristic acid cocrystal (APZ14C).

[0129] Example 8

[0130] Aripiprazole Form III (448 mg) and palmitic acid (256 mg) were weighed and mixed. 50 mL of acetonitrile was added and dissolved by ultrasonic heating. The mixture was filtered into a beaker and the solvent was slowly evaporated until crystals precipitated. The product was dried and characterized by PXRD, DSC, and TGA to confirm the preparation of aripiprazole-palmitic acid cocrystal (APZ16C).

[0131] Example 9

[0132] A certain amount of aripiprazole Form III (50 mg) and decanoic acid (19 mg) were weighed, dissolved in 5 mL of acetone, and slowly added dropwise to the aqueous solution under stirring. The product was filtered and dried. PXRD, DSC, and TGA characterization confirmed that aripiprazole-decanoic acid cocrystal (APZ10C) was obtained.

[0133] Example 10

[0134] A certain amount of aripiprazole Form III (50 mg) and lauric acid (22 mg) were weighed, dissolved in 5 mL of acetone, and slowly added dropwise to the aqueous solution under stirring. The product was filtered and dried. PXRD, DSC, and TGA characterization confirmed that aripiprazole-lauric acid cocrystal (APZ12C) was obtained.

[0135] Example 11

[0136] A certain amount of aripiprazole Form III (50 mg) and myristic acid (25 mg) were weighed, dissolved in 5 mL of acetone, and slowly added dropwise to the aqueous solution under stirring. The product was filtered and dried. PXRD, DSC, and TGA characterization confirmed the formation of aripiprazole-myristic acid cocrystal (APZ14C).

[0137] Example 12

[0138] A certain amount of aripiprazole Form III (50 mg) and palmitic acid (29 mg) were weighed, dissolved in 5 mL of acetone, and slowly added dropwise to the aqueous solution under stirring. The product was filtered and dried. PXRD, DSC, and TGA characterization confirmed that aripiprazole-palmitic acid cocrystal (APZ16C) was obtained.

[0139] Example 13

[0140] Aripiprazole Form III (448 mg) and decanoic acid (172 mg) were weighed and thoroughly mixed. The mixture was melted on a 140°C hot plate, removed from the heat, and quenched onto an aluminum block. The mixture was allowed to stand at room temperature for 30 minutes, and then heated again at 60°C until the amorphous form was completely crystallized. PXRD, DSC, and TGA characterization confirmed the formation of aripiprazole-decanoic acid cocrystal (APZ10C).

[0141] Example 14

[0142] Aripiprazole Form III (448 mg) and lauric acid (200 mg) were weighed and thoroughly mixed. The mixture was melted on a 140°C hot plate. The mixture was then removed and quenched onto an aluminum block. The mixture was allowed to stand at room temperature for 30 minutes and then heated again at 60°C until the amorphous form was completely crystallized. PXRD, DSC, and TGA characterization confirmed the formation of aripiprazole-lauric acid cocrystal (APZ12C).

[0143] Example 15

[0144] Aripiprazole Form III (448 mg) and myristic acid (228 mg) were weighed and thoroughly mixed. The mixture was melted on a 140°C hot plate, removed from the mixture, and quenched onto an aluminum block. The mixture was allowed to stand at room temperature for 30 minutes, and then heated again at 60°C until the amorphous form was completely crystallized. PXRD, DSC, and TGA characterization confirmed the formation of aripiprazole-myristic acid cocrystal (APZ14C).

[0145] Example 16

[0146] Aripiprazole Form III (448 mg) and palmitic acid (256 mg) were weighed and thoroughly mixed. The mixture was melted on a 140°C hot plate, removed from the heat, and quenched onto an aluminum block. The mixture was allowed to stand at room temperature for 30 minutes, and then heated again at 60°C until the amorphous form was completely crystallized. PXRD, DSC, and TGA characterization confirmed the formation of aripiprazole-palmitic acid cocrystal (APZ16C).

[0147] Example 17

[0148] A certain amount of aripiprazole Form III (448 mg) and decanoic acid (172 mg) were weighed, 40 mL of acetonitrile was added as a solvent, and the mixture was heated to 60°C for dissolution. The mixture was then cooled to 4°C and filtered. The product was dried and characterized by PXRD, DSC, and TGA to confirm that aripiprazole-decanoic acid cocrystal (APZ10C) was obtained.

[0149] Example 18

[0150] A certain amount of aripiprazole Form III (448 mg) and lauric acid (200 mg) were weighed, 50 mL of acetonitrile was added as solvent, and the mixture was heated to 60°C for dissolution. The mixture was then cooled to 4°C and filtered. The product was dried and characterized by PXRD, DSC, and TGA to confirm the preparation of aripiprazole-lauric acid cocrystal (APZ12C).

[0151] Example 19

[0152] A certain amount of aripiprazole Form III (448 mg) and myristic acid (228 mg) were weighed, 50 mL of acetonitrile was added as a solvent, and the mixture was heated to 60°C to dissolve. The mixture was then cooled to 4°C and filtered. The product was dried and characterized by PXRD, DSC, and TGA to confirm the preparation of aripiprazole-myristic acid cocrystal (APZ14C).

[0153] Example 20

[0154] A certain amount of aripiprazole Form III (448 mg) and palmitic acid (256 mg) were weighed, 50 mL of acetonitrile was added as solvent, and the mixture was heated to 60°C for dissolution. The mixture was then cooled to 4°C and filtered. The product was dried and characterized by PXRD, DSC, and TGA to confirm the preparation of aripiprazole-palmitic acid cocrystal (APZ16C).

[0155] Example 21

[0156] 996 mg of aripiprazole Form III and 344 mg of decanoic acid were weighed and uniformly mixed. 60 μL of acetonitrile was added to assist in grinding. The mixture was dried and characterized by PXRD, DSC, and TGA to confirm the preparation of aripiprazole-decanoic acid cocrystal (APZ10C).

[0157] Example 22

[0158] 996 mg of aripiprazole Form III and 400 mg of lauric acid were weighed and uniformly mixed. 60 μL of acetonitrile was added to assist in grinding. The mixture was dried and characterized by PXRD, DSC, and TGA to confirm the formation of aripiprazole-lauric acid cocrystal (APZ12C).

[0159] Example 23

[0160] 996 mg of aripiprazole Form III and 456 mg of myristic acid were weighed and uniformly mixed. 60 μL of acetonitrile was added to assist in grinding. The mixture was dried and characterized by PXRD, DSC, and TGA to confirm the formation of aripiprazole-myristic acid cocrystal (APZ14C).

[0161] Example 24

[0162] 996 mg of aripiprazole Form III and 512 mg of palmitic acid were weighed and uniformly mixed. 60 μL of acetonitrile was added to assist in grinding. The mixture was dried and characterized by PXRD, DSC, and TGA to confirm the aripiprazole-palmitic acid cocrystal (APZ16C).

[0163] Example 25

[0164] Aripiprazole (2.24 g) and stearic acid (1.42 g) raw materials were weighed, added to 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.

[0165] Example 26

[0166] Aripiprazole (2.24 g) and eicosanoid (1.56 g) raw materials were weighed, added to 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-eicosanoid cocrystal (APZ20C) was obtained.

[0167] Example 27

[0168] Aripiprazole (2.24 g) and behenic acid (1.70 g) raw materials were weighed, added to 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.

[0169] Example 28

[0170] Aripiprazole (2.24 g) and lignoceric acid (1.84 g) raw materials were weighed, added to 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.

[0171] Example 29

[0172] 448 mg of aripiprazole Form III and 284 mg of stearic acid were weighed, and 75 mL of acetonitrile was added as a solvent. After ultrasonic heating and dissolution, the mixture was filtered into a beaker and placed in a fume hood to evaporate the solvent. The product was dried and confirmed by solid-state characterization to obtain aripiprazole-stearic acid cocrystal (APZ18C).

[0173] Example 30

[0174] 448 mg of aripiprazole Form III and 312 mg of arachidic acid were weighed, and 100 mL of acetonitrile was added as a solvent. The mixture was dissolved by ultrasonic heating and filtered into a beaker. The solvent was evaporated in a fume hood, and the product was dried. Solid-state characterization confirmed that aripiprazole-arachidic acid cocrystal (APZ20C) was obtained.

[0175] Example 31

[0176] 448 mg of aripiprazole Form III and 340 mg of behenic acid were weighed, and 120 mL of acetonitrile was added as a solvent. After dissolution by ultrasonic heating, the mixture was filtered into a beaker and placed in a fume hood to evaporate the solvent. The product was dried and confirmed by solid-state characterization to obtain aripiprazole-behenic acid cocrystal (APZ22C).

[0177] Example 32

[0178] 448 mg of aripiprazole Form III and 368 mg of lignoceric acid were weighed, and 150 mL of acetonitrile was added as a solvent. After ultrasonic heating and dissolution, the mixture was filtered into a beaker and placed in a fume hood to evaporate the solvent. The product was dried and confirmed by solid-state characterization to obtain aripiprazole-lignoceric acid cocrystal (APZ24C).

[0179] Example 33

[0180] 50 mg of aripiprazole Form III and 32 mg of stearic acid were weighed, 5 mL of acetone was added to dissolve, and the mixture was slowly added dropwise to the aqueous solution under stirring. The product was filtered and dried. Solid-state characterization confirmed that aripiprazole-stearic acid cocrystal (APZ18C) was obtained.

[0181] Example 34

[0182] 50 mg of aripiprazole Form III and 35 mg of arachidic acid were weighed and dissolved in 5 mL of acetone. The mixture was slowly added dropwise to the aqueous solution under stirring. The product was filtered and dried. Solid-state characterization confirmed that aripiprazole-arachidic acid cocrystal (APZ20C) was obtained.

[0183] Example 35

[0184] 50 mg of aripiprazole Form III and 38 mg of behenic acid were weighed and dissolved in 5 mL of acetone. The mixture was slowly added dropwise to the aqueous solution under stirring. The product was filtered and dried. Solid-state characterization confirmed that aripiprazole-behenic acid cocrystal (APZ22C) was obtained.

[0185] Example 36

[0186] 50 mg of aripiprazole Form III and 41 mg of lignoceric acid were weighed and dissolved in 5 mL of acetone. The mixture was slowly added dropwise to the aqueous solution under stirring. The product was filtered and dried. Solid-state characterization confirmed that aripiprazole-lignoceric acid cocrystal (APZ24C) was obtained.

[0187] Example 37

[0188] Weigh 448 mg of aripiprazole Form III and 284 mg of stearic acid, mix thoroughly, and heat to melt on a 140°C hot plate. Remove from heat and quench onto an aluminum block. Then, heat again at 60°C until the amorphous phase is completely crystallized. Solid-state characterization confirmed the formation of aripiprazole-stearic acid cocrystal (APZ18C).

[0189] Example 38

[0190] Weigh 448 mg of aripiprazole Form III and 312 mg of arachidic acid, mix thoroughly, and melt on a 140°C hot plate. Remove the mixture and quench it onto an aluminum block. Then, heat it again at 60°C until the amorphous phase is completely crystallized. Solid-state characterization confirmed the formation of aripiprazole-arachidic acid cocrystal (APZ20C).

[0191] Example 39

[0192] Weigh 448 mg of aripiprazole Form III and 340 mg of behenic acid, mix thoroughly, and melt on a 140°C hot plate. Remove the mixture and quench on an aluminum block. Then, heat again at 60°C until the amorphous form is completely crystallized. Solid-state characterization confirmed the formation of aripiprazole-behenic acid cocrystal (APZ22C).

[0193] Example 40

[0194] Weigh 448 mg of aripiprazole Form III and 368 mg of lignoceric acid, mix thoroughly, and melt on a 140°C hot plate. Remove the mixture and quench it onto an aluminum block. Then, heat it again at 60°C until the amorphous form is completely crystallized. Solid-state characterization confirmed the formation of aripiprazole-lignoceric acid cocrystal (APZ24C).

[0195] Example 41

[0196] Weigh 10g of aripiprazole API and add 200mL of a 4:1 mixture of ethanol and water. Reflux at 70°C for 2h, slowly cool to room temperature, filter, and vacuum dry at 40°C for 48h. Solid-state characterization confirms the yield of aripiprazole monohydrate (APZMH). The aripiprazole monohydrate was then placed on a hot plate at 100°C and heated for 30min. Solid-state characterization confirmed the yield of aripiprazole Form III (APZF3).

[0197] Example 42

[0198] 296.3 mg of the aripiprazole-palmitic acid cocrystal prepared in Example 4 and passed through an 80-mesh sieve was weighed, and 3 mL of an aqueous solution containing 30 mg of Tween 20 and 4 g of 1 mm diameter zirconium oxide grinding beads were added. The mixture was ground at 800 rpm for 2 h. Appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate, and sodium hydrogen phosphate were then added to adjust the osmotic pressure and pH of the preparation to obtain an aripiprazole-palmitic acid cocrystal nanosuspension having a particle size of 516.87±2.87 nm and a PDI of 0.22±0.02.

[0199] Example 43

[0200] 308.1 mg of the aripiprazole-stearic acid cocrystal prepared in Example 25 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 milled at 800 rpm at room temperature for 2 h. Appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate, and sodium hydrogen phosphate were added to adjust the osmotic pressure and pH of the preparation to obtain an aripiprazole-stearic acid cocrystal nanosuspension (NAPZ18C) with a particle size of 304.47 ± 7.04 nm and a PDI of 0.18 ± 0.15. The mixture was stored at 4°C until use.

[0201] Example 44

[0202] 319.8 mg of the aripiprazole-arachidic acid cocrystals prepared in Example 26 and passed through an 80-mesh sieve were weighed and added to 3 mL of an aqueous solution containing 30 mg of Tween 20. 3 g of zirconia grinding beads with a diameter of 1 mm were added, and the mixture was milled at 700 rpm at room temperature for 2 h. Appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate, and sodium hydrogen phosphate were added to adjust the osmotic pressure and pH 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. The mixture was stored at 4°C until use.

[0203] Example 45

[0204] 343.5 mg of the aripiprazole-lignoceric acid cocrystals prepared in Example 28 and passed through an 80-mesh sieve were weighed, and 3 mL of an aqueous solution containing 30 mg of Tween 20 and 4 g of zirconia grinding beads with a diameter of 1 mm were added. The mixture was ground at 700 rpm at room temperature for 2 h. Appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate, and sodium hydrogen phosphate were added to adjust the osmotic pressure and pH of the preparation to obtain an aripiprazole-lignoceric acid cocrystal nanosuspension (NAPZ24C) with a particle size of 252.1±0.66 nm and a PDI of 0.19±0.02. The mixture was stored at 4°C until use.

[0205] Example 46

[0206] 188 mg of the aripiprazole-stearic acid cocrystal prepared in Example 25 was weighed and dissolved in 2 mL of dimethyl sulfoxide. The cocrystal 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 tested at a power of 70 W for 30 min. The particle size was 375.47 ± 6.97 nm, and the PDI was 0.136 ± 0.092.

[0207] Example 47

[0208] 308.1 mg of the aripiprazole-stearic acid eutectic prepared in Example 25 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 8 min 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 microsuspension (MAPZ18C). D 50 The particle size was 2.77±0.01μm and was stored at 4℃ for future use.

[0209] Example 48

[0210] 196.2 mg of the aripiprazole monohydrate prepared in Example 41 and passed through an 80-mesh sieve was weighed, and 3 mL of an aqueous solution containing 30 mg of Tween 20 and 6 g of zirconia grinding beads with a diameter of 1 mm were added. The mixture was ground at 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 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. The suspension was stored at 4°C until use.

[0211] The particle size of all prepared aripiprazole-fatty acid cocrystals and aripiprazole monohydrate micro-nanosuspensions was characterized. The results showed that the particle size of the nanoformulations prepared above was less than 500 nm, the PDI was less than 0.3, and the D of the aripiprazole-stearic acid cocrystal microsuspension was less than 0. 50 The formulation was freeze-dried and then subjected to solid-state characterization. The results, as shown in Figures 14 and 15, show a slight decrease in the melting point of the drug co-crystal after formulation, likely due to interactions between the drug and excipients. The X-ray powder diffraction pattern after formulation was essentially identical to that before formulation, indicating no crystal transformation occurred during the formulation process.

[0212] Example 49: Structural Characterization of Drug Cocrystals

[0213] The single crystal structures of the aripiprazole-fatty acid cocrystals prepared in Examples 5 to 8 and 29 were analyzed. The results showed (Table 1) that all the aripiprazole-fatty acid cocrystals belonged to the triclinic system. Space group, measuring the distance difference Δd between the two carbon-oxygen bonds in the carboxylic acid in different aripiprazole-fatty acid cocrystal crystal structures (C-O) , respectively (APZ10C), (APZ12C), (APZ14C), (APZ16C) and (APZ18C). According to the carboxylic acid rule for distinguishing cocrystals from salts (Δd (C-O) Greater than Δd of carboxylate anion (C-O) Less than ), indicating that the multi-component, single-phase solid prepared from aripiprazole and fatty acids is a cocrystal rather than a salt. The crystallographic parameters of aripiprazole-fatty acid cocrystals with different alkane chain lengths are shown in Table 1. The unit cell volume V, axial length c, and unit cell density ρ show a well-defined monotonic trend with changes in the fatty acid alkane chain length in the drug cocrystal. The asymmetric units of different aripiprazole-fatty acid cocrystals are shown in Figures 1 to 5.

[0214] By analyzing the crystal structure and interaction forces of aripiprazole-fatty acid cocrystals, it was found that the molecular packing characteristics of aripiprazole-fatty acid cocrystals with different alkane chain lengths were highly consistent (Figure 1, Table 2). Taking aripiprazole-decanoic acid cocrystal as an example, the amide groups of the two aripiprazole molecules are connected by NH…O hydrogen bonds (N3-H3…O2, ) self-assemble into a The further extension of the dimer is mainly through the hydroxyl group on the carboxyl end of decanoic acid and the nitrogen atom on the aripiprazole piperazine ring far away from the benzene ring to form OH...N(O3-H3...N2, ) hydrogen bond. In addition, the carbonyl group at the carboxyl end of decanoic acid forms a CH…O(C9-H9…O4, ) hydrogen bond and the CH…O(C3-H3…O3, formed by the hydroxyl group at the carboxyl end of decanoic acid and the benzene ring of aripiprazole ) Hydrogen bonds also participate in the construction of aripiprazole-decanoic acid cocrystal.

[0215] Table 1 Crystallographic parameters of aripiprazole-fatty acid cocrystals

[0216] Table 2 Hydrogen bonding information of aripiprazole-fatty acid cocrystal

[0217] The solid-state characterization results of aripiprazole-fatty acid cocrystal and aripiprazole crystal form III are shown in Figures 6 to 8. Before 100°C, aripiprazole-fatty acid cocrystal and aripiprazole crystal form III (APZF3) did not show significant weight loss with increasing temperature, indicating that all samples existed in a solvent-free form. When the temperature rose to 125°C, aripiprazole-fatty acid cocrystal samples began to lose weight one after another, and the starting temperature corresponding to the weight loss of drug cocrystal samples increased with the increase of the fatty acid alkane chain length in the drug cocrystal (Figure 6). The above results show that the fatty acid cocrystal strategy can be used to adjust the basic physicochemical properties of drugs. By rationally designing the fatty acid alkane chain length, cocrystals with desired physicochemical properties can be obtained for subsequent formulation development.

[0218] Differential scanning calorimetry (DSC) curves for all aripiprazole-fatty acid cocrystals (Figure 7) exhibited sharp melting endotherms, indicating high phase purity. The corresponding melting points of aripiprazole-fatty acid cocrystals were 75.33±0.52°C (APZ10C), 80.49±0.37°C (APZ12C), 85.35±0.29°C (APZ14C), 87.05±0.29°C (APZ16C), 89.5±0.3°C (APZ18C), 92.4±0.4°C (APZ20C), 93.7±0.8°C (APZ22C), and 95.5±0.1°C (APZ24C). Although the fatty acid alkane chain lengths in the fatty acid cocrystals are different, the overall basic physicochemical properties are basically consistent, that is, the melting point of the fatty acid cocrystal is between the melting points of the fatty acid and aripiprazole form III, and the melting point of aripiprazole-fatty acid cocrystals with different alkane chain lengths increases with the increase of the fatty acid alkane chain length.

[0219] The X-ray powder diffraction patterns of aripiprazole-fatty acid cocrystals are shown in Figure 8. The X-ray powder diffraction patterns of aripiprazole-fatty acid cocrystals with different alkane chain lengths are essentially identical. Specifically, the diffraction peak positions within the 2θ range of 16-25° are essentially consistent. However, the diffraction peaks at lower diffraction angles exhibit a regular shift. For example, the diffraction peaks at 2θ of 2.5° and 7.0° shift toward lower angles as the fatty acid alkane chain length in the drug cocrystal increases. These results demonstrate that the internal molecular packing arrangement of the aripiprazole-fatty acid cocrystals is highly consistent, and that the prepared single-phase materials of each component are cocrystals rather than salts.

[0220] Example 50: Evaluation of Powder Dissolution and Solution Stability of Drug Cocrystals

[0221] 1. Source of test samples

[0222] 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 the aripiprazole API.

[0223] 2. Experimental methods

[0224] 200 mg of aripiprazole-fatty acid cocrystals (APZ10C, APZ12C, APZ14C, APZ16C) and aripiprazole Form III (APZF3) powder passed through an 80-mesh sieve were weighed into a 50-mL centrifuge tube. 10 mL of a 0.25 wt.% sodium dodecyl sulfate (SDS) aqueous solution was added, and the tube was placed in a 37°C constant temperature shaker and shaken at 100 rpm for 48 h. At different time points, 1 mL of the supernatant was collected and supplemented with 1 mL of blank medium. The extracted liquid was centrifuged at 13,000 rpm for 5 min, diluted, and injected into HPLC, and the lower solid layer was characterized by Raman spectroscopy.

[0225] 3. Experimental results

[0226] Figure 9 shows the non-sink dissolution curves of aripiprazole-fatty acid cocrystals with different alkane chain lengths in 0.25 wt.% sodium dodecyl sulfate (SDS) aqueous solution. The dissolution curves of APZF3, APZ10C, and APZ12C exhibit a "spring-parachute" model, where the aripiprazole concentration in the solution initially rises and then rapidly decreases. During the ascending phase, APZ10C and APZ12C dissolve faster than APZF3. The descending phase is presumably due to phase transitions among APZF3, APZ10C, and APZ12C, but APZ12C still dissolves faster than APZF3. The dissolution curves of APZ14C and APZ16C exhibit a "spring-helicopter" model, where the aripiprazole concentration in the solution rapidly rises to a certain level within a short period of time and remains there throughout the dissolution process. Comparing the equilibrium solubilities of APZ14C and APZ16C, the aripiprazole-fatty acid cocrystal with the shorter alkane chain exhibits better solubility.

[0227] The residue after 24 hours of dissolution was characterized by Raman spectroscopy, and the results are shown in Figure 10. Compared with aripiprazole monohydrate (APZMH) at 1320 cm -1 Based on the characteristic Raman peaks at , it is believed that APZF3 and aripiprazole-fatty acid cocrystals with shorter alkane chains (APZ10C and APZ12C) are converted into aripiprazole monohydrate during the dissolution process, while the aripiprazole-fatty acid cocrystals with longer alkane chains (APZ14C and APZ16C) still exist as drug cocrystals after 24 h of dissolution.

[0228] Example 51: Evaluation of the intrinsic dissolution rate of drug cocrystals

[0229] 1. Source of test samples

[0230] 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 the aripiprazole API.

[0231] 2. Experimental methods

[0232] 50 mg of aripiprazole Form III and aripiprazole-fatty acid cocrystal powders passed through an 80-mesh sieve were weighed separately, placed into an inherent dissolution mold with a diameter of 4 mm, and pressed at a pressure of 200 kg for 1 minute. After the pressing is completed, the mold is removed to expose one side of the tablet to 550 mL of dissolution medium (0.25 wt.% sodium dodecyl sulfate aqueous solution (SDS)), and dissolution is carried out at 37°C and 50 rpm. At different time points (10-16 carbon fatty acid drug cocrystals: 2, 4, 6, 8, 10, 12, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180 min; 18-24 carbon fatty acid drug cocrystals: 30, 60, 90, 120, 150, 180 min), 4 mL of sample solution is sampled and supplemented with an equal amount of constant temperature blank medium. The sample solution is centrifuged at 13000 rpm for 5 min, and the supernatant is taken for HPLC injection.

[0233] HPLC experimental conditions:

[0234] Instrument: Shimadzu LC-20AT high performance liquid chromatograph;

[0235] Chromatographic UV detector model: Shimadzu SPD-20A;

[0236] Chromatographic quaternary pump model: Shimadzu LC-20AT;

[0237] Chromatographic column: Agilent Zorbax SB C-18 (4.6×250 mm, 5 μm);

[0238] Mobile phase: acetonitrile:0.1% formic acid-0.1% ammonia aqueous solution (v / v, 60:40);

[0239] Column temperature: 40°C;

[0240] Flow rate: 1 mL / min;

[0241] Injection volume: 50 μL;

[0242] Detection wavelength: 254nm.

[0243] 3. Experimental results

[0244] Table 3 Intrinsic dissolution rates of aripiprazole Form III for oral formulation and aripiprazole-fatty acid cocrystal in 0.25 wt.% SDS

[0245] Note: Aripiprazole Form III (APZF3) was tested separately according to the sampling time points of fatty acid cocrystals with different alkane chain lengths.

[0246] The intrinsic dissolution results of aripiprazole-fatty acid cocrystals are shown in Figures 11-12 and Table 3. Overall, the dissolution of both aripiprazole-fatty acid cocrystals and aripiprazole Form III occurred at a constant rate, demonstrating a good linear relationship between drug concentration in the dissolution medium and time. The intrinsic dissolution rates of aripiprazole-fatty acid cocrystals with different alkane chain lengths were calculated by extracting the slope, and linear fitting was performed within a relatively short time for some groups. The results showed that the intrinsic dissolution rates of aripiprazole-fatty acid cocrystals with 10-16 carbon atoms were all faster than those of aripiprazole Form III (APZF3). Furthermore, the intrinsic dissolution rates of aripiprazole-fatty acid cocrystals with different alkane chain lengths decreased with increasing chain length, in the order of APZ10C > APZ12C > APZ14C > APZ16C. Aripiprazole-fatty acid cocrystals with 18-24 carbon atoms exhibited delayed dissolution of aripiprazole, facilitating sustained drug release. Overall, the correlation between intrinsic dissolution rate and chain length shows that the fatty acid co-crystal strategy can be used to regulate the release behavior of drugs in vitro, indirectly indicating that the fatty acid co-crystal strategy has great potential to regulate drug release in vivo.

[0247] Raman characterization was performed on the surface of some aripiprazole-fatty acid cocrystals and aripiprazole Form III (APZF3) in contact with the dissolution medium after the intrinsic dissolution experiment. The results, as shown in Figure 13, show that aripiprazole Form III (APZF3), aripiprazole-decanoic acid cocrystal (APZ10C), and aripiprazole-lauric acid cocrystal (APZ12C) underwent crystalline form transformation during the intrinsic dissolution experiment, while the remaining aripiprazole-fatty acid cocrystals remained stable after dissolution. These results are consistent with the trend of the powder dissolution results, indicating that aripiprazole-fatty acid cocrystals with longer alkane chains have better solution stability.

[0248] Example 52: Solid-state stability evaluation of drug cocrystals

[0249] 1. Experimental methods

[0250] An appropriate amount of aripiprazole-fatty acid cocrystal powder passed through an 80-mesh sieve was weighed and placed in an open incubator at 40°C / 75% RH. The cocrystal was taken out at different time intervals (0 month, 1 month, 3 months, and 6 months) and characterized by X-ray powder diffraction. The test conditions were the same as those in Example 51.

[0251] 2. Experimental results

[0252] Figure 16 shows the solid-state stability of aripiprazole-fatty acid cocrystals with different alkane chain lengths at 40°C / 75% RH. Comparing the PXRD patterns of the aripiprazole-fatty acid cocrystals before deposition (indicated by 0 in the figure), the aripiprazole-fatty acid cocrystals with different alkane chain lengths showed no crystal phase transition after 6 months of storage under accelerated experimental conditions, nor did they exhibit any correlation with alkane chain length. This demonstrates that the aripiprazole-fatty acid cocrystals prepared by the present invention exhibit good physical stability and are suitable for long-term storage in the solid state.

[0253] Example 53: Pharmacokinetic Evaluation of Drug Cocrystals

[0254] 1. Experimental methods

[0255] Sixteen male SPF Sprague-Dawley rats (250-275 g) were randomly divided into four groups (n=4) and designated by ear number: Group A (aripiprazole Form III, APZF3), Group B (aripiprazole-lauric acid cocrystal, APZ12C), Group C (aripiprazole-myristic acid cocrystal, APZ14C), and Group D (aripiprazole-palmitic acid cocrystal, APZ16C). All rats were fasted for 12 hours prior to the experiment and had free access to water. The dose of aripiprazole was 3 mg / kg (calculated as aripiprazole) via oral gavage. At various time points (5 min, 15 min, 30 min, 60 min, 90 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h), 0.4 mL of blood was collected from the rat orbital cavity and transferred to a 2 mL sodium heparin centrifuge tube. The tube was centrifuged at 10,000 rpm for 10 min, and the supernatant plasma was stored at -80°C until LC-MS / MS analysis. LC-MS / MS analysis was performed using a Water C18 column (150 × 4.6 mm, 5 μm). The mobile phase consisted of 0.05% ammonia-0.05% formic acid in water: acetonitrile (v / v, 15:85). The injection volume was 5 μl, the flow rate was 0.5 ml / min, and the column temperature was 38°C.

[0256] 2. Experimental results

[0257] Table 4 Pharmacokinetic parameters of aripiprazole-fatty acid cocrystal and aripiprazole Form III

[0258] After oral administration of aripiprazole crystal form III (APZF3) and aripiprazole-fatty acid cocrystal to rats, the aripiprazole plasma concentration versus time curves and the calculated pharmacokinetic parameters are shown in Figure 17 and Table 4, respectively. Compared with aripiprazole crystal form III (APZF3), aripiprazole-fatty acid cocrystal had a faster release rate within 90 minutes and a higher peak plasma concentration (C max ). Among them, C of aripiprazole-myristic acid cocrystal (APZ14C)max (153.97±74.59ng / mL) is aripiprazole crystal form III (APZF3) (C max : 49.87±10.13 ng / mL), nearly 3 times that of aripiprazole-lauric acid cocrystal (APZ12C) and aripiprazole-palmitic acid cocrystal (APZ16C). max (APZ12C: 63.11 ± 14.93 ng / mL, APZ16C: 97.00 ± 18.33) were respectively aripiprazole crystal form III (APZF3) (C max : 49.87±10.13 ng / mL) was 1.3 and 1.9 times higher than that of the control group.

[0259] The area under the plasma concentration-time curve was calculated. When the dosage was the same, the bioavailability (AUC) of aripiprazole-myristic acid cocrystal (APZ14C) with the best powder dissolution properties in vitro was compared with that of aripiprazole crystal form III (APZF3). 0-24h :50811.80±8214.94ng / mL*min) was significantly improved, which was the Aripiprazole Form III (APZF3) group (AUC 0-24h :38697.01±1181.69ng / mL*min) is 1.3 times.

[0260] Example 54: Pharmacokinetic Evaluation of Drug Cocrystal Nanoformulations

[0261] 1. Experimental Materials

[0262] 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 43), aripiprazole-arachidic acid eutectic nanosuspension (prepared in Example 44), aripiprazole-lignoceric acid eutectic nanosuspension (prepared in Example 45), aripiprazole-stearic acid eutectic microsuspension (prepared in Example 47), and aripiprazole monohydrate nanosuspension (prepared in Example 48).

[0263] 2. Experimental methods

[0264] Thirty male SD rats were randomly divided into five groups (6 rats in each group) and uniquely identified by ear tags as groups A, B, C, D, and E. They had free access to water during the experiment. SD rats in groups A, B, C, and D received a single intramuscular injection of 100 mg / kg (calculated as aripiprazole) of aripiprazole-stearic acid cocrystal nanosuspension, aripiprazole-eicosanoic acid cocrystal nanosuspension, aripiprazole-lignoceric acid cocrystal nanosuspension, or aripiprazole-stearic acid cocrystal microsuspension. SD rats in group E received a single intramuscular injection of 100 mg / kg (calculated as aripiprazole) of aripiprazole monohydrate nanosuspension. 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 orbital cavity and transferred to a 2 mL centrifuge tube moistened with sodium heparin. The tubes were centrifuged at 4000 rpm for 15 min, and the supernatant plasma was stored at -80°C until LC-MS analysis.

[0265] Liquid chromatography-mass spectrometry conditions:

[0266] Instrument: Shimadzu LCMS 8045 triple quadrupole liquid chromatography-mass spectrometry;

[0267] Chromatographic column: Water C18 (150×4.6mm, 5μm);

[0268] Mobile phase: 0.05% ammonia-0.05% formic acid water: acetonitrile (v / v, 15:85);

[0269] Column temperature: 38°C;

[0270] Flow rate: 0.5 mL / min;

[0271] Injection volume: 5 μL;

[0272] Ion source: +ESI;

[0273] Interface temperature: 300℃;

[0274] Interface voltage: 4000V;

[0275] Heating block temperature: 400°C;

[0276] Ion pair: aripiprazole (precursor ion 448.3, product ion 285.2);

[0277] Carbamazepine (precursor ion 237.2, product ion 194.2).

[0278] 3. Experimental results

[0279] Table 5 Pharmacokinetic parameters of nanosuspensions of aripiprazole-fatty acid cocrystals and aripiprazole monohydrate

[0280] By regulating the fatty acid alkane chain length of the drug 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 18 and Table 5.

[0281] The aripiprazole plasma concentration-time curves in rats showed that the aripiprazole-fatty acid cocrystal nanosuspensions all showed significant pharmacokinetic advantages. After intramuscular injection, the aripiprazole plasma concentration of the aripiprazole-fatty acid cocrystal nanosuspension increased rapidly within the first 24 hours and was higher than that of the aripiprazole monohydrate nanosuspension. max ) is related to the chain length of the fatty acids in the cocrystal and is consistent with the in vitro dissolution trend. After 24 hours, aripiprazole plasma concentrations in rats were consistent across all formulations, indicating similar sustained-release duration and efficacy. Overall, there were no significant differences in the area under the concentration-time curve (AUC) among the formulations in rats, indicating no significant differences in bioavailability.

[0282] Therefore, while ensuring safety and therapeutic blood drug concentrations, the use of aripiprazole-fatty acid cocrystal nanosuspensions with appropriate fatty acid chain lengths allows rapid achievement of therapeutic blood drug concentrations without oral administration, improving patient compliance while maintaining a sustained-release period and efficacy comparable to the original formulation. This drug-release control strategy, which rapidly elevates blood drug concentrations within a short period of time, aligns with the existing strategy of combining long-acting aripiprazole injections with oral medications, and could serve as an alternative drug formulation.

[0283] Table 6 Pharmacokinetic parameters of aripiprazole-stearic acid cocrystal micro-nanosuspension and aripiprazole monohydrate nanosuspension

[0284] Furthermore, 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 19 and Table 6.

[0285] The aripiprazole plasma concentration-time curves in rats showed that the aripiprazole-stearic acid cocrystal micro-nanosuspensions exhibited significant pharmacokinetic advantages. Following intramuscular injection, the aripiprazole plasma concentrations of the aripiprazole-stearic acid cocrystal micro-nanosuspensions increased rapidly within the first 24 hours and were higher than those of the aripiprazole monohydrate nanosuspension. The highest plasma concentration (C max ) is the maximum plasma concentration of aripiprazole-stearic acid eutectic microsuspension (Cmax ). After 24 hours, aripiprazole plasma concentrations in rats were consistent across all formulations. Overall, there were no significant differences in the area under the concentration-time curve (AUC) between the formulations in rats, indicating no significant differences in bioavailability. This strategy demonstrates similar efficacy to the aforementioned fatty acid chain length manipulation strategy.

[0286] Obviously, whether it is regulating the fatty acid alkane chain length or the particle size of the preparation, the drug concentration in the body can be quickly increased to the therapeutic concentration level in a short period of time, improving the deficiency of the original long-acting preparation that requires oral medication to reach the therapeutic concentration level, improving patient compliance with medication and having the effect of long-term sustained release.

[0287] In summary, the present invention adopts a drug co-crystal strategy to prepare a new series of aripiprazole-fatty acid co-crystals without changing the drug efficacy, using saturated fatty acids with good biosafety as ligands. Through crystal structure analysis, the series of drug co-crystals designed by the present invention have a clear co-crystal crystal structure. Compared with existing pharmaceutical crystal forms, the physicochemical properties and in vitro drug release behavior of this series of drug co-crystals are significantly improved, including solubility, dissolution rate, and stability. In particular, the physicochemical properties and drug release behavior of the drug co-crystals show a good monotonic change trend with the alkane chain length. By regulating the fatty acid alkane chain length, it is possible to not only improve the bioavailability of the drug in the body, but also improve the deficiency of existing long-acting preparations that require oral medication to reach the drug therapeutic concentration level, thereby improving patient compliance with medication and achieving the effect of long-term sustained release. In addition, this series of drug co-crystals has good stability, no crystal transformation occurs during the preparation process, and the preparation method is convenient and economical, which is conducive to industrial production.

Claims

1. A quinolinone drug cocrystal, characterized in that: It is formed by aripiprazole and a saturated fatty acid ligand with 10 to 24 carbon atoms; in the cocrystal structure, the amide groups of the two aripiprazole molecules are connected by NH … O hydrogen bond self-assembly The homodimer is a dimer formed by the OH group on the carboxyl end of the saturated fatty acid molecule and the nitrogen atom on the piperazine ring away from the benzene ring in the aripiprazole molecule. … N hydrogen bond extension.

2. The quinolinone drug cocrystal according to claim 1, characterized in that The saturated fatty acid is selected from capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid, wherein the molar ratio of aripiprazole to the saturated fatty acid is 1-2:1-2.

3. The quinolinone drug cocrystal according to claim 1, characterized in that The molar ratio of aripiprazole to fatty acid is 1:

1.

4. An aripiprazole-decanoic acid cocrystal, characterized in that: It is a triclinic crystal system. Space group; unit cell parameters are α=81.285(4)°, β=82.440(5)°, γ=74.182(4)°.

5. The aripiprazole-decanoic acid cocrystal according to claim 4, characterized in that Expressed as a diffraction angle of 2θ±0.2°, it has characteristic diffraction peaks at 4.16°, 8.32°, 16.72°, 19.74°, and 22.24°.

6. The aripiprazole-decanoic acid cocrystal according to claim 4, characterized in that There is a characteristic melting peak at 75.3±0.5℃.

7. An aripiprazole-lauric acid cocrystal, characterized in that: It is a triclinic crystal system. Space group; unit cell parameters are α=91.364(2)°, β=98.872(2)°, γ=106.0730(10)°.

8. The aripiprazole-lauric acid cocrystal according to claim 7, characterized in that Expressed as a diffraction angle of 2θ±0.2°, it has characteristic diffraction peaks at 3.90°, 7.82°, 9.64°, 15.7°, 18.14°, 20.76°, 21.54°, 23.62°, and 24.44°.

9. The aripiprazole-lauric acid cocrystal according to claim 7, characterized in that There is a characteristic melting peak at 80.5±0.4℃.

10. An aripiprazole-myristic acid cocrystal, characterized in that: It is a triclinic crystal system. Space group; unit cell parameters are α=95.2340(10)°, β=93.7410(10)°, γ=106.2470(10)°.

11. The aripiprazole-myristic acid cocrystal according to claim 10, characterized in that Expressed as a diffraction angle of 2θ±0.2°, it has characteristic diffraction peaks at 3.72°, 7.43°, 14.90°, 17.18°, 18.22°, 18.67°, 23.10°, 26.52°, and 27.82°.

12. The aripiprazole-myristic acid cocrystal according to claim 10, characterized in that There is a characteristic melting peak at 85.3±0.3℃.

13. An aripiprazole-palmitic acid cocrystal, characterized in that: It is a triclinic crystal system. Space group; unit cell parameters are α=70.367(2)°, β=80.901(2)°, γ=78.615(2)°.

14. The aripiprazole-palmitic acid cocrystal according to claim 13, characterized in that Expressed as a diffraction angle of 2θ±0.2°, it has characteristic diffraction peaks at 3.56°, 7.02°, 14.10°, 17.18°, 17.70°, 18.28°, 21.14°, 21.58°, 21.78°, 24.20°, and 24.92°.

15. The aripiprazole-palmitic acid cocrystal according to claim 13, characterized in that There is a characteristic melting peak at 87.1±0.3℃.

16. An aripiprazole-stearic acid cocrystal, characterized in that: It is a triclinic crystal system. Space group; unit cell parameters are α=79.412(4)°, β=88.984(5)°, γ=75.058(4)°.

17. The aripiprazole-stearic acid cocrystal according to claim 16, wherein: Expressed as a diffraction angle of 2θ±0.2°, it has characteristic diffraction peaks 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°, and 27.00°.

18. The aripiprazole-stearic acid cocrystal according to claim 16, wherein: There is a characteristic melting peak at 89.5±0.3℃.

19. An aripiprazole-eicosanoic acid cocrystal, characterized in that: Expressed as a diffraction angle of 2θ±0.2°, it has characteristic diffraction peaks 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°.

20. The aripiprazole-eicosanoic acid cocrystal according to claim 19, wherein There is a characteristic melting peak at 92.4±0.4℃.

21. An aripiprazole-behenic acid cocrystal, characterized in that: Expressed as a diffraction angle of 2θ±0.2°, there is 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°.

22. The aripiprazole-behenic acid cocrystal according to claim 21, wherein There is a characteristic melting peak at 93.7±0.8℃.

23. An aripiprazole-lignoceric acid cocrystal, characterized in that: Expressed as a diffraction angle of 2θ±0.2°, there is 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°.

24. The aripiprazole-lignoceric acid cocrystal according to claim 23, wherein There is a characteristic melting peak at 95.5±0.1℃.

25. A method for preparing the cocrystal according to any one of claims 1 to 24, characterized in that: Choose from any of the following methods: Method 1: preparing a suspension of aripiprazole and fatty acid, stirring, and removing the solvent to obtain the cocrystal; Method 2: dissolving aripiprazole and fatty acid, filtering, removing the solvent from the filtrate, and crystallizing to obtain the co-crystal; Method 3: dissolving aripiprazole and fatty acid, then mixing with an anti-solvent, and removing the solvent to obtain the co-crystal; Method 4: heating aripiprazole and fatty acid until melted and cooling to obtain the cocrystal; Method 5: dissolving aripiprazole and fatty acid, cooling, and removing the solvent to obtain the cocrystal; Method 6: Aripiprazole and fatty acid are mixed and ground to obtain the co-crystal.

26. A pharmaceutical composition, characterized in that The co-crystal according to any one of claims 1 to 24 is used as the active ingredient.

27. The pharmaceutical composition according to claim 26, characterized in that The particle size is 0.1~5μm.

28. Use of the cocrystal according to any one of claims 1 to 24 or the pharmaceutical composition according to claim 26 in the preparation of a medicament for preventing and / or treating central nervous system diseases or disorders related to the central nervous system.

29. The use according to claim 28, characterized in that The drug is used to prevent and / or treat schizophrenia, mania, bipolar disorder, mixed episodes of bipolar disorder, depression, autism, autism-related hypersensitivity, Tourette syndrome, Alzheimer's disease, dementia, epilepsy, anxiety, tic disorder, irritability associated with childhood autism, Tourette syndrome, alcoholism, trichotillomania, dermatitis, autism spectrum disorder, tumors, emergence delirium, attention deficit disorder with hyperactivity, metabolic syndrome, postpartum depression, developmental disorders, opioid dependence, cocaine addiction, Asperger syndrome, HIV infection, fragile X syndrome, post-traumatic stress disorder, and weight changes caused by mental disorders.

Images