Quinolinone drug cocrystals, their preparation methods, pharmaceutical compositions and applications

Abstract

This invention discloses a quinolinone drug cocrystal, its preparation method, pharmaceutical composition, and applications. This drug cocrystal is a series of drug cocrystals formed by aripiprazole and fatty acid ligands, which can significantly improve the physicochemical properties and drug release behavior of aripiprazole. Compared with commercially available aripiprazole crystal form III, it has higher solubility, faster drug dissolution, greater stability in the liquid state, and better bioavailability, which is beneficial for drug development and clinical applications. Furthermore, the preparation method is convenient and economical, and easily scalable for industrial production.

Description

Technical Field

[0001] This invention relates to a quinolinone drug cocrystal, its preparation method, pharmaceutical composition, and application, and particularly to a quinolinone drug cocrystal with excellent physicochemical properties and the ability to regulate drug release behavior, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] Aripiprazole is an atypical antipsychotic drug of the quinolinone class, characterized by good efficacy and few side effects. According to the BDDCS classification system, aripiprazole belongs to class II drugs. Its solubility in water at 25°C is only 0.045 mg / L, affecting its absorption in vivo. Furthermore, aripiprazole has a slightly bitter taste and readily undergoes crystallization in vitro and in vivo, forming aripiprazole monohydrate, which has even lower water solubility, thus affecting its metabolic pharmacokinetics and limiting its further application.

[0003] A deep eutectic system of aripiprazole and capric acid was disclosed in *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). 1H NMR analysis revealed that in this aripiprazole-capric acid deep eutectic system, the drug interacts weakly with capric acid through the amide group and the nitrogen atom of the adjacent benzene ring on the piperazine ring. Regarding basic physicochemical properties, this aripiprazole-capric acid deep eutectic system has a lower melting point than its single-component counterparts, exists as a liquid or slurry at room temperature, and possesses a certain viscosity, which is unfavorable for subsequent formulation processing such as grinding, mixing, tableting, and granulation, making formulation preparation relatively difficult. Summary of the Invention

[0004] Objectives of the invention: The first objective of this invention is to provide a novel quinolinone drug cocrystal; the second objective is to provide a method for preparing the drug cocrystal; the third objective is to provide a pharmaceutical composition containing the drug cocrystal; and the fourth objective is to provide a pharmaceutical application of the drug cocrystal.

[0005] Technical solution: The quinolinone drug cocrystal of the present invention is formed by aripiprazole and a saturated fatty acid ligand with 10-16 carbon atoms; in the drug cocrystal structure, the amide groups of two aripiprazole molecules self-assemble through NH…O hydrogen bonds to form The homodimer is extended by an OH…N hydrogen bond formed between the hydroxyl group at the carboxyl terminus of the saturated fatty acid molecule and the nitrogen atom on the piperazine ring of the aripiprazole molecule that is far from the benzene ring.

[0006] Preferably, in the drug cocrystal structure, the CH…O hydrogen bonds formed by the carbonyl group at the carboxyl terminus of the saturated fatty acid molecule and the alkane on the piperazine ring of the aripiprazole molecule, as well as the CH…O hydrogen bonds formed by the hydroxyl group at the carboxyl terminus of the saturated fatty acid molecule and the benzene ring of the aripiprazole molecule, also participate in the construction of the aripiprazole cocrystal of the present invention.

[0007] Further preferred, the amide groups of the two aripiprazole molecules are connected by NH…O hydrogen bonds (bond length...) Self-assembly The homodimer is formed by a hydrogen bond (bond length OH…N) between a hydroxyl group at the carboxyl terminus of a saturated fatty acid molecule and a nitrogen atom on the piperazine ring of an aripiprazole molecule that is far from the benzene ring. (Extending further, the CH…O hydrogen bond (bond length) formed between the carbonyl group at the carboxyl terminus of the saturated fatty acid molecule and the alkane on the piperazine ring of the aripiprazole molecule.) The CH…O hydrogen bonds formed between the hydroxyl group at the carboxyl terminus of the saturated fatty acid molecule and the benzene ring in the aripiprazole molecule (bond length) It participated in the construction of the aripiprazole cocrystal described in this invention.

[0008] Preferably, the saturated fatty acid is selected from decanoic acid, lauric acid, myristic acid, and palmitic acid, wherein the molar ratio of aripiprazole to the saturated fatty acid is 1-2:1-2.

[0009] Further optimization yields a molar ratio of aripiprazole to saturated fatty acids of 1:1.

[0010] Drug cocrystals refer to solid, single-phase substances in which the active pharmaceutical ingredient and ligands are linked by weak interactions in a specific chemical ratio. These substances exhibit no charge transfer and are not solvates. Compared to other strategies for regulating the in vivo and in vitro properties of active pharmaceutical ingredients, drug cocrystal strategies can effectively regulate the basic physicochemical properties and in vivo and in vitro release behavior of drugs without affecting their efficacy. Fatty acids are essential substances for maintaining normal physiological activities and are widely distributed in nature. Due to their good biocompatibility and safety, they have been widely used in the design of multi-component drugs (drug cocrystals, salts).

[0011] This invention addresses the shortcomings of aripiprazole in terms of its physicochemical properties (solubility, stability, medication adherence, etc.) and bioavailability by employing a drug cocrystallization strategy. This strategy combines fatty acids with aripiprazole via non-covalent bonds, improving the solubility, dissolution rate, stability, and bioavailability of aripiprazole without altering its efficacy. Compared to commercially available aripiprazole crystal form III, the aripiprazole-fatty acid cocrystallization designed in this invention significantly improves solubility and bioavailability, accelerates inherent dissolution, and enhances stability. Furthermore, solubility, dissolution rate, and solution stability show a clear correlation with the alkane chain length of the fatty acid; shorter alkane chains result in higher solubility and faster inherent dissolution rates in the drug cocrystallization formed with aripiprazole, while longer alkane chains result in higher solution stability in water.

[0012]

[0013] Furthermore, the aripiprazole-fatty acid drug cocrystal designed in this invention exists in a solid state at room temperature, and its physical morphology is suitable for various formulation processes, thus enabling its development in different formulation forms. In particular, the improved liquid stability allows it to maintain an effective crystal morphology even in liquid formulations. In addition, the drug and ligand in the aripiprazole-fatty acid cocrystal are linked by weak interactions at a specific stoichiometric ratio, exhibiting a well-defined crystal structure with a more obvious correspondence to solid-state physicochemical properties, offering advantages in quality evaluation and process control.

[0014] The aripiprazole-decanoic acid eutectic described in this invention is a triclinic crystal system. Space group; cell parameters are α=81.285(4)°, β=82.440(5)°, γ=74.182(4)°.

[0015] In the above aripiprazole cocrystal structure, the amide groups of the two aripiprazole molecules are linked by NH…O hydrogen bonds (N3-H3…O2, Self-assembly It is a homodimer. Further extension of the dimer mainly occurs through the formation of OH…N(O3-H3B…N2, ) between the hydroxyl group at the carboxyl terminus of decanoic acid and the nitrogen atom on the aripiprazole piperazine ring, which is far from the benzene ring. Hydrogen bonds. Furthermore, the carbonyl group at the carboxyl terminus of decanoic acid forms CH…O(C9-H9A…O4, ) with the alkane on the aripiprazole piperazine ring. Hydrogen bonds and the hydroxyl group at the carboxyl terminus of decanoic acid forming CH…O(C3-H3A…O3, ) with the aripiprazole benzene ring Hydrogen bonds also participate in the construction of the aripiprazole-decanoic acid eutectic.

[0016] Preferably, the aripiprazole-decanoic acid eutectic has characteristic diffraction peaks at 4.14°, 8.32°, 16.72°, 19.74°, and 22.24°, expressed as diffraction angle 2θ±0.2°.

[0017] Further preferably, the aripiprazole-decanoic acid eutectic exhibits characteristic diffraction peaks at 4.14°, 8.32°, 16.72°, 17.10°, 19.74°, 21.64°, 22.24°, 23.28°, and 25.16°, expressed as a diffraction angle of 2θ±0.2°.

[0018] More preferably, the aripiprazole-decanoic acid eutectic exhibits 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°, expressed as a diffraction angle of 2θ±0.2°.

[0019] Preferably, the aripiprazole-decanoic acid eutectic has a characteristic melting peak at 75.3±0.5℃.

[0020] The aripiprazole-lauric acid eutectic described in this invention is a triclinic crystal system. Space group; cell parameters are α=91.364(2)°, β=98.872(2)°, γ=106.0730(10)°.

[0021] In the above aripiprazole cocrystal structure, the amide groups of the two aripiprazole molecules are linked by NH…O hydrogen bonds (N3-H3…O2, Self-assembly It is a homodimer. Further extension of the dimer mainly occurs through the formation of OH…N(O4-H4A…N2, ) between the hydroxyl group at the carboxyl terminus of laurate and the nitrogen atom on the aripiprazole piperazine ring, which is far from the benzene ring. Hydrogen bonds. Furthermore, the carbonyl group at the carboxyl terminus of laurate forms CH…O(C9-H9A…O3, ) with the alkane on the aripiprazole piperazine ring. Hydrogen bonds and the hydroxyl group at the carboxyl terminus of laurate forming CH…O(C3-H3A…O4, ) with the aripiprazole benzene ring Hydrogen bonds also participate in the construction of aripiprazole-lauric acid eutectic.

[0022] Preferably, the aripiprazole-lauric acid eutectic has characteristic diffraction peaks at 3.90°, 7.82°, 9.64°, 15.7°, 18.14°, 20.76°, 21.54°, 23.62°, and 24.44°, expressed as diffraction angle 2θ±0.2°.

[0023] Further preferably, the aripiprazole-lauric acid eutectic exhibits 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°, expressed as a diffraction angle of 2θ±0.2°.

[0024] More preferably, the aripiprazole-lauric acid eutectic exhibits 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°, expressed as a diffraction angle of 2θ±0.2°.

[0025] Preferably, the aripiprazole-lauric acid eutectic has a characteristic melting peak at 80.5±0.4℃.

[0026] The aripiprazole-myristic acid eutectic described in this invention is triclinic. Space group; cell parameters are α=95.2340(10)°, β=93.7410(10)°, γ=106.2470(10)°.

[0027] In the above aripiprazole cocrystal structure, the amide groups of the two aripiprazole molecules are linked by NH…O hydrogen bonds (N3-H3…O2, Self-assembly It is a homodimer. Further extension of the dimer mainly occurs through the formation of OH…N(O3-H3B…N2, ) between the hydroxyl group at the carboxyl terminus of myristic acid and the nitrogen atom on the aripiprazole piperazine ring, which is far from the benzene ring. Hydrogen bonds. Furthermore, the carbonyl group at the carboxyl terminus of myristic acid forms CH…O(C9-H9A…O4, ) with the alkane on the aripiprazole piperazine ring. Hydrogen bonds and the hydroxyl group at the carboxyl terminus of myristic acid forming CH…O(C3-H3A…O3, ) with the benzene ring of aripiprazole Hydrogen bonds also participate in the construction of the aripiprazole-myristic acid eutectic.

[0028] Preferably, the aripiprazole-myristic acid eutectic has characteristic diffraction peaks at 3.72°, 7.43°, 14.90°, 17.18°, 18.22°, 18.67°, 23.10°, 26.52°, and 27.82°, expressed as diffraction angle 2θ±0.2°.

[0029] Further preferably, the aripiprazole-myristic acid eutectic exhibits 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°, expressed as a diffraction angle of 2θ±0.2°.

[0030] More preferably, the aripiprazole-myristic acid eutectic exhibits 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°, expressed as a diffraction angle of 2θ±0.2°.

[0031] Preferably, the aripiprazole-myristic acid eutectic has a characteristic melting peak at 85.3±0.3℃.

[0032] The aripiprazole-palmitic acid eutectic described in this invention is a triclinic crystal system. Space group; cell parameters are α=70.367(2)°, β=80.901(2)°, γ=78.615(2)°.

[0033] In the above aripiprazole cocrystal structure, the amide groups of the two aripiprazole molecules are linked by NH…O hydrogen bonds (N6-H6…O5, N9-H9…O2, N3-H3…O10, Self-assembly It is a homodimer. Further extension of the dimer mainly occurs through the formation of OH…N(O4-H4A…N2, ) between the hydroxyl group at the carboxyl terminus of palmitic acid and the nitrogen atom on the aripiprazole piperazine ring, which is far from the benzene ring. O8-H8…N5, O12-H12…N8, Hydrogen bonds. Furthermore, the carbonyl group at the carboxyl terminus of palmitic acid forms CH…O(C10-H10C…O11, ) with the alkane on the aripiprazole piperazine ring. C88-H88A…O7, C48-H48A…O3, Hydrogen bonds and the formation of CH…O(C3-H3A…O4, ) by the hydroxyl group at the carboxyl terminus of palmitic acid and the aripiprazole benzene ring C22-H22A…O5, C42-H42…O8, C81-H81…O12, Hydrogen bonds also participate in the construction of aripiprazole-palmitic acid eutectic.

[0034] Preferably, the aripiprazole-palmitic acid eutectic exhibits 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°, expressed as diffraction angle 2θ±0.2°.

[0035] Further preferably, the aripiprazole-palmitic acid eutectic exhibits 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°, expressed as a diffraction angle of 2θ±0.2°.

[0036] More preferably, the aripiprazole-palmitic acid eutectic exhibits 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°, expressed as a diffraction angle of 2θ±0.2°.

[0037] Preferably, the aripiprazole-palmitic acid eutectic has a characteristic melting peak at 87.1±0.3℃.

[0038] The method for preparing the aripiprazole cocrystal described in this invention is selected from any of the following methods:

[0039] Method 1: Prepare a suspension of aripiprazole and fatty acids, stir, remove the solvent, and obtain the eutectic.

[0040] Method 2: Dissolve aripiprazole in fatty acids, filter, remove solvent from the filtrate, and crystallize to obtain the eutectic.

[0041] Method 3: Dissolve aripiprazole in fatty acids, then mix with the reverse mixture to remove the solvent, thus obtaining the eutectic.

[0042] Method 4: Heat aripiprazole and fatty acids until they melt, then cool to obtain the eutectic.

[0043] Method 5: Dissolve aripiprazole in fatty acids, cool, and remove the solvent to obtain the eutectic.

[0044] Method 6: Mix and grind aripiprazole with fatty acids to obtain the eutectic.

[0045] 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 solvent is removed by filtration.

[0046] 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-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-assisted dissolution, and the solvent removal method is atmospheric pressure evaporation or vacuum evaporation.

[0047] 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 solvent is removed by filtration.

[0048] Preferably, in method four, 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, even more 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.

[0049] 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-assisted dissolution, and the cooling method is natural cooling or programmed cooling.

[0050] Preferably, in method six, the molar ratio of aripiprazole to fatty acid is 1:2 to 2:1, more preferably 1:1; the grinding process may or may not involve the addition of a solvent, more preferably the addition of a solvent to assist grinding, the solvent being 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.

[0051] The pharmaceutical composition of the present invention uses the aripiprazole-fatty acid cocrystal of the present invention as the active ingredient.

[0052] Preferably, the aripiprazole-fatty acid cocrystal of the present invention can be formulated into common pharmaceutical preparations by adding a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be an excipient widely used in the pharmaceutical manufacturing field. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and can also provide methods to allow the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipient can be an inert filler, or provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipient can include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners, etc.

[0053] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0054] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or sustained-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, 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 preparations. Examples of parenteral formulations 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 tablets.

[0055] The aripiprazole-fatty acid cocrystal or its pharmaceutical composition described in this invention is used in the preparation of medicaments for the prevention and / or treatment of central nervous system diseases or conditions related to the central nervous system.

[0056] Preferably, the drug is a medication for the prevention and / or treatment of schizophrenia, mania, bipolar disorder, mixed episodes of bipolar disorder, depression, autism, autism-related hypersensitivity, Tourette syndrome, Alzheimer's disease, dementia, epilepsy, anxiety, tic disorders, childhood autism-related irritability, ADHD, alcoholism, trichotillomania, dermatitis, autism spectrum disorder, tumors, post-traumatic delirium, attention deficit hyperactivity disorder, metabolic syndrome, postpartum depression, developmental disorders, opioid dependence, cocaine addiction, Asperger's syndrome, HIV infection, fragile X syndrome, post-traumatic stress disorder, and weight changes caused by mental disorders.

[0057] Preferably, the target users of the drug include adults, adolescents, and children.

[0058] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0059] The aripiprazole-fatty acid series cocrystal designed in this invention can significantly improve the physicochemical properties of aripiprazole and regulate its release behavior. Compared with commercially available aripiprazole crystal form III, it has higher solubility, faster drug dissolution, greater stability in the liquid state, and better bioavailability, which is beneficial for drug development and clinical application. At the same time, the preparation method is convenient and economical, and easy to realize industrial-scale preparation. Attached Figure Description

[0060] Figure 1 The single-crystal asymmetric unit structure and molecular packing diagram of the aripiprazole-decanoic acid eutectic prepared in Example 5 are shown below.

[0061] Figure 2 The single-crystal asymmetric unit structure diagram of the aripiprazole-lauric acid eutectic prepared in Example 6;

[0062] Figure 3 This is a single-crystal asymmetric unit structure diagram of the aripiprazole-myristic acid eutectic prepared in Example 7;

[0063] Figure 4 This is a single-crystal asymmetric unit structure diagram of the aripiprazole-palmitic acid eutectic prepared in Example 8;

[0064] Figure 5 Thermogravimetric analysis (TGA) diagrams of aripiprazole-fatty acid eutectic prepared in Examples 1-4 and aripiprazole crystal form III prepared in Example 25 are shown.

[0065] Figure 6 Differential scanning calorimetry (DSC) images of aripiprazole-fatty acid cocrystals prepared in Examples 1-4 and aripiprazole crystal form III prepared in Example 25;

[0066] Figure 7X-ray powder diffraction patterns of aripiprazole-fatty acid eutectic prepared in Examples 1-4 and aripiprazole crystal form III prepared in Example 25;

[0067] Figure 8 Powder dissolution diagrams of aripiprazole-fatty acid eutectic prepared in Examples 1-4 and aripiprazole crystal form III prepared in Example 25;

[0068] Figure 9 Raman images of the powder dissolution residues of aripiprazole-fatty acid eutectic prepared in Examples 1-4 and aripiprazole crystal form III prepared in Example 25;

[0069] Figure 10 The inherent dissolution time-concentration diagrams are for the aripiprazole-fatty acid cocrystals prepared in Examples 1-4 and for aripiprazole crystal form III prepared in Example 25;

[0070] Figure 11 The intrinsic dissolution rate diagrams are for the aripiprazole-fatty acid cocrystals prepared in Examples 1-4 and the aripiprazole crystal form III prepared in Example 25;

[0071] Figure 12 Raman images of the inherent dissolution residues of aripiprazole-fatty acid eutectic prepared in Examples 1-4 and aripiprazole crystal form III prepared in Example 25;

[0072] Figure 13 The stability of the aripiprazole-fatty acid cocrystals prepared in Examples 1-4 under accelerated testing conditions (40°C / 75% RH);

[0073] Figure 14 The pharmacokinetic curves of aripiprazole-fatty acid cocrystals prepared in Examples 2-4 and aripiprazole crystal form III prepared in Example 25 are shown. Detailed Implementation

[0074] The technical solution of the present invention will be further described below with reference to the embodiments.

[0075] The instruments used in this invention for solid-state characterization of drug cocrystals are as follows:

[0076] Thermogravimetric analysis was performed using a TAQ500 thermogravimetric analyzer. The method involved adding 5–15 mg of sample to a platinum dish and heating it 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.

[0077] The differential scanning calorimetry (DSC) instrument used was a TAQ2000 DSC. The method involved weighing 3–5 mg of sample into a sealed aluminum crucible and heating it to 160 °C at a heating rate of 10 °C / min. The instrument was periodically calibrated using metallic indium, and the heating environment was a high-purity (99.99%) nitrogen atmosphere with a nitrogen flow rate of 50 mL / min.

[0078] The instrument used for powder X-ray diffraction characterization was a Rigaku SmartLab SE powder X-ray diffractometer; target: Cu-Kα rays. Tube voltage: copper palladium 40kV; current: 40mA; 2θ range: 3~40°; scan step size: 0.02°; scan rate: 10° / min.

[0079] The instrument used for Raman spectroscopy was a Thermo Fisher Scientific DXR, 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.

[0080] Example 1

[0081] Weigh 2.24 g of aripiprazole and 0.86 g of decanoic acid, mix them, add 10 mL of acetonitrile solution to form a suspension, stir at room temperature for 3 days, filter, dry under vacuum at 40 °C for 48 h, and characterize by PXRD, DSC and TGA to confirm that the aripiprazole-decanoic acid eutectic (APZ-C10) was obtained.

[0082] Example 2

[0083] Weigh 2.24 g of aripiprazole and 1.00 g of lauric acid, mix them, add 10 mL of acetonitrile solution to form a suspension, stir at room temperature for 3 days, filter, dry under vacuum at 40 °C for 48 h, and characterize by PXRD, DSC and TGA to confirm that the aripiprazole-lauric acid eutectic (APZ-C12) was obtained.

[0084] Example 3

[0085] Weigh 2.24 g of aripiprazole and 1.14 g of myristic acid, mix them, add 10 mL of acetonitrile solution to form a suspension, stir at room temperature for 3 days, filter, vacuum dry at 40 °C for 48 h, and characterize by PXRD, DSC and TGA to confirm that the aripiprazole-myristic acid eutectic (APZ-C14) was obtained.

[0086] Example 4

[0087] Weigh 2.24 g of aripiprazole and 1.28 g of palmitic acid, mix them, add 10 mL of acetonitrile solution to form a suspension, stir at room temperature for 3 days, filter, dry under vacuum at 40 °C for 48 h, and characterize by PXRD, DSC and TGA to confirm that aripiprazole-palmitic acid eutectic (APZ-C16) was obtained.

[0088] Example 5

[0089] Weigh aripiprazole crystal form III (448 mg) and decanoic acid (172 mg), mix them, add 40 mL of acetonitrile, sonicate to dissolve, filter into a beaker, slowly evaporate the solvent until crystals precipitate, dry the product, and characterize it by PXRD, DSC, and TGA to confirm that aripiprazole-decanoic acid eutectic (APZ-C10) was obtained.

[0090] Example 6

[0091] Weigh aripiprazole crystal form III (448 mg) and lauric acid (200 mg), mix them, add 50 mL of acetonitrile, sonicate to dissolve, filter into a beaker, slowly evaporate the solvent until crystals precipitate, dry the product, and characterize it by PXRD, DSC, and TGA to confirm that aripiprazole-lauric acid eutectic (APZ-C12) was obtained.

[0092] Example 7

[0093] Weigh aripiprazole crystal form III (448 mg) and myristic acid (228 mg), mix them, add 50 mL of acetonitrile, sonicate to dissolve, filter into a beaker, slowly evaporate the solvent until crystals precipitate, dry the product, and characterize it by PXRD, DSC and TGA to confirm that aripiprazole-myristic acid eutectic (APZ-C14) was obtained.

[0094] Example 8

[0095] Weigh aripiprazole crystal form III (448 mg) and palmitic acid (256 mg), mix them, add 50 mL of acetonitrile, sonicate to dissolve, filter into a beaker, slowly evaporate the solvent until crystals precipitate, dry the product, and characterize it by PXRD, DSC and TGA to confirm that aripiprazole-palmitic acid eutectic (APZ-C16) was obtained.

[0096] Example 9

[0097] Weigh a certain amount of aripiprazole crystal form III (50 mg) and decanoic acid (19 mg), add 5 mL of acetone to dissolve, and slowly add dropwise to an aqueous solution under stirring. Filter, dry the product, and characterize it by PXRD, DSC, and TGA to confirm that the aripiprazole-decanoic acid eutectic (APZ-C10) was obtained.

[0098] Example 10

[0099] Weigh a certain amount of aripiprazole crystal form III (50 mg) and lauric acid (22 mg), add 5 mL of acetone to dissolve, and slowly add dropwise to an aqueous solution under stirring. Filter, dry the product, and characterize it by PXRD, DSC, and TGA to confirm that the aripiprazole-lauric acid eutectic (APZ-C12) was obtained.

[0100] Example 11

[0101] Weigh a certain amount of aripiprazole crystal form III (50 mg) and myristic acid (25 mg), add 5 mL of acetone to dissolve, and slowly add dropwise to an aqueous solution under stirring. Filter, dry the product, and characterize it by PXRD, DSC, and TGA to confirm that the aripiprazole-myristic acid eutectic (APZ-C14) was obtained.

[0102] Example 12

[0103] Weigh a certain amount of aripiprazole crystal form III (50 mg) and palmitic acid (29 mg), add 5 mL of acetone to dissolve, and slowly add dropwise to an aqueous solution under stirring. Filter, dry the product, and characterize it by PXRD, DSC, and TGA to confirm that the aripiprazole-palmitic acid eutectic (APZ-C16) was obtained.

[0104] Example 13

[0105] A certain amount of aripiprazole crystal form III (448 mg) and decanoic acid (172 mg) were weighed and thoroughly mixed. The mixture was then heated to 140 °C on a hot plate to melt the mixture. After being removed, the mixture was quenched on an aluminum block and left at room temperature for 30 min. Then, it was heated again at 60 °C until amorphous crystals were completely formed. The mixture was characterized by PXRD, DSC, and TGA to confirm the formation of the aripiprazole-decanoic acid eutectic (APZ-C10).

[0106] Example 14

[0107] A certain amount of aripiprazole crystal form III (448 mg) and lauric acid (200 mg) were weighed and thoroughly mixed. The mixture was then heated to 140 °C on a hot plate to melt, removed and quenched on an aluminum block. After being left at room temperature for 30 min, the mixture was heated again at 60 °C until amorphous crystals were completely formed. PXRD, DSC, and TGA characterization confirmed the formation of an aripiprazole-lauric acid eutectic (APZ-C12).

[0108] Example 15

[0109] A certain amount of aripiprazole crystal form III (448 mg) and myristic acid (228 mg) were weighed and thoroughly mixed. The mixture was then heated to 140 °C on a hot plate to melt, removed and quenched on an aluminum block. After being placed at room temperature for 30 min, the mixture was heated again at 60 °C until amorphous crystals were completely formed. PXRD, DSC, and TGA characterization confirmed the formation of an aripiprazole-myristic acid eutectic (APZ-C14).

[0110] Example 16

[0111] A certain amount of aripiprazole crystal form III (448 mg) and palmitic acid (256 mg) were weighed and thoroughly mixed. The mixture was then heated to 140 °C on a hot plate to melt, removed and quenched on an aluminum block. After being left at room temperature for 30 min, the mixture was heated again at 60 °C until amorphous crystals were completely formed. PXRD, DSC, and TGA characterization confirmed the formation of the aripiprazole-palmitic acid eutectic (APZ-C16).

[0112] Example 17

[0113] Weigh a certain amount of aripiprazole crystal form III (448 mg) and decanoic acid (172 mg), add 40 mL of acetonitrile as solvent, heat to 60 °C to dissolve, then cool to 4 °C, filter, dry the product, and characterize it by PXRD, DSC and TGA to confirm that aripiprazole-decanoic acid eutectic (APZ-C10) was obtained.

[0114] Example 18

[0115] Weigh a certain amount of aripiprazole crystal form III (448 mg) and lauric acid (200 mg), add 50 mL of acetonitrile as solvent, heat to 60 °C to dissolve, then cool to 4 °C, filter, dry the product, and characterize it by PXRD, DSC and TGA to confirm that aripiprazole-lauric acid eutectic (APZ-C12) was obtained.

[0116] Example 19

[0117] Weigh a certain amount of aripiprazole crystal form III (448 mg) and myristic acid (228 mg), add 50 mL of acetonitrile as solvent, heat to 60 °C to dissolve, then cool to 4 °C, filter, dry the product, and characterize it by PXRD, DSC and TGA to confirm that aripiprazole-myristic acid eutectic (APZ-C14) was obtained.

[0118] Example 20

[0119] Weigh a certain amount of aripiprazole crystal form III (448 mg) and palmitic acid (256 mg), add 50 mL of acetonitrile as solvent, heat to 60 °C to dissolve, then cool to 4 °C, filter, dry the product, and characterize it by PXRD, DSC and TGA to confirm that aripiprazole-palmitic acid eutectic (APZ-C16) was obtained.

[0120] Example 21

[0121] Weigh 996 mg of aripiprazole crystal form III and 344 mg of decanoic acid, mix them evenly, add 60 μL of acetonitrile to assist grinding, dry, and perform PXRD, DSC and TGA characterization to confirm that the aripiprazole-decanoic acid eutectic (APZ-C10) was obtained.

[0122] Example 22

[0123] Weigh 996 mg of aripiprazole crystal form III and 400 mg of lauric acid, mix them evenly, add 60 μL of acetonitrile to assist grinding, dry, and perform PXRD, DSC and TGA characterization to confirm that the aripiprazole-lauric acid eutectic (APZ-C12) was obtained.

[0124] Example 23

[0125] Weigh 996 mg of aripiprazole crystal form III and 456 mg of myristic acid, mix them evenly, add 60 μL of acetonitrile to assist grinding, dry, and perform PXRD, DSC and TGA characterization to confirm that the aripiprazole-myristic acid eutectic (APZ-C14) was obtained.

[0126] Example 24

[0127] Weigh 996 mg of aripiprazole crystal form III and 512 mg of palmitic acid, mix them evenly, add 60 μL of acetonitrile to assist grinding, dry, and perform PXRD, DSC and TGA characterization to confirm that the aripiprazole-palmitic acid eutectic (APZ-C16) was obtained.

[0128] Example 25

[0129] 10 g of aripiprazole raw material was weighed and added to 200 mL of a mixture of ethanol and water (4:1). The mixture was refluxed at 70 °C for 2 h, slowly cooled to room temperature, filtered, and vacuum dried at 40 °C for 48 h. Solid-state characterization confirmed the presence of aripiprazole monohydrate (APZMH). The aripiprazole monohydrate was then spread out on a 100 °C hot plate and heated for 30 min. Solid-state characterization confirmed the presence of aripiprazole crystal form III (APZF3).

[0130] Example 26

[0131] Weigh 296.3 mg of aripiprazole-palmitic acid eutectic that has passed through an 80-mesh sieve, add 3 mL of an aqueous solution containing 30 mg of Tween 20 and 4 g of 1 mm diameter zirconia grinding beads, and grind at 800 rpm for 2 h. Then add appropriate amounts of sodium chloride, sodium citrate, sodium dihydrogen phosphate, and disodium hydrogen phosphate to adjust the osmotic pressure and pH of the preparation, to obtain an aripiprazole-palmitic acid eutectic nano-suspension with a particle size of 516.87 ± 2.87 nm and a PDI of 0.22 ± 0.02.

[0132] Example 27: Characterization of Drug Cocrystal Structure

[0133] The single-crystal structures of the aripiprazole-fatty acid eutectics prepared in Examples 5-8 were analyzed, and the results showed that all aripiprazole-fatty acid eutectics belonged to the triclinic crystal system. Space group, measuring the distance difference Δd between two carbon-oxygen bonds in the carboxylic acid within different aripiprazole-fatty acid eutectic crystal structures. (C-O) The values ​​were 0.119 (APZ-C10), 0.121 (APZ-C12), 0.116 (APZ-C14), and 0.120 (APZ-C16), respectively. According to the carboxylic acid rule for distinguishing eutectic from salt (Δd in the neutral carboxyl group)... (C-O) Greater than Δd of carboxylate anion (C-O) Less than It can be seen that the multi-component single-phase solid obtained by aripiprazole and fatty acids is a eutectic rather than a salt. The crystallographic parameters of aripiprazole-fatty acid eutectics with different alkane chain lengths are shown in Table 1. The cell volume V, axial length c, and cell density ρ show a good monotonic trend in relation to the alkane chain length of the fatty acids in the drug eutectic. The asymmetric units of different aripiprazole-fatty acid eutectics are shown in Table 1. Figures 1-4 .

[0134] Analysis of the crystal structure and interaction forces of aripiprazole-fatty acid cocrystals revealed a high degree of consistency in the molecular packing characteristics of aripiprazole-fatty acid cocrystals with different alkane chain lengths. Figure 1 (Table 2). Taking aripiprazole-decanoic acid eutectic as an example, the amide groups of the two aripiprazole molecules are linked by NH…O hydrogen bonds (N3-H3…O2, ) self-assemble into a It is a homodimer. Further extension of the dimer mainly occurs through the formation of OH…N(O3-H3…N2) between the hydroxyl group at the carboxyl terminus of the decanoic acid and the nitrogen atom on the aripiprazole piperazine ring, which is far from the benzene ring. Hydrogen bonds connect the decanoic acid group to the alkane on the aripiprazole piperazine ring. Furthermore, the carbonyl group at the carboxyl terminus of the decanoic acid forms CH…O(C9-H9…O4, Hydrogen bonds and the CH…O(C3-H3…O3) formed by the carboxyl-terminal hydroxyl group of decanoic acid and the aripiprazole benzene ring Hydrogen bonds also participate in the construction of the aripiprazole-decanoic acid eutectic.

[0135] Table 1. Crystallographic parameters of aripiprazole-fatty acid cocrystal

[0136]

[0137]

[0138] Table 2 Hydrogen bond information of aripiprazole-fatty acid cocrystal

[0139]

[0140]

[0141] Solid-state characterization results of aripiprazole-fatty acid eutectic and aripiprazole crystal form III are as follows: Figures 5-7 Before 100℃, neither the aripiprazole-fatty acid cocrystal nor aripiprazole crystal form III (APZF3) showed significant weight loss with increasing temperature, indicating that all samples existed in a solvent-free form. At 125℃, the aripiprazole-fatty acid cocrystal samples began to show weight loss, and the initial temperature corresponding to the weight loss of the drug cocrystal samples increased with the increase of the alkane chain length of the fatty acids in the drug cocrystal.

[0142] Differential scanning calorimetry curves of all aripiprazole-fatty acid cocrystals ( Figure 6 All exhibited sharp endothermic melting peaks, indicating high phase purity. The melting points of the aripiprazole-fatty acid eutectic were 75.33±0.52℃ (APZ-C10), 80.49±0.37℃ (APZ-C12), 85.35±0.29℃ (APZ-C14), and 87.05±0.29℃ (APZ-C16), respectively. The melting points of all aripiprazole-fatty acid eutectics were between those of saturated fatty acids and aripiprazole crystal form III (139℃). The melting points of aripiprazole-fatty acid eutectics with different alkane chain lengths increased with increasing fatty acid alkane chain length.

[0143] X-ray powder diffraction of aripiprazole-fatty acid cocrystal as follows Figure 7 As shown, the PXRD patterns of aripiprazole-fatty acid cocrystals with different alkane chain lengths exhibit largely consistent diffraction peak positions in the 2θ range of 16–25°. However, the diffraction peaks in the lower diffraction angle region show a regular shift; for example, the diffraction peaks at 2θ of 2.5° and 7.0° shift towards lower angle regions as the alkane chain length of the fatty acid in the drug cocrystal increases. This result indicates that the internal molecular packing arrangement of the aripiprazole-fatty acid cocrystal has good consistency.

[0144] Example 28: Evaluation of powder dissolution and solution stability

[0145] 1. Source of the test sample

[0146] Aripiprazole raw material was purchased from Jiangsu Aikon Biopharmaceutical R&D Co., Ltd., and fatty acids were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; aripiprazole crystal form III was purified from aripiprazole raw material.

[0147] 2. Experimental Methods

[0148] Weigh 200 mg of aripiprazole-fatty acid eutectic powder (passed through an 80-mesh sieve) into a 50 mL centrifuge tube, add 10 mL of 0.25 wt.% sodium dodecyl sulfate (SDS) aqueous solution, place in a 37°C constant temperature shaker, and shake at 100 rpm for 48 h. Take 1 mL of supernatant at different time points and add 1 mL of blank medium. Centrifuge the extract at 13000 rpm for 5 min, dilute, and inject into HPLC. The lower solid layer is then characterized by Raman spectroscopy.

[0149] 3. Experimental Results

[0150] Non-drain dissolution curves of aripiprazole-fatty acid eutectics with different alkane chain lengths in 0.25 wt.% sodium dodecyl sulfate (SDS) aqueous solution are shown below. Figure 8 As shown, the dissolution curves of APZF3, APZ-C10, and APZ-C12 exhibit a "spring-parachute" model, with the concentration of aripiprazole in the solution initially increasing and then rapidly decreasing. During the increasing phase, APZ-C10 and APZ-C12 dissolve faster than APZF3. The decreasing phase is presumably due to phase transitions during dissolution of APZF3, APZ-C10, and APZ-C12, but APZ-C12 still dissolves faster than APZF3. The dissolution curves of APZ-C14 and APZ-C16 exhibit a "spring-helicopter" model, with the concentration of aripiprazole in the solution rapidly increasing to a certain level within a short time and maintaining this level throughout the subsequent dissolution process. Comparing the equilibrium solubility of APZ-C14 and APZ-C16, the aripiprazole-fatty acid eutectic, with its shorter alkane chain, shows better solubility.

[0151] Raman characterization was performed on the residue 24 hours after dissolution, and the results are as follows: Figure 9 As shown. In contrast, aripiprazole monohydrate (APZMH) at 1320 cm⁻¹ -1 Based on the characteristic Raman peaks, it is believed that APZF3 and the aripiprazole-fatty acid cocrystals with shorter alkane chains (APZ-C10, APZ-C12) are transformed into aripiprazole monohydrate during the dissolution process, while the aripiprazole-fatty acid cocrystals with longer alkane chains (APZ-C14 and APZ-C16) still exist as drug cocrystals in the residue 24 hours after dissolution.

[0152] Example 29: Evaluation of Inherent Dissolution Rate

[0153] 1. Source of the test sample

[0154] Aripiprazole raw material was purchased from Jiangsu Aikon Biopharmaceutical R&D Co., Ltd., and fatty acids were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; aripiprazole crystal form III was purified from aripiprazole raw material.

[0155] 2. Experimental Methods

[0156] Weigh 50 mg of aripiprazole crystal form III and aripiprazole-fatty acid eutectic powder (passed through an 80-mesh sieve) separately, place them into a 4 mm diameter inherent dissolution mold, and press them under a pressure of 200 kg for 1 min. After pressing, remove the mold so that one side of the tablet is exposed to 550 mL of dissolution medium (0.25 wt.% sodium dodecyl sulfate aqueous solution (SDS)). Dissolution is performed at 37 °C and 50 rpm. At different time points (2, 4, 6, 8, 10, 12, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180 min), take 4 mL of sample solution and simultaneously add an equal volume of constant-temperature blank medium. Centrifuge the sample solution at 13000 rpm for 5 min, and inject the supernatant into the HPLC system.

[0157] Experimental conditions for high performance liquid chromatography determination:

[0158] Instrument: Shimadzu LC-20AT high performance liquid chromatograph;

[0159] Chromatography UV detector model: Shimadzu SPD-20A;

[0160] Chromatography quaternary pump model: Shimadzu LC-20AT;

[0161] Column: Agilent Zorbax SB C-18 (4.6 × 250 mm, 5 μm);

[0162] Mobile phase: Acetonitrile: 0.1% formic acid-0.1% ammonia aqueous solution (v / v, 60:40);

[0163] Column temperature: 40℃;

[0164] Flow rate: 1 mL / min;

[0165] Injection volume: 50 μL;

[0166] Detection wavelength: 254nm.

[0167] 3. Experimental Results

[0168] The inherent dissolution results of aripiprazole-fatty acid cocrystal are as follows: Figure 10As shown. Overall, the dissolution of aripiprazole-fatty acid cocrystal and aripiprazole crystal form III occurred at a constant rate, and the drug concentration in the dissolution medium showed a good linear relationship with time. The intrinsic dissolution rate of aripiprazole-fatty acid cocrystal with different alkane chain lengths was calculated using the extraction slope. Figure 11 (See Table 3). Linear fitting was performed on some groups within a short time. The results showed that the intrinsic dissolution rate of all aripiprazole-fatty acid cocrystals was faster than that of the aripiprazole crystal form III (APZF3) group. Furthermore, the intrinsic dissolution rate of aripiprazole-fatty acid cocrystals with different alkane chain lengths decreased with increasing chain length, in the following order: APZ-C10 > APZ-C12 > APZ-C14 > APZ-C16.

[0169] Table 3. Intrinsic dissolution rates of aripiprazole crystal form III and aripiprazole-fatty acid eutectic in 0.25 wt.% SDS aqueous solution.

[0170]

[0171] Raman characterization was performed on the side of all aripiprazole-fatty acid cocrystals and aripiprazole crystal form III (APZF3) after the inherent dissolution test, in contact with the dissolution medium. The results are as follows: Figure 12 As shown, aripiprazole crystal form III (APZF3), aripiprazole-decanoic acid eutectic (APZ-C10), and aripiprazole-lauric acid eutectic (APZ-C12) underwent crystal form transformation during the inherent dissolution experiment, while the remaining aripiprazole-fatty acid eutectic crystals maintained stable crystal forms after dissolution. This result is consistent with the powder dissolution results, indicating that aripiprazole-fatty acid eutectic solutions with longer alkane chains have better stability.

[0172] Example 30: Solid-state stability evaluation

[0173] 1. Experimental Methods

[0174] Weigh an appropriate amount of aripiprazole-fatty acid eutectic powder that has passed through an 80-mesh sieve, and place it in an open constant temperature oven at 40℃ / 75%RH. Take it out at different time intervals (0 months, 1 month, 3 months, 6 months) and perform X-ray powder diffraction characterization. The test conditions are the same as the detection method in Example 29.

[0175] 2. Experimental Results

[0176] The solid-state stability characterization results of aripiprazole-fatty acid cocrystals with different alkane chain lengths at 40℃ / 75%RH are as follows: Figure 13As shown in the figure, by comparing the PXRD patterns of the aripiprazole-fatty acid cocrystal before sampling (indicated by 0 in the figure), aripiprazole-fatty acid cocrystals with different alkane chain lengths did not undergo crystal transformation after being placed under accelerated experimental conditions for up to 6 months, nor did they show any correlation with alkane chain length. This indicates that the aripiprazole-fatty acid cocrystal prepared in this invention has good physical stability and is suitable for long-term storage under solid conditions.

[0177] Example 31: Pharmacokinetic Evaluation

[0178] 1. Experimental Methods

[0179] Sixteen male SPF-grade SD rats (250–275 g) were randomly divided into four groups (n = 4) and numbered by ear: Group A (aripiperazole crystal form III, APZF3), Group B (aripiperazole-lauric acid cocrystal, APZ-C12), Group C (aripiperazole-myristic acid cocrystal, APZ-C14), and Group D (aripiperazole-palmitic acid cocrystal, APZ-C16). Rats were fasted for 12 hours prior to the experiment but allowed free access to water. The dosage was 3 mg / kg (calculated as aripiprazole) administered orally via gavage. Blood samples of 0.4 mL were collected from the orbital sinus of rats at different time points (5 min, 15 min, 30 min, 60 min, 90 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 24 h) and transferred to 2 mL heparin sodium centrifuge tubes. The tubes were centrifuged at 10,000 rpm for 10 min, and the supernatant plasma was collected and stored at -80℃ until LC-MS / MS analysis. The chromatographic column used for LC-MS / MS analysis was a Water C18 column (150 × 4.6 mm, 5 μm). The mobile phase was 0.05% ammonia-0.05% formic acid: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℃.

[0180] 2. Experimental Results

[0181] Following oral administration of aripiprazole crystal form III (APZF3) and aripiprazole-fatty acid cocrystal to rats, the in vivo plasma concentration-time curves of aripiprazole and the calculated pharmacokinetic parameters are as follows: Figure 14 As shown in Table 4, compared with the aripiprazole crystal form III (APZF3) group, the aripiprazole-fatty acid cocrystal had a faster release rate within 90 min and a higher peak plasma concentration (C). max Among them, the C of aripiprazole-myristic acid eutectic (APZ-C14) is... max (153.97±74.59 ng / mL) is aripiprazole crystal form III (APZF3) (C maxThe concentration of aripiprazole was nearly three times that of 49.87 ± 10.13 ng / mL, and the concentration of aripiprazole-lauric acid eutectic (APZ-C12) and aripiprazole-palmitic acid eutectic (APZ-C16) was also significantly higher. max (APZ-C12: 63.11±14.93 ng / mL, APZ-C16: 97.00±18.33) are respectively aripiprazole crystal form III (APZF3)(C max The levels were 1.3 and 1.9 times higher than those of 49.87 ± 10.13 ng / mL.

[0182] The area under the plasma concentration-time curve was calculated to determine the bioavailability (AUC) of the aripiprazole-myristic acid cocrystal (APZ-C14), which exhibits the best in vitro powder dissolution properties compared to the aripiprazole crystal form III (APZF3) group, under the same dosage conditions. 0-24h The AUC (50811.80±8214.94 ng / mL*min) was significantly increased, which is higher than that of the aripiprazole crystal form III (APZF3) group. 0-24h (38697.01±1181.69ng / mL*min) is 1.3 times that of the previous dose.

[0183] Table 4. Pharmacokinetic parameters of aripiprazole-fatty acid cocrystal and aripiprazole crystal form III in rats.

[0184]

[0185] In summary, this invention employs a drug co-crystallization strategy to prepare a novel series of aripiprazole-fatty acid co-crystallies using biocompatible fatty acids as ligands without altering drug efficacy. Crystal structure analysis reveals that the designed series of drug co-crystallies possess well-defined co-crystallized crystal structures. Compared to commercially available aripiprazole crystal form III, the physicochemical properties and drug release behavior of this series of drug co-crystallies are significantly improved, including solubility, dissolution rate, stability, and bioavailability. Furthermore, the properties of the drug co-crystallies exhibit a favorable monotonic variation trend with alkane chain length, allowing for the design of drugs with desired properties by selecting fatty acids with appropriate alkane chain lengths as ligands. In addition, this series of drug co-crystallies exhibits good stability, and the preparation method is convenient and economical, facilitating industrial production.

Claims

1. An aripiprazole-decanoic acid eutectic, characterized in that, It belongs to the triclinic crystal system. Space group; cell parameters are a = 7.6061(8) Å, b = 10.8563(12) Å, c = 21.0839(17) Å, α = 81.285(4) °, β = 82.440(5) °, γ = 74.182(4) °; where the molar ratio of aripiprazole to decanoic acid is 1:

1.

2. The aripiprazole-decanoic acid eutectic according to claim 1, characterized in that, With diffraction angle 2 θ ± 0.2 ° indicates that there are characteristic diffraction peaks at 4.16 °, 8.32 °, 16.72 °, 19.74 °, and 22.24 °.

3. The aripiprazole-decanoic acid eutectic according to claim 1, characterized in that, It has a characteristic melting peak at 75.3 ± 0.5 °C.

4. An aripiprazole-lauric acid eutectic, characterized in that, It belongs to the triclinic crystal system. Space group; cell parameters are a = 7.6053(4) Å, b = 10.6506(4) Å, c = 22.6719(10) Å, α = 91.364(2) °, β = 98.872(2) °, γ = 106.0730(10) °; wherein the molar ratio of aripiprazole to lauric acid is 1:

1.

5. The aripiprazole-lauric acid eutectic according to claim 4, characterized in that, With diffraction angle 2 θ ± 0.2 ° indicates that there are characteristic diffraction peaks at 3.90 °, 7.82 °, 9.64 °, 15.7 °, 18.14 °, 20.76 °, 21.54 °, 23.62 °, and 24.44 °.

6. The aripiprazole-lauric acid eutectic according to claim 4, characterized in that, It has a characteristic melting peak at 80.5 ± 0.4 °C.

7. An aripiprazole-myristic acid eutectic, characterized in that, It belongs to the triclinic crystal system. Space group; cell parameters are a = 7.6205(3) Å, b = 10.6527(4) Å, c = 23.7460(9) Å, α = 95.2340(10) °, β = 93.7410(10) °, γ = 106.2470(10) °; wherein the molar ratio of aripiprazole to myristic acid is 1:

1.

8. The aripiprazole-myristic acid eutectic according to claim 7, characterized in that, With diffraction angle 2 θ ± 0.2 ° indicates that there are characteristic diffraction peaks at 3.72 °, 7.43 °, 14.90 °, 17.18 °, 18.22 °, 18.67 °, 23.10 °, 26.52 °, and 27.82 °.

9. The aripiprazole-myristic acid eutectic according to claim 7, characterized in that, It has a characteristic melting peak at 85.3 ± 0.3 °C.

10. An aripiprazole-palmitic acid eutectic, characterized in that, It belongs to the triclinic crystal system. Space group; cell parameters are a = 10.8806(6) Å, b = 22.3137(13) Å, c = 26.0163(15) Å, α = 70.367(2) °, β = 80.901(2) °, γ = 78.615(2) °; where the molar ratio of aripiprazole to palmitic acid is 1:

1.

11. The aripiprazole-palmitic acid eutectic according to claim 10, characterized in that, With diffraction angle 2 θ ± 0.2 ° indicates that there are 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 °.

12. The aripiprazole-palmitic acid eutectic according to claim 10, characterized in that, It has a characteristic melting peak at 87.1 ± 0.3 °C.

13. A method for preparing a eutectic according to any one of claims 1 to 12, characterized in that, Choose from any of the following methods: Method 1: Prepare a suspension of aripiprazole and fatty acids, stir, remove the solvent, and obtain the eutectic. Method 2: Dissolve aripiprazole in fatty acids, filter, remove solvent from the filtrate, and crystallize to obtain the eutectic. Method 3: Dissolve aripiprazole in fatty acids, then mix with an antisolvent, remove the solvent, and obtain the eutectic. Method 4: Heat aripiprazole and fatty acids until they melt, then cool to obtain the eutectic. Method 5: Dissolve aripiprazole in fatty acids, cool, and remove the solvent to obtain the eutectic. Method 6: Mix and grind aripiprazole with fatty acids to obtain the eutectic. The fatty acid is selected from decanoic acid, lauric acid, myristic acid, or palmitic acid.

14. A pharmaceutical composition, characterized in that, The eutectic as described in any one of claims 1 to 12 is used as the active ingredient.

15. The use of a eutectic as described in any one of claims 1 to 12 or a pharmaceutical composition as described in claim 14 in the preparation of a medicament for the prevention and / or treatment of schizophrenia, bipolar disorder, depression, autism, and Tourette syndrome.

16. The application according to claim 15, characterized in that, The medications mentioned are for the prevention and / or treatment of mania, mixed episodes of bipolar disorder, autism-related hypersensitivity, childhood autism-related irritability, and postpartum depression.

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