Molecular complex of lenvatinib and a preparation method thereof

Abstract

This invention relates to a lenvatinib molecular complex and its preparation method. Specifically, this invention discloses a lenvatinib molecular complex that exhibits excellent solubility and hygroscopicity, effectively improving the absorption and bioavailability of the resulting drug, and facilitating drug production, storage, and subsequent formulation processing. This invention also provides a method for preparing the complex, which is characterized by its simple process, stable and reliable quality, and suitability for industrial production.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to the lenvatinib molecular complex and its preparation method. Background Technology

[0002] Lenvatinib (LEN), codenamed E7080, is also known as lenvatinib. Its chemical name is 4-[3-chloro-4-(N'-cyclopropylurea)phenoxy]-7-methoxyquinoline-6-carboxamide (structure as shown). Figure 1 As shown, lenvatinib (LEM) is a multi-target receptor kinase inhibitor developed and marketed by Eisai. It exerts its anti-tumor effect by inhibiting the activity of VEGFR 1, 2, 3, FGFR 1, 2, 3, 4, and PDGF-Rα, RET, and KIT kinases, which are associated with tumor growth and pathogenic angiogenesis. In 2015, lenvatinib mesylate (LEM), marketed as Lenvatinib, was approved by the FDA. Lenvatinib is a capsule formulation used to treat solid tumors, differentiated thyroid cancer, and other malignancies. For example, lenvatinib has proven effective in treating advanced thyroid cancer, even though the prognosis remains very poor. A year later, the FDA approved LEM in combination with everolimus for the treatment of advanced renal cell carcinoma; this combination therapy showed manageable toxicity and better efficacy compared to monotherapy. In 2018, lenvatinib mesylate was approved as a first-line treatment for unresectable hepatocellular carcinoma (HCC). Sorafenib was the first systemic therapy for HCC, and lenvatinib mesylate was the first approved first-line treatment for HCC after sorafenib, providing a better option for HCC patients. my country has a large number of hepatitis B patients, and for hepatitis B virus-positive liver cancer patients, lenvatinib mesylate has a significant advantage over sorafenib. However, lenvatinib mesylate has many adverse reactions, including fatigue, nausea, headache, decreased appetite, vomiting, hypertension, proteinuria, joint pain, and palmoplantar erythema syndrome. Therefore, adverse reactions need to be monitored after taking lenvatinib mesylate.

[0003] LEN has poor solubility, bioavailability, and stability. Numerous companies have conducted extensive research on various salts of LEN and their polymorphs, solvates, and amorphous forms, hoping to improve its properties through solid-state chemistry. Eisai disclosed a series of LEN salts and their polymorphs in its original patent WO 2005063713 A1, ultimately choosing mesylates as the product for market. The patent discloses several polymorphs of mesylates: crystal forms A, B, and C (anhydrous), crystal form F (hydrate), crystal form I (acetic acid compound), and dimethyl sulfoxide compound. Crystal form A has lower solubility than crystal form C; crystal form B can transform into crystal form C under high humidity or high temperature conditions; crystal form F has poorer thermodynamic stability than crystal form C; and crystal form I, being an acetate compound, is highly hygroscopic and unstable. The pharmaceutically acceptable crystal form of mesylate is crystal form C, and the lenvatinib mesylate API used in this patent is also crystal form C.

[0004] Because the original patent selected methanesulfonates, subsequent patents have also focused on methanesulfonates. In addition to the three anhydrous crystalline forms mentioned above, many novel anhydrous crystalline forms of methanesulfonates have been disclosed in the patents, such as crystalline form H2O-1 (WO 2018054792 A1) published by Nicola, crystalline form M (WO 2016184436 A1) published by Suzhou Jingyun, and crystalline form 1 (WO 2018196687 A1) published by Suzhou Keruisi. Among these, crystalline forms M and crystalline form 1 show improved solubility, which may indicate improved drug efficacy.

[0005] In addition, various patents disclose solvates of lenvatinib mesylate, such as dimethyl sulfoxide (CN109867626 A), water, acetic acid, chloroform, formic acid, ethyl acetate (WO 2018054792 A1), and methyl isobutyl ketone (WO2018122780 A1). Among them, the dimethyl sulfoxide solvate exhibits excellent chemical stability and better flowability. However, the suitability of solvates as pharmaceutical crystal forms is limited by the type and amount of solvent.

[0006] Currently, most of the LEN salt types mentioned in the patents focus on commercially available methanesulfonates. However, when the reaction medium is an alcohol, especially a lower alcohol such as isopropanol, ethanol, and methanol, methanesulfonates are prone to forming alkyl methanesulfonates, which have genotoxic and carcinogenic effects.

[0007] Therefore, current research on lenvatinib focuses on selecting a more suitable ligand to enhance its solubility, thereby further improving drug bioavailability and reducing the incidence of adverse reactions. Summary of the Invention

[0008] The purpose of this invention is to provide a type of lenvatinib complex with excellent solubility and hygroscopicity and a method for preparing the same.

[0009] In a first aspect, the present invention provides a lenvatinib molecular complex, said complex being a complex of lenvatinib and a substance selected from the group consisting of: sulfadiazine, salicylic acid, maleic acid, mucoic acid, and baicalein.

[0010] In another preferred embodiment, the composite is a crystal.

[0011] In another preferred embodiment, the molar ratio of lenvatinib to substance A in the complex is 1:0.98-1.05, preferably 1:1.

[0012] In another preferred embodiment, the complex is lenvatinib-sulfamethazine, and the lenvatinib-sulfamethazine has one or more characteristics selected from the group consisting of:

[0013] 1) The molar ratio of lenvatinib to sulfamethazine is 1:1;

[0014] 2) The lenvatinib-sulfamethazine is a crystal, and its XRPD spectrum has diffraction peaks at three or more 2θ values ​​selected from the group consisting of: 14.8±0.2°, 20.9±0.2°, 23.3±0.2°, 16.9±0.2°, 23.9±0.2°, 4.9±0.2°, 19.2±0.2°, 15.3±0.2°, and 27.7±0.2°.

[0015] 3) The lenvatinib-sulfamethazine described herein is a monoclinic crystal system;

[0016] 4) The space group of the lenvatinib-sulfamethazine is P2. 1 / C ;

[0017] 5) The lattice parameters of the lenvatinib-sulfamethazine are as follows: α=90°, β=102.3000(10)°, γ=90°;

[0018] 6) The lenvatinib-sulfamethazine described herein has the basic properties as follows: Figure 3 The DSC spectrum shown;

[0019] 7) The lenvatinib-sulfamethazine described herein has the basic properties as follows: Figure 4 The TGA spectrum shown.

[0020] In another preferred embodiment, the XRPD spectrum of the lenvatinib-sulfamethazine has diffraction peaks at six or more 2θ values ​​selected from the group consisting of: 14.8±0.2°, 20.9±0.2°, 23.3±0.2°, 16.9±0.2°, 23.9±0.2°, 4.9±0.2°, 19.2±0.2°, 15.3±0.2°, and 27.7±0.2°.

[0021] In another preferred embodiment, the XRPD spectrum of the lenvatinib-sulfamethazine has diffraction peaks at nine or more 2θ values ​​selected from the group consisting of: 14.8±0.2°, 20.9±0.2°, 23.3±0.2°, 16.9±0.2°, 23.9±0.2°, 4.9±0.2°, 19.2±0.2°, 15.3±0.2°, 27.7±0.2°, 21.4±0.2°, 6.4±0.2°, 22.6±0.2°, 26.1±0.2°, 29.8±0.2°, 13.7±0.2°, 32.3±0.2°, 17.9±0.2°, 25.4±0.2°, and 25.2±0.2°.

[0022] In another preferred embodiment, the XRPD spectrum of the lenvatinib-sulfamethazine exhibits diffraction peaks at the following 2θ values: 14.8±0.2°, 20.9±0.2°, 23.3±0.2°, 16.9±0.2°, 23.9±0.2°, 4.9±0.2°, 19.2±0.2°, 15.3±0.2°, 27.7±0.2°, 21.4±0.2°, 6.4±0.2°, 22.6±0.2°, 26.1±0.2°, 29.8±0.2°, 13.7±0.2°, 32.3±0.2°, 17.9±0.2°, 25.4±0.2°, 25.2±0.2°, 22.0±0.2°. 9.5±0.2°, 16.5±0.2°, 19.6±0.2°, 10.6±0.2°, 13.1±0.2°, 24.5±0.2°, 26.9±0.2°, 19.7±0.2°, 12.7±0.2°, 26.7±0.2°, 8.1±0.2°, 15.7±0.2°, 18.8±0.2°, 31.0±0.2° 26.4±0.2°, 31.6±0.2°, 36.4±0.2°, 37.1±0.2°, 29.1±0.2°, 24.3±0.2°, 38.7±0.2°, 30.3±0.2°, 40.3±0.2°, 28.7±0.2°, 38.9±0.2°, 40.1±0.2°, 34.3±0.2°, 36.9±0.2°, 13.3±0.2° 35.2±0.2°, 41.4±0.2°, 42.3±0.2°, 28.2±0.2°, 39.4±0.2°, 32.8±0.2°, 41.0±0.2°, 27.3±0.2°, 34.7±0.2°, 35.9±0.2°, 38.2±0.2°, 33.9±0.2°, 33.5±0.2°, 42.7±0.2°, 11.8±0.2°.

[0023] In another preferred embodiment, the XRPD spectrum of the lenvatinib-sulfamethazine exhibits diffraction peaks at the following 2θ values: 14.77°, 20.9°, 23.26°, 16.87°, 23.89°, 4.89°, 19.17°, 15.33°, 27.67°, 21.36°, 6.35°, 22.64°, 26.09°, 29.78°, 13.74°, 32.31°, 17.9°, 25.43°, 25.21°, 22.02°, 9.46°, 16.47°, 19.56°, 10.62°, 13.1°, 24.45°, 26.93°, 19.71°, 12.74°. 26.67°, 8.07°, 15.65°, 18.75°, 30.96°, 26.37°, 31.6°, 36.4°, 37.13°, 29.08°, 24.26°, 38.66°, 30.33°, 40.34°, 28.72°, 38.92°, 40.12°, 34.31°, 36.92°, 13.3°, 35.19°, 41.36°, 42.34°, 28.17°, 39.4°, 32.8°, 41.01°, 27.33°, 34.7°, 35.89°, 38.16°, 33.86°, 33.52°, 42.67°, 11.82°.

[0024] In another preferred embodiment, the lenvatinib-sulfamethazine has essentially the following properties: Figure 2 The XRPD map shown.

[0025] In another preferred embodiment, the complex is lenvatinib-salicylic acid, and the lenvatinib-salicylic acid has one or more characteristics selected from the group consisting of:

[0026] 1) The molar ratio of lenvatinib to salicylic acid is 1:1;

[0027] 2) The lenvatinib-salicylic acid is a crystal, and its XRPD spectrum has diffraction peaks at three or more 2θ values ​​selected from the group consisting of: 10.7±0.2°, 17.9±0.2°, 14.9±0.2°, 12.7±0.2°, 27.1±0.2°, 22.4±0.2°, 24.8±0.2°, 26.4±0.2°, and 25.8±0.2°.

[0028] 3) The lenvatinib-salicylic acid described herein is a monoclinic crystal system;

[0029] 4) The space group of the lenvatinib-salicylic acid is C2 / c;

[0030] 5) The lattice parameters of the lenvatinib-salicylic acid are as follows: α=90°, β=95.9790(10)°, γ=90°;

[0031] 6) The lenvatinib-salicylic acid described herein has the basic properties as follows: Figure 7 The DSC spectrum shown;

[0032] 7) The lenvatinib-salicylic acid described herein has the basic properties as follows: Figure 8 The TGA spectrum shown.

[0033] In another preferred embodiment, the XRPD spectrum of the lenvatinib-salicylic acid has diffraction peaks at six or more 2θ values ​​selected from the group consisting of: 10.7±0.2°, 17.9±0.2°, 14.9±0.2°, 12.7±0.2°, 27.1±0.2°, 22.4±0.2°, 24.8±0.2°, 26.4±0.2°, and 25.8±0.2°.

[0034] In another preferred embodiment, the XRPD spectrum of the lenvatinib-salicylic acid has diffraction peaks at nine or more 2θ values ​​selected from the group consisting of: 10.7±0.2°, 17.9±0.2°, 14.9±0.2°, 12.7±0.2°, 27.1±0.2°, 22.4±0.2°, 24.8±0.2°, 26.4±0.2°, 25.8±0.2°, 16.1±0.2°, 25.5±0.2°, 27.9±0.2°, 21.8±0.2°, 28.8±0.2°, 19.7±0.2°, 12.4±0.2°, 21.5±0.2°, 28.2±0.2°, and 18.4±0.2°.

[0035] In another preferred embodiment, the XRPD spectrum of the lenvatinib-salicylic acid exhibits diffraction peaks at the following 2θ values: 10.7±0.2°, 17.9±0.2°, 14.9±0.2°, 12.7±0.2°, 27.1±0.2°, 22.4±0.2°, 24.8±0.2°, 26.4±0.2°, 25.8±0.2°, 16.1±0.2°, 25.5±0.2°, 27.9±0.2°, 21.8±0.2°. 28.8±0.2°, 19.7±0.2°, 12.4±0.2°, 21.5±0.2°, 28.2±0.2°, 18.4±0.2°, 27.5±0.2°, 13.1±0.2°, 13.8±0.2°, 20.0±0.2°, 32.1±0.2°, 25.2±0.2°, 20.4±0.2°, 21.0±0.2°, 29.1±0.2°, 9.7±0.2°, 14.3±0.2°, 30.7±0.2°, 7.2±0.2°, 1 5.2±0.2°, 23.9±0.2°, 44.5±0.2°, 14.0±0.2°, 30.4±0.2°, 21.2±0.2°, 33.8±0.2°, 37.3±0.2°, 37.8±0.2°, 16.8±0.2°, 40.2±0.2°, 36.0±0.2°, 34.1±0.2°, 39.6±0.2°, 29.8±0.2°, 33.6±0.2°, 41.0±0.2°, 41.4±0.2°, 30.0±0.2°.

[0036] In another preferred embodiment, the XRPD spectrum of the lenvatinib-salicylic acid exhibits diffraction peaks at the following 2θ values: 10.74°, 17.91°, 14.87°, 12.7°, 27.07°, 22.38°, 24.83°, 26.37°, 25.79°, 16.11°, 25.53°, 27.88°, 21.77°, 28.8°, 19.68°, 12.4°, 21.54°, 28.24°, 18.44°, 27.47°, 13.07°, 13.76°, 20°, 32.14°, 25.23°, 20.4°, 20.96°, 29.14°, 9.69°. 14.31°, 30.66°, 7.15°, 15.16°, 23.88°, 44.53°, 13.97°, 30.44°, 21.24°, 33.82°, 37.32°, 37.76°, 16.83°, 40.21°, 35.95°, 34.05°, 39.64°, 29.76°, 33.63°, 40.96°, 41.43°, 29.98°.

[0037] In another preferred embodiment, the lenvatinib-salicylic acid has essentially the following properties: Figure 6 The XRPD map shown.

[0038] In another preferred embodiment, the complex is lenvatinib-maleic acid, and the lenvatinib-maleic acid has one or more characteristics selected from the group consisting of:

[0039] 1) The molar ratio of lenvatinib to maleic acid is 1:1;

[0040] 2) The lenvatinib-maleic acid is a crystal, and its XRPD spectrum has diffraction peaks at three or more 2θ values ​​selected from the group consisting of: 18.9±0.2°, 8.8±0.2°, 29.26±0.2°, 21.54±0.2°, 10.18±0.2°, 14.52±0.2°, 28.64±0.2°, and 26.58±0.2°.

[0041] In another preferred embodiment, the XRPD spectrum of the lenvatinib-maleic acid has diffraction peaks at six or more 2θ values ​​selected from the group consisting of: 18.9±0.2°, 8.8±0.2°, 29.26±0.2°, 21.54±0.2°, 10.18±0.2°, 14.52±0.2°, 28.64±0.2°, 26.58±0.2°, 19.88±0.2°, 18.02±0.2°, 19.32±0.2°, 15.76±0.2°, 13.88±0.2°, and 22.62±0.2°.

[0042] In another preferred embodiment, the XRPD spectrum of the lenvatinib-maleic acid has diffraction peaks at nine or more 2θ values ​​selected from the group consisting of: 18.9±0.2°, 8.8±0.2°, 29.26±0.2°, 21.54±0.2°, 10.18±0.2°, 14.52±0.2°, 28.64±0.2°, 26.58±0.2°, 19.88±0.2°, 18.02±0.2°, 19.32±0.2°, 15.76±0.2°, 13.88±0.2°, and 22.62±0.2°.

[0043] In another preferred embodiment, the XRPD pattern of the lenvatinib-maleic acid exhibits diffraction peaks at the following 2θ values: 18.9±0.2°, 8.8±0.2°, 29.26±0.2°, 21.54±0.2°, 10.18±0.2°, 14.52±0.2°, 28.64±0.2°, 26.58±0.2°, 19.88±0.2°, 18.02±0.2°, 19.32±0.2°, 15.76±0.2°, 13.88±0.2°, 22.62±0.2°, 6.14±0.2°, 31.2±0.2°, 34.58±0.2°, 39.02±0.2°. 12.24±0.2°, 41.32±0.2°, 38.61±0.2°, 17.14±0.2°, 30.47±0.2°, 6.72±0.2°, 43.16±0.2°, 40.57±0.2°, 36.88±0.2°, 9.58±0.2°.

[0044] In another preferred embodiment, the lenvatinib-maleic acid has essentially the following properties: Figure 10 The XRPD map shown.

[0045] In another preferred embodiment, the complex is lenvatinib-mucin, and the lenvatinib-mucin has one or more characteristics selected from the group consisting of:

[0046] 1) The molar ratio of lenvatinib to mucin is 1:1;

[0047] 2) The lenvatinib-mucolytic acid is a crystal, and its XRPD spectrum has diffraction peaks at three or more 2θ values ​​selected from the group consisting of: 7.74±0.2°, 19.34±0.2°, 11.94±0.2°, 10.38±0.2°, 10.96±0.2°, 30.5±0.2°, 21.86±0.2°, 28.32±0.2°, 28.04±0.2°, 18.48±0.2°, and 21.42±0.2°.

[0048] In another preferred embodiment, the XRPD pattern of the lenvatinib-mucin has diffraction peaks at six or more 2θ values ​​selected from the group consisting of: 7.74±0.2°, 19.34±0.2°, 11.94±0.2°, 10.38±0.2°, 10.96±0.2°, 30.5±0.2°, 21.86±0.2°, 28.32±0.2°, 28.04±0.2°, 18.48±0.2°, and 21.42±0.2°.

[0049] In another preferred embodiment, the XRPD pattern of the lenvatinib-mucin has diffraction peaks at nine or more 2θ values ​​selected from the group consisting of: 7.74±0.2°, 19.34±0.2°, 11.94±0.2°, 10.38±0.2°, 10.96±0.2°, 30.5±0.2°, 21.86±0.2°, 28.32±0.2°, 28.04±0.2°, 18.48±0.2°, 21.42±0.2°, 24.2±0.2°, 26.6±0.2°, 37.37±0.2°, 23.14±0.2°, 34.2±0.2°. 36.86±0.2°, 32.18±0.2°, 34.66±0.2°, 15±0.2°.

[0050] In another preferred embodiment, the XRPD spectrum of the lenvatinib-mucin exhibits diffraction peaks at the following 2θ values: 7.74±0.2°, 19.34±0.2°, 11.94±0.2°, 10.38±0.2°, 10.96±0.2°, 30.5±0.2°, 21.86±0.2°, 28.32±0.2°, 28.04±0.2°, 18.48±0.2°, 21.42±0.2°, 24.2±0.2°. 26.6±0.2°, 37.37±0.2°, 23.14±0.2°, 34.2±0.2°, 36.86±0.2°, 32.18±0.2°, 34.66±0.2°, 15±0.2°, 25.76±0.2°, 22.53±0.2°, 20.16±0.2°, 44.26±0.2°, 25.5±0.2°, 28.87±0.2°, 12.7±0.2°, 29.5±0.2°, 39.56±0.2°, 40.66±0.2°, 3.72±0.2°, 43.82±0.2°.

[0051] In another preferred embodiment, the lenvatinib-mucin has essentially the following properties: Figure 11 The XRPD map shown.

[0052] In another preferred embodiment, the complex is lenvatinib-baicalein, and the lenvatinib-baicalein has one or more characteristics selected from the group consisting of:

[0053] 1) The molar ratio of lenvatinib to baicalein is 1:1;

[0054] 2) The lenvatinib-baicalein is a crystal, and its XRPD spectrum has diffraction peaks at three or more 2θ values ​​selected from the group below: 18.82±0.2°, 15.66±0.2°, 13.96±0.2°, 12.26±0.2°, 17.84±0.2°, 29.2±0.2°, 10.1±0.2°, 21.46±0.2°, 13.56±0.2°, 8.48±0.2°, 28.54±0.2°, 9.54±0.2°;

[0055] 3) The lenvatinib-baicalein described herein has the basic properties as follows: Figure 13 The DSC spectrum shown;

[0056] 4) The lenvatinib-baicalein described herein has the basic properties as follows: Figure 14 The TGA spectrum shown.

[0057] In another preferred embodiment, the XRPD spectrum of the lenvatinib-baicalein has diffraction peaks at six or more 2θ values ​​selected from the group consisting of: 18.82±0.2°, 15.66±0.2°, 13.96±0.2°, 12.26±0.2°, 17.84±0.2°, 29.2±0.2°, 10.1±0.2°, 21.46±0.2°, 13.56±0.2°, 8.48±0.2°, 28.54±0.2°, and 9.54±0.2°.

[0058] In another preferred embodiment, the XRPD spectrum of the lenvatinib-baicalein has diffraction peaks at nine or more 2θ values ​​selected from the group consisting of: 18.82±0.2°, 15.66±0.2°, 13.96±0.2°, 12.26±0.2°, 17.84±0.2°, 29.2±0.2°, 10.1±0.2°, 21.46±0.2°, 13.56±0.2°, 8.48±0.2°, 28.54±0.2°, 9.54±0.2°, 25.84±0.2°, 6.06±0.2°, 28.82±0.2°, 20.94±0.2°, 24.92±0.2°, and 26.49±0.2°.

[0059] In another preferred embodiment, the XRPD spectrum of the lenvatinib-baicalein exhibits diffraction peaks at the following 2θ values: 18.82±0.2°, 15.66±0.2°, 13.96±0.2°, 12.26±0.2°, 17.84±0.2°, 29.2±0.2°, 10.1±0.2°, 21.46±0.2°, 13.56±0.2°, 8.48±0.2°, 28.54±0.2°, 9.54±0.2°, 25.84±0.2°, 6.06±0.2°, 28.82±0.2°, 20.94±0.2°, 24.92±0.2°. 26.49±0.2°, 11.52±0.2°, 19.26±0.2°, 24.1±0.2°, 24.37±0.2°, 30.8±0.2°, 7.74±0.2°, 36.38±0.2°, 14.76±0.2°, 9.04±0.2°, 12.86±0.2°, 38.96±0.2°, 3.66±0.2°.

[0060] In another preferred embodiment, the lenvatinib-baicalein has essentially the following properties: Figure 12 The XRPD map shown.

[0061] A second aspect of the present invention provides a method for preparing the complex described in the first aspect of the present invention, comprising the following steps:

[0062] 1) Provide lenvatinib, substance A, and a first solvent;

[0063] 2) Mix the lenvatinib, substance A, and the first solvent to obtain a first mixture;

[0064] 3) Allow to stand and evaporate to obtain the first solid;

[0065] 4) Dry the first solid to obtain the composite.

[0066] In another preferred embodiment, the first solvent is selected from the group consisting of methanol, water, or combinations thereof.

[0067] In another preferred embodiment, the molar ratio of lenvatinib to substance A in the first mixture is 1:1.

[0068] In another preferred embodiment, the mass-to-volume ratio of lenvatinib in the first mixture is 2-10 mg / mL, more preferably 3-8 mg / mL, and even more preferably 5-6 mg / mL.

[0069] In another preferred embodiment, the following steps are included before step 3):

[0070] 3-1) Optionally heat-treat the product obtained in the preceding steps; preferably, the heat treatment temperature is 50-80°C (more preferably, 55-65°C);

[0071] 3-2) Use ultrasound to dissolve the product obtained in the above steps;

[0072] 3-3) Filter the product obtained in the above steps;

[0073] 3-4) Transfer the product obtained in the above steps to a sample vial and seal it with a puncture.

[0074] In another preferred embodiment, the drying process is carried out at 30-60°C (preferably 35-50°C) for 10-40 hours (preferably 15-30 hours).

[0075] A third aspect of the present invention provides a method for preparing the complex described in the first aspect of the present invention, comprising the following steps:

[0076] 1) Provide lenvatinib, substance A, and a second solvent;

[0077] 2) Mix the lenvatinib, substance A, and the second solvent to obtain a second mixture;

[0078] 3) Stir the second mixture and filter to obtain the second solid;

[0079] 4) Dry the second solid to obtain the composite.

[0080] In another preferred embodiment, the second solvent is methanol.

[0081] In another preferred embodiment, the molar ratio of lenvatinib to substance A in the second mixture is 1:1.

[0082] In another preferred embodiment, the mass-to-volume ratio of lenvatinib in the second mixture is 6-10 mg / mL, more preferably 8-10 mg / mL, and even more preferably 9-10 mg / mL.

[0083] In another preferred embodiment, the stirring is carried out at 10-40°C (preferably 15-30°C) for 10-100 h (preferably 15-80 h).

[0084] In another preferred embodiment, the drying process is carried out at 30-60°C (preferably 35-50°C) for 10-40 hours (preferably 15-30 hours).

[0085] A fourth aspect of the invention provides a pharmaceutical composition comprising a therapeutically and / or preventively effective amount of one or more of the complexes described in the first aspect of the invention and a pharmaceutically acceptable carrier.

[0086] A fifth aspect of the invention provides the use of the complex described in the first aspect of the invention for preparing a medicament for the prevention and / or treatment of cancer.

[0087] In another preferred embodiment, the cancer is selected from the group consisting of thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, or a combination thereof.

[0088] In another preferred embodiment, the hepatocellular carcinoma is unresectable hepatocellular carcinoma.

[0089] In another preferred embodiment, the cancer is advanced.

[0090] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0091] Figure 1 This is the chemical structure of lenvatinib and its mesylate.

[0092] Figure 2 This is the XRPD spectrum of lenvatinib-sulfamethazine obtained in Example 1.

[0093] Figure 3 This is the DSC spectrum of lenvatinib-sulfamethazine obtained in Example 1.

[0094] Figure 4 This is the TGA spectrum of lenvatinib-sulfamethazine obtained in Example 1.

[0095] Figure 5 It is the structural unit of the lenvatinib-sulfamethazine eutectic single crystal obtained in Example 3.

[0096] Figure 6 This is the XRPD pattern of the lenvatinib-salicylic acid cocrystal obtained in Example 4.

[0097] Figure 7 This is the DSC spectrum of the lenvatinib-salicylic acid eutectic obtained in Example 4.

[0098] Figure 8 This is the TGA spectrum of the lenvatinib-salicylic acid cocrystal obtained in Example 4.

[0099] Figure 9 It is the structural unit of the lenvatinib-salicylic acid eutectic single crystal obtained in Example 6.

[0100] Figure 10 This is the XRPD pattern of the lenvatinib-maleic acid eutectic obtained in Example 7.

[0101] Figure 11 This is the XRPD pattern of the lenvatinib-mucin eutectic obtained in Example 9.

[0102] Figure 12 This is the XRPD pattern of the lenvatinib-baicalein eutectic obtained in Example 11.

[0103] Figure 13 This is the DSC spectrum of the lenvatinib-baicalein eutectic obtained in Example 11.

[0104] Figure 14 This is the TGA spectrum of the lenvatinib-baicalein eutectic obtained in Example 11.

[0105] Figure 15 This is the DVS result obtained in Example 14. Detailed Implementation

[0106] Through long-term and in-depth research, the inventors unexpectedly prepared a lenvatinib complex with excellent solubility and hygroscopicity. Based on this, the inventors completed this invention.

[0107] complex

[0108] Drug cocrystallization technology refers to a method that involves selecting cocrystal ligands or cocrystal formers (CCFs) and active pharmaceutical ingredients (APIs) to self-assemble into new solid forms under the induction of weak intermolecular forces such as hydrogen bonding, π-π stacking interactions, and van der Waals forces. This process alters the physicochemical properties of the active pharmaceutical ingredient, such as solubility, dissolution rate, melting point, pharmacological activity, and stability. The greatest application value of drug cocrystallization lies in its ability to not only alter the molecular structure of the API itself but also improve its physicochemical properties. Furthermore, different cocrystal ligands can influence the properties of the active pharmaceutical ingredient to varying degrees. The emergence of drug cocrystallization opens up a broader prospect for the practical application of APIs in the pharmaceutical field.

[0109] This scheme provides five new lenvatinib cocrystals, namely lenvatinib-sulfamethazine, lenvatinib-salicylic acid, lenvatinib-maleic acid, lenvatinib-mucin, and lenvatinib-baicalein, the structural formulas of which are shown in Table 1.

[0110] Table 1 Eutectic structure of lenvatinib

[0111]

[0112]

[0113] By comparison, the five lenvatinib cocrystals in this invention have better solubility than the commercially available lenvatinib salt mesylate.

[0114] The XRPD pattern of the lenvatinib-sulfamethazine cocrystal shows diffraction peaks at at least 14.77°, 20.9°, 23.26°, 16.87°, 23.89°, 4.89°, 19.17°, 15.33°, 27.67°, 21.36°, 6.35°, and 22.64° at 2θ values, with an error range of ±0.2°. The cocrystal is monoclinic with space group P2. 1 / C , α=90°, β=102.3000(10)°, γ=90°.

[0115] The XRPD pattern of the lenvatinib-salicylic acid eutectic shows diffraction peaks at at least 10.74°, 17.91°, 14.87°, 12.7°, 27.07°, 22.38°, 24.83°, 26.37°, 25.79°, 16.11°, 25.53°, 27.88°, 21.77°, and 28.8°, with an error range of ±0.2° for the 2θ values. The eutectic space group is monoclinic, and the space group is C2 / c. α=90°, β=95.9790(10)°, γ=90°.

[0116] The XRPD pattern of the lenvatinib-maleic acid eutectic has diffraction peaks at least at 2θ values ​​of 8.80, 10.18, 14.52, 18.90, 21.54, and 29.26°, with an error range of ±0.2° for the 2θ values.

[0117] The XRPD pattern of the lenvatinib-mucin cocrystal shows diffraction peaks at least at 2θ values ​​of 7.74, 10.38, 10.96, 11.94, 18.48, 19.34, 21.42, 21.86, 28.04, 28.32, and 30.50°, with an error range of ±0.2° for the 2θ values.

[0118] The XRPD pattern of the lenvatinib-baicalein cocrystal shows diffraction peaks at least at 2θ values ​​of 8.48, 9.54, 10.10, 12.26, 13.56, 13.96, 15.66, 17.84, 18.82, 21.46, and 29.20°, with an error range of ±0.2° for the 2θ values.

[0119] The methods for preparing lenvatinib-sulfamethazine, lenvatinib-salicylic acid, lenvatinib-maleic acid, lenvatinib-mucin, and lenvatinib-baicalein utilize volatile or suspension methods, which are simple and easy to perform.

[0120] The prepared lenvatinib-sulfamethazine, lenvatinib-salicylic acid, lenvatinib-maleic acid, lenvatinib-mucin, and lenvatinib-baicalein have better solubility than lenvatinib, while lenvatinib-sulfamethazine and lenvatinib-salicylic acid have lower hygroscopicity than lenvatinib and its mesylate.

[0121] Composition

[0122] Because the complex of the present invention has excellent anti-tumor activity, it can be used to treat, prevent and alleviate tumor-related diseases.

[0123] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0124] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can interact with and be mixed with the complex of the present invention without significantly reducing the efficacy of the complex. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers. Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0125] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0126] There are no particular limitations on the administration of the complexes or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0127] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active complex is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in the dosage forms of capsules, tablets, and pills.

[0128] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opaque agents, and the release of the active complex or complex in such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active complex may also be formed into microcapsules with one or more of the excipients described above.

[0129] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active complex, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof.

[0130] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0131] In addition to the active complex, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0132] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0133] Dosage forms of the complexes of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as necessary.

[0134] The complex of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0135] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0136] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0137] Compared with the prior art, the present invention has the following main advantages:

[0138] (1) Using a simple and feasible preparation method, lenvatinib eutectic with improved solubility was prepared, which is easy to industrialize and has stable and reliable quality.

[0139] (2) The eutectic with improved solubility described in this invention is beneficial for improving drug absorption and increasing drug bioavailability;

[0140] (3) The complex described in this invention has excellent hygroscopicity, which is beneficial to drug production, storage, and subsequent formulation processing.

[0141] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0142] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0143] General testing methods

[0144] XRPD (X-ray Powder Diffraction)

[0145] Figure 2 , 6 The following conditions were used: a Bruker D8 discovery powder diffractometer was used, which was irradiated with Cu-K (40kV, 40mA), with a scanning range of 2, an interval from 3 to 45, a step size of 0.02, an exposure time of 0.1s per step, and detection at room temperature.

[0146] Figure 10 , 11 The following conditions were used: a Rigaku Ultima IV powder diffractometer was employed, irradiated with a Cu-K irradiator (40 kV, 30 mA), and a D / tex Ultra detector was used at room temperature. The scanning range was from 3 to 45 Å in the 2-meter interval, and the scanning speed was 20 rpm.

[0147] Measurement discrepancies associated with these X-ray powder diffraction (XPD) analysis results are caused by a variety of factors, including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration discrepancies, (d) operator errors (including errors occurring when determining peak positions), and (e) the properties of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in shifts in the same direction for all peaks. When using a flat support, small differences in sample height can lead to large shifts in XRPD peak positions. Systematic studies have shown that a 1 mm sample height difference can result in peak shifts as high as 1° 2θ. These shifts can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the shifts (applying a systematic calibration factor to all peak position values) or by recalibrating the instrument. As mentioned above, measurement errors from different instruments can be corrected by applying a systematic calibration factor to ensure consistent peak positions.

[0148] DSC

[0149] A TA Q2000 differential scanning calorimeter was used in a nitrogen atmosphere with a gas flow rate of 50 mL / min and a heating rate of 10 °C / min.

[0150] TGA

[0151] The TA Q500 thermogravimetric analyzer was used under N2 atmosphere, with a gas flow rate of 50 mL / min and a heating rate of 10 ℃ / min.

[0152] X-ray single crystal diffraction

[0153] A Bruker SMART APEX II single-crystal X-ray diffractometer was used. The test conditions were: wavelength Mo-Kα radiation. The temperature was 170(2)K, the voltage was 50kV, and the current was 30mA. Data reconstruction was performed using the SAINT-5.0 program, and the structure was analyzed using the SHELX-2014 software via the direct method. Refinement was then performed using the full matrix least squares technique. Non-hydrogen atoms were anisotropically corrected; most hydrogen atoms were placed in appropriate positions through theoretical calculations, while a few hydrogen atoms were located using difference Fourier plots. A schematic diagram of the crystal structure was drawn using Mercury 4.3.1 software.

[0154] HPLC

[0155] System: Agilent 1260 high performance liquid chromatograph

[0156] Chromatographic column: SHMADZU VP-ODS C18 column (250mm × 4.6mm)

[0157] Mobile phase: A – Acetonitrile

[0158] B - Ultrapure Water

[0159] A:B = 40:60

[0160] Flow rate: 1.0 mL / min

[0161] Column temperature: 35℃

[0162] Injection volume: 20 μL

[0163] Example 1: Preparation of Lenvatinib-Sulfamethazine Cocrystal

[0164] Weigh LEN (20.00 mg) and SMR (sulfamethazine) (12.38 mg) (molar ratio 1:1), dissolve in 4.0 mL of methanol, heat to 60 °C, and sonicate until clear. Filter the solution through a microporous membrane to obtain a clear liquid, transfer to a 10 mL sample vial, seal and punch a hole, allow to stand for evaporation, filter to precipitate the solid, place in a vacuum drying oven, and dry at 40 °C for 24 h to obtain a white lenvatinib-sulfamethazine eutectic powder.

[0165] X-ray powder diffraction (XRPD) analysis was performed on the lenvatinib-sulfamethazine cocrystal in Example 1, and the results are as follows: Figure 2 As shown in Table 2.

[0166] Table 2 Characteristic diffraction peaks of lenvatinib-sulfamethazine cocrystal

[0167]

[0168]

[0169]

[0170] Differential scanning calorimetry (DSC) analysis was performed on the lenvatinib-sulfamethazine cocrystal in Example 1, and the results are as follows: Figure 3 As shown, the endothermic peak corresponds to the melting process.

[0171] from Figure 3 It can be seen that the lenvatinib-sulfamethazine eutectic has a single endothermic peak in the range of 30-250℃, which corresponds to the melting peak of the lenvatinib-sulfamethazine eutectic. The melting onset temperature is 216.70℃, the peak temperature is 220.63℃, and the melting enthalpy is 142.8J / g.

[0172] Thermogravimetric analysis (TGA) was performed on the lenvatinib-sulfamethazine cocrystal from Example 1, and the results are as follows: Figure 4 As shown in the figure, there is basically no weight loss before the decomposition temperature.

[0173] Example 2: Preparation of lenvatinib-sulfamethazine cocrystal

[0174] A mixture of LEN (20.00 mg) and SMR (12.38 mg) (molar ratio 1:1) was weighed and suspended in 2.0 mL of methanol. After stirring at room temperature for 24 h, the resulting solid powder was filtered and placed in a vacuum drying oven and dried at 40 °C for 24 h to obtain a white lenvatinib-sulfamethazine eutectic powder.

[0175] Example 3: Preparation of lenvatinib-sulfamethazine eutectic single crystal

[0176] Weigh 10.00 mg of the lenvatinib-sulfamethazine eutectic powder obtained in Example 1 into a 10 mL glass container, add 4.0 mL of methanol, and heat to 60 °C to obtain a clear solution. Filter the solution through a microporous membrane to obtain a clear liquid, and transfer it to a 10 mL sample bottle. Seal the bottle and punch a hole. After standing at room temperature for 7 days to evaporate, colorless blocky crystals are obtained, which are the lenvatinib-sulfamethazine eutectic single crystals.

[0177] X-ray single-crystal diffraction was performed on the lenvatinib-sulfamethazine co-crystal single crystal from Example 3, and the resulting lenvatinib-sulfamethazine co-crystal structural unit is shown in the figure. Figure 5As shown, the eutectic space group is monoclinic, and the space group is P2. 1 / C , α=90°, β=102.3000(10)°, γ=90°.

[0178] Example 4: Preparation of Lenvatinib-Salicylic Acid Cocrystal

[0179] Weigh lenvatinib (20.00 mg) and salicylic acid (SA) (6.47 mg) (molar ratio 1:1), dissolve in 4.0 mL of methanol, and sonicate until clear. Filter the solution through a microporous membrane to obtain a clear liquid, transfer it to a 10 mL sample vial, seal and punch a hole, allow to stand for evaporation, filter to precipitate the solid, and place in a vacuum drying oven at 40 °C for 24 h to obtain a white lenvatinib-salicylic acid eutectic powder.

[0180] X-ray powder diffraction (XRPD) analysis was performed on the lenvatinib-salicylic acid eutectic in Example 4, and the results are as follows: Figure 6 As shown in Table 3.

[0181] Table 3 Characteristic diffraction peaks of lenvatinib-salicylic acid eutectic

[0182]

[0183]

[0184] Differential scanning calorimetry (DSC) analysis was performed on the lenvatinib-salicylic acid eutectic in Example 4, and the results are as follows: Figure 7 As shown, the endothermic peak corresponds to the melting and decomposition process.

[0185] from Figure 7 It can be seen that the lenvatinib-salicylic acid eutectic has a single endothermic peak in the range of 20-200℃, which corresponds to the melting peak of the lenvatinib-salicylic acid eutectic. The melting onset temperature is 164.61℃, the peak temperature is 167.12℃, and the melting enthalpy is 73.06J / g.

[0186] Thermogravimetric analysis (TGA) was performed on the lenvatinib-salicylic acid eutectic from Example 4, and the results are as follows: Figure 8 As shown in the figure, there is basically no weight loss before the decomposition temperature.

[0187] Example 5: Preparation of Lenvatinib-Salicylic Acid Cocrystal

[0188] The mixture of lenvatinib (20.00 mg) and salicylic acid (6.47 mg) (molar ratio 1:1) was weighed and suspended in 2.0 mL of methanol. After stirring at room temperature for 72 h, the suspension was filtered and placed in a vacuum drying oven and dried at 40 °C for 24 h to obtain white lenvatinib-salicylic acid powder.

[0189] Example 6: Preparation of Lenvatinib-Salicylic Acid Co-crystal Single Crystal

[0190] Weigh 10.00 mg of the lenvatinib-salicylic acid eutectic powder obtained in Example 4 into a 10 mL container, add 2.0 mL of methanol, and heat to 60 °C to obtain a clear solution. Filter the solution through a microporous membrane to obtain a clear liquid, and transfer it to a 10 mL sample bottle. Seal the bottle and punch a hole. After standing at room temperature for evaporation for 1 month, colorless needle-like crystals are obtained, which are the lenvatinib-salicylic acid eutectic single crystals.

[0191] X-ray single-crystal diffraction was performed on the lenvatinib-salicylic acid eutectic single crystal in Example 6. The structural unit of the lenvatinib-salicylic acid eutectic single crystal is as follows: Figure 9 As shown, the eutectic space group is monoclinic, and the space group is C2 / c. α=90°, β=95.9790(10)°, γ=90°.

[0192] Example 7: Preparation of lenvatinib-maleic acid eutectic

[0193] Weigh lenvatinib (20.00 mg) and maleic acid (MLA) (5.44 mg) (molar ratio 1:1), dissolve in 4.0 mL of methanol, heat to 60 °C, and sonicate until clear. Filter the solution through a microporous membrane to obtain a clear liquid, transfer to a 10 mL sample vial, seal and punch a hole, allow to stand for evaporation, filter to precipitate the solid, place in a vacuum drying oven, and dry at 40 °C for 24 h to obtain a white maleic acid eutectic powder.

[0194] X-ray powder diffraction (XRPD) analysis was performed on the lenvatinib-maleic acid eutectic in Example 7, and the results are as follows: Figure 10 As shown in Table 4.

[0195] Table 4 Characteristic diffraction peaks of lenvatinib-maleic acid eutectic

[0196]

[0197]

[0198] Example 8: Preparation of lenvatinib-maleic acid eutectic

[0199] The mixture of lenvatinib (20.00 mg) and maleic acid (5.44 mg) (molar ratio 1:1) was weighed and suspended in 2.0 mL of methanol. After stirring at room temperature for 24 h, the suspension was filtered and placed in a vacuum drying oven and dried at 40 °C for 24 h to obtain a white lenvatinib-maleic acid eutectic powder.

[0200] Example 9: Preparation of lenvatinib-mucin eutectic

[0201] Weigh lenvatinib (20.00 mg) and mucoacid (MCA) (9.85 mg) (molar ratio 1:1), dissolve in 8.0 mL methanol and 1.0 mL purified water, heat to 60 °C but still do not dissolve, centrifuge at 10000 rpm for 1 min, take the supernatant, filter through a microporous membrane to obtain the supernatant, transfer to a 10 mL sample bottle, seal and punch holes, allow to stand to evaporate, filter to precipitate solid, place in a vacuum drying oven, dry at 40 °C for 24 h to obtain white lenvatinib-mucoacid powder.

[0202] X-ray powder diffraction (XRPD) analysis was performed on the lenvatinib-mucin eutectic from Example 9, and the results are as follows: Figure 11 As shown in Table 5.

[0203] Table 5 Characteristic diffraction peaks of lenvatinib-mucin cocrystal

[0204]

[0205]

[0206] Example 10: Preparation of lenvatinib-mucin eutectic

[0207] The mixture of lenvatinib (20.00 mg) and mucin (9.85 mg) (molar ratio 1:1) was weighed and suspended in 2.0 mL of methanol. After stirring at room temperature for 24 h, the suspension was filtered and placed in a vacuum drying oven and dried at 40 °C for 24 h to obtain a white lenvatinib-mucin eutectic powder.

[0208] Example 11 Preparation of Lenvatinib-Baicalein Cocrystal

[0209] Weigh lenvatinib (20.00 mg) and baicalein (BAI) (12.66 mg) (molar ratio 1:1), dissolve in 4.0 mL of methanol, and sonicate until clear. Filter the solution through a microporous membrane to obtain a clear liquid, transfer it to a 10 mL sample vial, seal and punch a hole, allow to stand and evaporate, filter to precipitate the solid, and place in a vacuum drying oven at 40 °C for 24 h to obtain a yellow lenvatinib-baicalein eutectic powder.

[0210] X-ray powder diffraction (XRPD) analysis was performed on the lenvatinib-baicalein cocrystal in Example 11, and the results are as follows: Figure 12 As shown in Table 6.

[0211] Table 6 Characteristic diffraction peaks of lenvatinib-baicalein eutectic

[0212]

[0213] Differential scanning calorimetry (DSC) analysis was performed on the lenvatinib-baicalein cocrystal in Example 11, and the results are as follows: Figure 13 As shown, the endothermic peak corresponds to the melting and decomposition process.

[0214] from Figure 13 It can be seen that the lenvatinib-baicalein eutectic has a single endothermic peak in the range of 30-250℃, which corresponds to the melting peak of the lenvatinib-baicalein eutectic. The melting onset temperature is 204.27℃, the peak temperature is 211.37℃, and the melting enthalpy is 83.15J / g.

[0215] Thermogravimetric analysis (TGA) was performed on the lenvatinib-baicalein eutectic from Example 11, and the results are as follows: Figure 14 As shown in the figure, there is basically no weight loss before the decomposition temperature.

[0216] Example 12 Preparation of lenvatinib-baicalein cocrystal

[0217] The mixture of lenvatinib (20.00 mg) and BAI (baicalein) (12.66 mg) (molar ratio 1:1) was weighed and suspended in 2.0 mL of methanol. After stirring at room temperature for 24 h, the suspension was filtered and placed in a vacuum drying oven and dried at 40 °C for 24 h to obtain a yellow lenvatinib-baicalein eutectic powder.

[0218] Example 13: Determination of the solubility of lenvatinib eutectic

[0219] Excess sample was added to a 10 mL glass container containing 5 mL of pH 4.5 buffer solution and stirred with a magnetic stirrer (300 rpm, 25 ± 0.3 °C). After 24 h, the sample was removed, filtered through a 0.22 μm cellulose acetate membrane, and the concentration of the filtrate was determined by HPLC.

[0220] The solubility in a medium at pH 4.5 is shown in Table 7. Compared with the free base of lenvatinib and the marketed salt form of lenvatinib mesylate, the solubility of the prepared cocrystals was improved to varying degrees. In particular, the solubility of lenvatinib-sulfamethazine (LEN-SMR), lenvatinib-baicalein (LEN-BAI), lenvatinib-maleic acid (LEN-MLA), and lenvatinib-salicylic acid (LEN-SA) were all more than 2 times higher than that of lenvatinib (LEN), and they were able to maintain the cocrystal state. The improved solubility is beneficial to drug absorption, thereby improving drug bioavailability.

[0221] Table 7. Solubility of LEN cocrystal in buffer solution at pH 4.5

[0222]

[0223]

[0224] Example 14: Determination of the hygroscopicity of lenvatinib eutectic

[0225] Approximately 30 mg of sample was accurately weighed onto a DVS built-in balance and analyzed using a Dynamic Moisture Adsorption Analyzer (DVSIntrinsic, Surface Measurement Systems). Temperature: 25℃; Gas: Nitrogen; Gas Flow: 200 ± 70 sccm; Humidity Range (RH%): 0-90-0-90-0%; 10% RH increments. Judgment Criteria: Weight change less than 0.02% within 10 minutes, with a maximum time limit of 360 minutes for each step. DVS results are as follows: Figure 15 The percentage of weight gain is calculated based on the test results.

[0226] Within the RH range of 0-80%, the moisture adsorption percentage of lenvatinib mesylate is lower than that of lenvatinib. However, when RH > 80%, the moisture adsorption percentage increases rapidly, exceeding that of lenvatinib. When the RH reaches 90%, the moisture adsorption percentage is 1.047%, which is 1.34 times that of lenvatinib. The moisture adsorption percentages of lenvatinib-sulfamethazine, lenvatinib-salicylic acid, lenvatinib mesylate, and lenvatinib are 0.3346%, 0.3939%, 1.047%, and 0.7835%, respectively. The hygroscopicity of lenvatinib decreases significantly after forming a eutectic, even lower than that of lenvatinib mesylate. Furthermore, across all RH ranges, the moisture adsorbed by lenvatinib-salicylic acid and lenvatinib-sulfamethazine is <0.5%, demonstrating excellent hygroscopic stability. Furthermore, it was observed that lenvatinib-sulfamethazine and lenvatinib-salicylic acid reversibly lost absorbed water during desorption, without any solid-state transformation or dissociation. A very small hysteresis gap (<0.1%) was observed in both different isotherm comparison plots, indicating that lenvatinib-sulfamethazine and lenvatinib-salicylic acid do not form hydrates even at high RH. Lenvatinib-sulfamethazine and lenvatinib-salicylic acid can be used to reduce the hygroscopicity of lenvatinib, and are superior to the marketed lenvatinib mesylate, which is beneficial for drug production, storage, and subsequent formulation processing.

[0227] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A lenvatinib molecular complex, characterized in that, The complex is a complex of lenvatinib and substance A selected from the group consisting of: sulfamethazine, salicylic acid, and baicalein; The lenvatinib-sulfamethazine is a crystal, and its XRPD spectrum has diffraction peaks at three or more 2θ values ​​selected from the group consisting of: 14.8±0.2°, 20.9±0.2°, 23.3±0.2°, 16.9±0.2°, 23.9±0.2°, 4.9±0.2°, 19.2±0.2°, 15.3±0.2°, and 27.7±0.2°. The lenvatinib-salicylic acid is a crystal, and its XRPD spectrum exhibits diffraction peaks at the following 2θ values: 10.7±0.2°, 17.9±0.2°, 14.9±0.2°, 12.7±0.2°, 27.1±0.2°, 22.4±0.2°, 24.8±0.2°, 26.4±0.2°, 25.8±0.2°, 16.1±0.2°. 25.5±0.2°, 27.9±0.2°, 21.8±0.2°, 28.8±0.2°, 19.7±0.2°, 12.4±0.2°, 21.5±0.2°, 28.2±0.2°, 18.4±0.2°, 27.5±0.2°, 13.1±0.2°, 13.8±0.2°, 20.0±0.2°, 32.1±0 0.2°, 25.2±0.2°, 20.4±0.2°, 21.0±0.2°, 29.1±0.2°, 9.7±0.2°, 14.3±0.2°, 30.7±0.2°, 7.2±0.2°, 15.2±0.2°, 23.9±0.2°, 44.5±0.2°, 14.0±0.2°, 30.4±0.2°, 21.2 ±0.2°, 33.8±0.2°, 37.3±0.2°, 37.8±0.2°, 16.8±0.2°, 40.2±0.2°, 36.0±0.2°, 34.1±0.2°, 39.6±0.2°, 29.8±0.2°, 33.6±0.2°, 41.0±0.2°, 41.4±0.2°, 30.0±0.2°; The lenvatinib-baicalein is a crystal, and its XRPD spectrum has diffraction peaks at three or more 2θ values ​​selected from the group consisting of: 18.82±0.2°, 15.66±0.2°, 13.96±0.2°, 12.26±0.2°, 17.84±0.2°, 29.2±0.2°, 10.1±0.2°, 21.46±0.2°, 13.56±0.2°, 8.48±0.2°, 28.54±0.2°, and 9.54±0.2°. Furthermore, the molar ratio of lenvatinib to substance A is 1:0.98-1.

05.

2. The complex according to claim 1, characterized in that, The complex is lenvatinib-sulfamethazine, and the lenvatinib-sulfamethazine has one or more characteristics selected from the group consisting of: 1) The molar ratio of lenvatinib to sulfamethazine is 1:1; 2) The lenvatinib-sulfamethazine described herein is a monoclinic crystal system; 3) The space group of the lenvatinib-sulfamethazine is P2. 1 / C ; 4) The lattice parameters of the lenvatinib-sulfamethazine are as follows: α=90°, β=102.3000(10)°, γ=90°; 5) The lenvatinib-sulfamethazine has a basic DSC spectrum as shown in Figure 3; 6) The lenvatinib-sulfamethazine has a basic TGA spectrum as shown in Figure 4.

3. The complex according to claim 1, characterized in that, The complex is lenvatinib-salicylic acid, and the lenvatinib-salicylic acid has one or more characteristics selected from the group consisting of: 1) The molar ratio of lenvatinib to salicylic acid is 1:1; 2) The lenvatinib-salicylic acid described herein is a monoclinic crystal system; 3) The space group of the lenvatinib-salicylic acid is C2 / c; 4) The lattice parameters of the lenvatinib-salicylic acid are as follows: α=90°, β=95.9790(10)°, γ=90°; 5) The lenvatinib-salicylic acid has a basic DSC spectrum as shown in Figure 7; 6) The lenvatinib-salicylic acid has a basic TGA spectrum as shown in Figure 8.

4. The complex according to claim 1, characterized in that, The complex is lenvatinib-baicalein, and the lenvatinib-baicalein has one or more characteristics selected from the group consisting of: 1) The molar ratio of lenvatinib to baicalein is 1:1; 2) The lenvatinib-baicalein has a basic DSC spectrum as shown in Figure 13; 3) The lenvatinib-baicalein has a basic TGA spectrum as shown in Figure 14.

5. A method for preparing the lenvatinib molecular complex according to claim 1, characterized in that, Includes the following steps: 1) Provide lenvatinib, substance A, and a first solvent; 2) Mix the lenvatinib, substance A, and the first solvent to obtain a first mixture; 3) Allow to stand and evaporate to obtain the first solid; 4) Dry the first solid to obtain the composite; The first solvent is selected from the group consisting of methanol, water, or combinations thereof.

6. A method for preparing the lenvatinib molecular complex according to claim 1, characterized in that, Includes the following steps: 1) Provide lenvatinib, substance A, and a second solvent; 2) Mix the lenvatinib, substance A, and the second solvent to obtain a second mixture; 3) Stir the second mixture and filter to obtain the second solid; 4) Dry the second solid to obtain the composite; The second solvent is methanol.

7. A pharmaceutical composition, characterized in that, The product comprises one or more of the lenvatinib molecular complexes of claim 1 and a pharmaceutically acceptable carrier, which are effective for treatment and / or prevention.

8. Use of the lenvatinib molecular complex according to claim 1, characterized in that, Used to prepare a drug for the prevention and / or treatment of cancer.

9. The use as described in claim 8, characterized in that, The cancer is selected from the group consisting of thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, or a combination thereof.

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