WO2023098853A1

WO2023098853A1 - Cocrystal of cabozantinib, preparation method therefor and application thereof as drug or in pharmaceutical preparation

Info

Publication number: WO2023098853A1
Application number: PCT/CN2022/136101
Authority: WO
Inventors: 刘晓忠; 郑和校; 李郡; 靳奇峰
Original assignee: 湖南湘源美东医药科技有限公司
Priority date: 2021-12-03
Filing date: 2022-12-02
Publication date: 2023-06-08

Abstract

The present invention relates to a cocrystal of cabozantinib, a preparation method therefor and an application thereof as a drug or in a pharmaceutical preparation, more particularly an application for the treatment of progressive medullary thyroid carcinoma (MTC), kidney cancer, and prostate cancer. The cocrystal has good solubility, better stability and process developability, etc., and the preparation method is simple and low in cost, and has important values for optimization and development of the drug in the future.

Description

Cabozantinib co-crystal, preparation method and application as medicine or in pharmaceutical preparations

technical field

The present invention relates to a co-crystal formed by cabozantinib, a preparation method thereof and its application as a medicine or in a pharmaceutical preparation for the treatment of progressive, metastatic medullary thyroid cancer (MTC) patients, renal cancer and prostate cancer.

technical background

Cabozantinib is an anticancer drug developed by Exelixis. Its indications for the treatment of metastatic medullary thyroid carcinoma and kidney cancer were approved by the FDA in November 2012 and April 2016, respectively. In addition, Its indication for the treatment of liver cancer was also approved by the FDA in January 2019. Cabozantinib is marketed as (S)-malate.

The Chinese patent application CN102388024A of Exeli Axis Company discloses the 1:1 malate of cabozantinib. In 2012, the U.S. FDA approved the company’s cabozantinib malate (1:1) to be launched under the trade name COMETRIQ. WO2015177758 A1 discloses crystal form 1, crystal form 2, crystal form 3 and crystal form 4 of compound I, wherein crystal form 4 is a better crystal form, but this crystal form also has low solubility, fluidity, compressibility, The problem of poor tensile strength and adhesion. Therefore, a large number of experimental studies are still needed to provide more crystal forms and forms with better properties to support the development of drugs.

Cabozantinib, codenamed XL184, is a multi-target small molecule tyrosine kinase inhibitor, including nine targets of MET, VEGFR1 23, ROS1, RET, AXL, NTRK, and KIT. The most common adverse reactions of cabozantinib included: diarrhea (63%), oral inflammation (51%), PPES or hand-foot syndrome (50%), weight loss (48%), decreased appetite (46%), nausea ( 43%), fatigue (41%), mouth pain (36%), hair color change (34%), taste disturbance (34%), high blood pressure (33%), constipation (27%), abdominal pain (27%) , vomiting (24%), weakness (21%), dysarthria (20%), rash (19%), dry skin (19%), headache (18%), hair loss (16%), dizziness (14%) , arthralgia (14%), dysphagia (13%), muscle cramps (12%), erythema (11%), dyspepsia (11%),

Grade 3-4 adverse reactions include: diarrhea (16%), PPES (hand-foot syndrome) (13%), fatigue (9%), hypertension (8%), weakness (6%), oral inflammation (5%) , weight loss (5%), decreased appetite (5%), dysphagia (4%), abdominal pain (3%), oral pain (2%), nausea (2%), dehydration (2%), erythema (1 %), hypotension (1%), rash (1%), arthralgia (1%), musculoskeletal chest pain (1%), nausea (1%).

The most common abnormal laboratory data in the cabozantinib group included: increased AST (86%), increased ALT (86%), decreased lymphocytes (53%), increased ALP (52%), hypocalcemia ( 52%), neutropenia (35%), thrombocytopenia (35%), hypophosphatemia (28%), hyperbilirubin (25%), hypomagnesemia (19%), hypokalemia hyperemia (18%), hyponatremia (10%).

Due to the many side effects of cabozantinib and the relatively high probability of occurrence, it has a greater impact on the efficacy and safety. Therefore, improving the basic structure of cabozantinib drug using co-crystal technology can improve its properties, such as solubility, stability, permeability, and bioavailability. A series of co-crystals of cabozantinib in the present invention with gallic acid, DL-tartaric acid, maleic acid, and piperazine as co-crystal precursors. The co-crystals of the present invention can meet one or more objectives such as but not limited to improved solubility, stability and bioavailability and better safety in pharmaceutical applications.

Contents of the invention

The present invention relates to the co-crystal of cabozantinib and gallic acid, DL-tartaric acid, maleic acid and piperazine.

In some embodiments, the active substance is selected from cabozantinib, and in some embodiments, the co-crystal precursor is selected from gallic acid, DL-tartaric acid, maleic acid, piperazine.

The co-crystals of the present invention are formed when cabozantinib (active pharmaceutical ingredient API) and gallic acid, DL-tartaric acid, maleic acid, piperazine (co-crystal precursor) are bound together by hydrogen bonding. In some embodiments, other non-covalent bonds and covalent interactions may also exist in the co-crystal.

One aspect of the invention contemplates cabozantinib-based co-crystals that provide sufficient levels of bioavailability to be therapeutically effective in pharmaceutical applications and to maintain levels for a therapeutically effective period of time.

Compared with cabozantinib, the cabozantinib co-crystal designed in the present invention has better solubility and stability, is convenient for storage and use; and can be directly used for the preparation of solid preparations, and has good powder properties.

Description of drawings

Figure 1 shows the X-ray powder diffraction (XRPD) pattern of cabozantinib and gallic acid co-crystal.

Figure 2 shows the X-ray powder diffraction (XRPD) patterns of cabozantinib and DL-tartaric acid co-crystals.

Figure 3 shows the X-ray powder diffraction (XRPD) patterns of cabozantinib and maleic acid co-crystals.

Figure 4 shows the X-ray powder diffraction (XRPD) pattern of cabozantinib and piperazine co-crystals.

Figure 5 shows the effect of cabozantinib co-crystals on the survival rate of medullary thyroid cancer cells.

Figure 6 shows the effect of cabozantinib co-crystal on the survival rate of renal cancer cell line 786-O.

Figure 7 shows the effect of cabozantinib co-crystal on the survival rate of prostate cancer cell PC-3.

The invention relates to a co-crystal of cabozantinib and a preparation method thereof. The co-crystal contains cabozantinib and the co-crystal precursors gallic acid, DL-tartaric acid, maleic acid, piperazine.

In some embodiments, cabozantinib and gallic acid are combined in a 1:1 ratio. The co-crystal contained an X-ray diffraction pattern as shown in FIG. 1 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 1 .

In some embodiments, cabozantinib and DL-tartaric acid are combined in a 1:1 ratio. The co-crystal has an XRPD pattern comprised of 10.280°, 11.380°, 13.860°, 15.801°, 17.901°, 20.639°, 22.960°, and 27.881° (rounded to 10.3°, 11.4°, 13.9°, 15.8 °, 17.9°, 20.6°, 23.0° and 27.9°) (corresponding to

d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 10.280°, 11.380°, 13.860°, 15.801°, 17.901°, 20.639°, 22.960°, and 27.881° ± 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 10.280°, 11.380°, 13.860°, 15.801°, 17.901°, 20.639°, 22.960°, and 27.881° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 2 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 2 .

In some embodiments, cabozantinib and maleic acid co-crystal are combined in a 1:1 ratio. The co-crystal had an XRPD pattern comprised of 6.999°, 8.760°, 10.159°, 11.919°, 13.939°, 17.460°, 23.381° and 25.359° (rounded to 7.0°, 8.8°, 10.2°, 11.9°, respectively , 13.9°, 17.5°, 23.4 and 25.4°) (corresponding to

d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 6.999°, 8.760°, 10.159°, 11.919°, 13.939°, 17.460°, 23.381° and 25.359° ± 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 6.999°, 8.760°, 10.159°, 11.919°, 13.939°, 17.460°, 23.381°, and 25.359° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 3 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 3 .

In some embodiments, the cabozantinib and piperazine co-crystals are combined in a 1:2 ratio. The co-crystal has an XRPD pattern. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 4 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 4 .

The co-crystal of the present invention comprises: gallic acid, DL-tartaric acid, maleic acid, piperazine as co-former; and cabozantinib as co-former and active drug Ingredients (APIs).

In some embodiments, cabozantinib and gallic acid, DL-tartaric acid, maleic acid are combined in a 1:1 ratio.

In some embodiments, cabozantinib and maleic acid are combined in a 1:2 ratio.

The solid state of the co-crystal of the present invention is any crystalline polymorph or other mixture. Co-crystals can also be made in amorphous form, which can be combined with any crystalline form. In other embodiments, the solid state of the co-crystal is an amorphous form, different forms of the co-crystal of the present invention can be obtained by different crystallization processes, and the co-crystal can be made into an amorphous form using known techniques.

The co-crystals of the present invention can be prepared by methods comprising:

(a) Dissolving or suspending the gallic acid, DL-tartaric acid, maleic acid, and piperazine respectively in a solvent, optionally heating the solution or dispersion to a temperature higher than room temperature and lower than the boiling point of the solution or dispersion temperature;

Preferably, for the gallic acid, the solvent used is selected from ethanol; for the DL-tartaric acid, the solvent used is selected from isopropanol; for the maleic acid, the solvent used is selected from water; for the piperazine, the solvent used Solvent is selected from ethanol;

(b) adding cabozantinib to dissolve or suspend in a solvent together with or after step (a);

(c) The reaction time can be selected from 0.1-24 hours, during which the temperature described in (a) is kept and stirred;

(d) cooling the solution or dispersion of steps (a), (b), (c) to ambient temperature or below;

(e) optionally evaporating some or all of said solvent; and

(f) The resulting co-crystals are filtered off.

In some embodiments, the specific conditions of the process can be adjusted, and the appropriate ratios are in the following molar ranges: 1:0.1-1:20, 1:0.2-1:20, 1:0.3-1:20, 1:0.3-1:20, 0.4-1:20, 1:0.5-1:20, 1:0.6-1:20, 1:0.7-1:20, 1:0.8-1:20, 1:0.9-1:20, 1:1- 1:20, 1:2-1:20, 1:3-1:20, 1:4-1:20, 1:5-1:20, 1:6-1:18, 1:7-1: 15. 1:8-1:13, 1:9-1:12 or 1:10-1:11. In some embodiments, a suitable ratio is about 1:1 (molar). In some embodiments, the period of time for pulping or stirring the mixture may be in the range of: 0.1-24 hours, 0.2-12 hours, 0.25-6 hours, 0.3-2 hours, 0.4-1 hours, or 0.5-1 hours Hour. In some embodiments, the time period for pulping or stirring the mixture may be about 0.5 hours. In some embodiments, co-crystal compounds can be obtained by drying, filtering, centrifuging, pipetting, or combinations thereof. In some embodiments, co-crystal compounds can be obtained by centrifugation.

Example 1

Add 84.8mg (0.5mmol) of gallic acid and 5ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 50mg (0.1mmol) of cabozantinib, heat to 70°C, stop heating after stirring for 4 hours, and cool to room temperature , spin-dried the solvent, and dried under vacuum at 40°C to obtain the crude co-crystal, which was detected as amorphous by XRPD.

Example 2

Add 33.92mg (0.2mmol) of gallic acid and 12ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 100mg (0.2mmol) of cabozantinib, heat to 70°C, stir for 4 hours and then cool to room temperature naturally. Spin the solvent to dryness, add 5 ml of ethanol, stir for 3 hours, and filter to obtain crude crystals, treat with ethanol and heptane, and dry in vacuum at 40°C to obtain 109.95 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.

Example 3

Add 67.84mg (0.4mmol) of gallic acid and 22ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 200mg (0.4mmol) of cabozantinib, heat to 70°C, stir for 4 hours and then cool to room temperature naturally. The solvent was spin-dried, and 5 ml of ethanol was added, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 231.14 mg of co-crystal. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.

Example 4

Add 101.76mg (0.6mmol) of gallic acid and 30ml of ethanol into a 50ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 300mg (0.6mmol) of cabozantinib, heat to 70°C, stir for 4 hours and then cool to room temperature naturally. Spin the solvent to dryness, add 5ml of ethanol, stir for 3 hours, and filter to obtain crude crystals, treat with ethanol and heptane, and dry in vacuum at 40°C to obtain 357.90 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.

Example 5

Add 149.64mg (1.0mmol) DL-tartaric acid and 10ml isopropanol to a 25ml eggplant-shaped bottle, stir for 0.5 hours, then add 50mg (0.1mmol) cabozantinib, heat to 70°C, stir for 4 hours and then cool naturally to At room temperature, the solvent was spin-dried and dried in vacuum at 40°C to obtain the crude co-crystal, which had characteristic peaks detected by XRPD.

Example 6

Add 29.93mg (0.2mmol) DL-tartaric acid and 5ml isopropanol into a 25ml eggplant-shaped bottle, heat to 70°C, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) cabozantinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with isopropanol and heptane, and dried in vacuum at 40°C to obtain 110.39 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 7

Add 89.78mg (0.6mmol) DL-tartaric acid and 11ml isopropanol to a 25ml eggplant-shaped bottle, heat to 70°C, stir for 0.5 hour to dissolve, add 300mg (0.6mmol) cabozantinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with isopropanol and heptane, and dried in vacuum at 40°C to obtain 329.09 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 8

Add 115.72mg (1.0mmol) of maleic acid and 5ml of water into a 25ml eggplant-shaped bottle, stir for 0.5 hours, then add 50mg (0.1mmol) of cabozantinib, heat to 70°C, stir for 4 hours and then cool to room temperature naturally. The solvent was spin-dried and dried in vacuum at 40°C to obtain the crude co-crystal, which had characteristic peaks detected by XRPD.

Example 9

Add 23.14mg (0.2mmol) of maleic acid and 5ml of water into a 25ml eggplant-shaped bottle, heat to 70°C, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) of cabozantinib, stir for 6 hours and then cool to room temperature naturally. Then, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with water and heptane, and dried under vacuum at 40°C to obtain 101.77 mg of co-crystal. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 10

Add 69.43mg (0.6mmol) of maleic acid and 15ml of water into a 50ml eggplant-shaped bottle, heat to 70°C, stir for 0.5 hours to dissolve, add 300mg (0.6mmol) of cabozantinib, stir for 6 hours and then cool to room temperature naturally. Then, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with water and heptane, and dried under vacuum at 40°C to obtain 326.61 mg of co-crystal. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 11

Add 85.88 mg (1.0 mmol) of piperazine and 8 ml of ethanol in a 25 ml eggplant-shaped bottle, stir for 0.5 hour, then add 50 mg (0.1 mmol) of cabozantinib, heat to 70 ° C, and naturally cool to room temperature after stirring for 4 hours. The solvent was dried and dried under vacuum at 40°C to obtain the crude co-crystal, which was detected as amorphous by XRPD.

Example 12

Add 34.34mg (0.4mmol) of piperazine and 10ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 100mg (0.2mmol) of cabozantinib, heat to 70°C, stir for 4 hours and then cool to room temperature naturally. The solvent was spin-dried, and 5 ml of ethanol was added, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 114.83 mg of co-crystal. It was determined to be amorphous and the ratio was 1:2 by XRPD and HPLC detection.

Example 13

Add 68.68mg (0.8mmol) of piperazine and 15ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 200mg (0.4mmol) of cabozantinib, heat to 70°C, stir for 4 hours and then cool to room temperature naturally. Spin the solvent to dryness, add 5ml of ethanol, stir for 3 hours, and filter to obtain crude crystals, treat with ethanol and heptane, and dry at 40°C in vacuum to obtain 223.54 mg of co-crystals. It was determined to be amorphous and the ratio was 1:2 by XRPD and HPLC detection.

Example 14

Add 103.06mg (0.12mmol) of piperazine and 27ml of ethanol into a 50ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 300mg (0.6mmol) of cabozantinib, heat to 70°C, stir for 4 hours and then cool to room temperature naturally. The solvent was spin-dried, and 10 ml of ethanol was added, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 339.22 mg of co-crystal. It was determined to be amorphous and the ratio was 1:2 by XRPD and HPLC detection.

Example 15

The inhibitory effect of cabozantinib co-crystals on the proliferation of medullary thyroid cancer cells, renal cancer cell line 786-O and prostate cancer cell line PC-3 was detected by MTT method, as shown in Figure 5, Figure 6 and Figure 7, Cabozantinib Nicocrystals can effectively enhance the inhibitory effect on medullary thyroid cancer cells, renal cancer cells 786-O and prostate cancer cells PC-3, which is stronger than cabozantinib itself, and cabozantinib cocrystals can effectively enhance the inhibitory effect on these three cancer cells. The lethality of the cells is stronger, indicating that the cabozantinib co-crystal enhances the anti-tumor effect of the drug and shows a stronger anti-tumor effect.

Comparative example 1

Add 68.85 mg (0.5 mmol) of salicylic acid and 5 ml of water into a 25 ml eggplant-shaped bottle, heat to 70 ° C, stir for 0.5 hours, add 50 mg (0.1 mmol) cabozantinib, and naturally cool to room temperature after stirring for 6 hours. The reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain a crude product, treated with isopropanol and heptane, and dried under vacuum at 40°C to obtain 102.56 mg of a sample. The XRPD detection sample pattern overlapped with the cabozantinib pattern, and no co-crystal was formed.

Comparative example 2

Add 84.8mg (0.5mmol) of gallic acid and 5ml of toluene into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 50mg (0.1mmol) of cabozantinib, heat to 70°C, stop heating after stirring for 4 hours, and cool to room temperature , the solvent was spin-dried, and dried in vacuum at 40°C to obtain a crude co-crystal. The XRPD detection of the sample pattern overlapped with the cabozantinib pattern, and no co-crystal was formed.

Comparative example 3

Add 149.64mg (1.0mmol) DL-tartaric acid and 10ml isopropanol to a 25ml eggplant-shaped bottle, stir for 0.5 hours, then add 50mg (0.1mmol) cabozantinib, react at room temperature (25°C), and stir for 4 hours Naturally cooled to room temperature, spin-dried the solvent, and dried under vacuum at 40°C to obtain a crude co-crystal. The sample pattern overlapped with that of DL-tartaric acid detected by XRPD, and no co-crystal was formed.

Comparative example 4

Add 17.17mg (0.2mmol) of piperazine and 10ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 200mg (0.4mmol) of cabozantinib, heat to 70°C, stir for 4 hours and then cool to room temperature naturally. The solvent was spin-dried, and 5ml of ethanol was added, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 180.96mg of co-crystal. Detected by XRPD that the sample spectrum overlaps with the cabozantinib spectrum, and co-crystals are not formed.

Cabozantinib co-crystal inhibits prostate cancer xenografts in nude mice

PC-3m cells in logarithmic growth phase were treated with 0.25% trypsin digestion solution, washed twice with PBS solution, and the cell suspension density of serum-free medium was adjusted to 1×10 ⁷ /ml. Store in sterile centrifuge tubes and bring them to the animal room with insulation. On an ultra-clean workbench, use a 1ml disposable sterile syringe to inoculate 0.2ml of cell solution per nude mouse subcutaneously in the right quarter, with a cell number of 2×10 ⁶ . Subcutaneous nodules were visible to the naked eye 7 days after inoculation. 14 days after inoculation, the transplanted tumor can be seen to be about 5 mm ² , which means that the modeling is successful.

The rats were randomly divided into 3 groups, 20 in each group. ① 20 rats in the treatment group were given 30 mg/kg (calculated as cabozantinib) cabozantinib and cabozantinib co-crystal for 14 consecutive days. ②The 20 rats in the model group were administered with normal saline (30 mg/kg) for 14 consecutive days after successful modeling. ③The 20 rats in the control group were not modeled, but were only administered with normal saline (30 mg/kg) for 14 consecutive days. At the end of the treatment, the animals were sacrificed, the tumor tissues were dissected, and the tumor tissues of the three groups of rats were weighed and the tumor inhibition rates were calculated. Use a vernier caliper to measure the short diameter (W) and long diameter (L) of the transplanted tumor, and calculate the volume of the tumor: V=W2×L×0.52; tumor inhibition rate (%)=(average tumor mass of the blank tumor-bearing group- Average tumor mass of each experimental group)/average tumor mass of blank tumor-bearing group×100%.

Compared with the control group, the tumor weight and tumor volume in the model group and the treatment group increased significantly; compared with the model group, the tumor weight decreased and the tumor inhibition rate increased significantly in the treatment group. And in the treatment group, the tumor inhibition rate of cabozantinib co-crystal was significantly higher than that of cabozantinib group and L-malate cabozantinib group.

Solubility test

Solubility test data are shown in Table 1.

Table 1

stability test

Stability test data are shown in Table 2-Table 3.

Table 2

table 3

Claims

A co-crystal, forming a co-crystal with cabozantinib as an active substance and other compounds as a co-crystal precursor; wherein, the co-crystal precursor is selected from one or more of the following compounds: DL-tartaric acid, Gallic acid, maleic acid, piperazine.
The co-crystal of claim 1, wherein said cabozantinib is combined with said co-crystal precursor DL-tartaric acid, gallic acid, and maleic acid in a ratio of 1:1, wherein said cabozantinib and said The eutectic precursor piperazine was combined in a 1:2 ratio.
The co-crystal of claim 1 selected from the group consisting of:

Contains a co-crystal of cabozantinib and DL-tartaric acid combined in a 1:1 ratio,

Contains a co-crystal of cabozantinib and gallic acid combined in a 1:1 ratio,

A co-crystal comprising cabozantinib and maleic acid combined in a 1:1 ratio, and

Contains a co-crystal of cabozantinib and piperazine combined in a 1:2 ratio.
The co-crystal of claim 1, which comprises a co-crystal of cabozantinib and DL-tartaric acid combined in a 1:1 ratio, having a range of °, and the X-ray diffraction powder diffraction (XRPD) pattern of the peak at the diffraction angle 2θ of 27.881°±0.2°.
The co-crystal of claim 1, comprising a co-crystal of cabozantinib and gallic acid combined in a 1:1 ratio, having an amorphous X-ray Diffraction Powder Diffraction (XRPD) pattern.
The co-crystal of claim 1 , comprising a co-crystal of cabozantinib and maleic acid combined in a 1:1 ratio, having a range of 6.999°, 8.760°, 10.159°, 11.919°, 13.939°, 17.460°, 23.381 ° and 25.359 ° ± 0.2 ° of diffraction angle 2θ of the peak X-ray diffraction powder diffraction (XRPD) pattern.
The co-crystal of claim 1 , comprising a co-crystal of cabozantinib and piperazine combined in a 1:2 ratio, having an amorphous X-ray Diffraction Powder Diffraction (XRPD) pattern.
A pharmaceutical composition comprising the co-crystal compound according to any one of claims 1-7, optionally further comprising a pharmaceutically acceptable carrier.
The pharmaceutical composition of claim 8, wherein said compound exists in the solid state of any crystalline polymorph or amorphous form or a mixture thereof.
A method for preparing the co-crystal according to claim 9, comprising the steps of:

(a) respectively dissolving or suspending the co-crystal precursor gallic acid, DL-tartaric acid, maleic acid, and piperazine in a solvent, optionally heating the solution or dispersion to a temperature higher than room temperature and lower than that of the solution or the temperature of the boiling point of the dispersion;

Preferably, for the gallic acid, the solvent used is selected from ethanol; for the DL-tartaric acid, the solvent used is selected from isopropanol; for the maleic acid, the solvent used is selected from water; for the piperazine, the solvent used Solvent is selected from ethanol;

(b) adding cabozantinib to dissolve or suspend in a solvent together with or after step (a);

(c) The reaction time can be selected from 0.1-24 hours, during which the temperature described in (a) is kept and stirred;

(d) cooling the solution or dispersion of steps (a), (b), (c) to ambient temperature or below;

(e) optionally evaporating some or all of said solvent; and

(f) The resulting co-crystals are filtered off.
The co-crystal comprising cabozantinib and gallic acid combined at a ratio of 1:1 prepared by the method of claim 10 has an XRPD pattern as shown in FIG. 1 .
The co-crystal comprising cabozantinib and DL-tartaric acid combined at a ratio of 1:1 prepared by the method of claim 10 has an XRPD pattern as shown in FIG. 2 .
The co-crystal comprising cabozantinib and maleic acid combined in a 1:1 ratio prepared by the method of claim 10 has an XRPD spectrum as shown in Figure 3.
The co-crystal comprising cabozantinib and piperazine combined at a ratio of 1:2 prepared by the method of claim 10 has an XRPD pattern as shown in FIG. 4 .
The application of the co-crystal described in any one of claims 1-7 or the pharmaceutical composition described in any one of claims 8-9 in the preparation of medicine, the medicine is used for the treatment of progressive metastatic medullary thyroid carcinoma (MTC ), kidney cancer, prostate cancer.