CN113968822A

CN113968822A - Gefitinib-resveratrol eutectic crystal

Info

Publication number: CN113968822A
Application number: CN202010725153.8A
Authority: CN
Inventors: 翟立海; 张朝花; 余军厚; 王聚聚
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2020-07-24
Filing date: 2020-07-24
Publication date: 2022-01-25
Anticipated expiration: 2040-07-24
Also published as: CN113968822B

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a gefitinib-resveratrol eutectic crystal and a preparation method thereof, wherein the molar ratio of gefitinib to resveratrol in the gefitinib-resveratrol eutectic crystal provided by the invention is 1:1, the gefitinib-resveratrol eutectic provided by the invention has higher solubility and good solubility, is beneficial to improving bioavailability, and has important value for optimization and development of gefitinib preparations.

Description

Gefitinib-resveratrol eutectic crystal

Technical Field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to gefitinib-resveratrol eutectic crystal and a preparation method thereof.

Background

Gefitinib, which is sold as Iressa and has a chemical name of 4- (3-chloro-4-fluorophenylamino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline, is a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor developed by Aslicon, is suitable for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) which is not effective or suitable for chemotherapy by platinum antineoplastic agents and docetaxel chemotherapy in the past, is the 1 st small molecular protein tyrosine kinase inhibitor targeted anticancer drug for treating solid tumors, and is officially released to be marketed in China in 2005 with 2-month approval.

At present, many documents report that gefitinib has a polymorphism problem, and different crystal forms of a drug can directly influence the solubility, dissolution rate, target effect and the like of the drug in vivo so as to influence the exertion of drug effect.

Patent WO9633980a1 discloses for the first time a process for the preparation of gefitinib compounds, but this patent does not specifically disclose whether the compounds prepared are crystalline or amorphous, nor whether the compounds can exist in solvated form.

Patent CN100404032C discloses four crystal forms of gefitinib Form 1 (polymorphic substance), Form 2 (methanol solvate), Form 3(DMSO solvate) and Form 5 (trihydrate) and a preparation method thereof, the patent indicates that Form 1 polymorphic substance can be obtained by separation after Form 3, Form 2 or Form 5 is washed by solvent or solvent mixture, and research shows that Form 1 has good stability and is suitable for solid preparations of gefitinib, such as tablets and capsules, but in the actual preparation process, the Form 1 is obtained with poor reproducibility. Form 2 methanol solvate and Form 3DMSO solvate are both less stable than Form 1, and the content of methanol in the Form 2 crystal Form is about 10 times the pharmacopeia limit (pharmacopeia limit of 0.3%), and the content of DMSO in the Form 3 crystal Form is about 30 times the pharmacopeia limit (pharmacopeia limit of 0.5%), which shows that the Form 2 and Form 3 crystal forms are also easier to prepare, but excessive solvent residue makes them unsuitable for pharmaceutical crystal forms. Form 5 trihydrate is also not as stable as Form 1, is only very stable in water, is suitable for administration in the Form of an aqueous suspension, and greatly limits the application of the Form 5 crystal Form.

Patent WO2006090413A1 discloses a gefitinib Form 6 crystal Form and a preparation method thereof, the preparation method comprises the steps of mixing anhydrous gefitinib with water, stirring for 18-20h at ambient temperature, filtering air and drying to obtain Form 6, the crystal Form is a monohydrate crystal Form, the stability is lower than Form 1, and the problem of application limitation similar to Form 5 crystal Form also exists.

Patent CN103896863B discloses a new Form 7 Form of gefitinib crystal Form and a preparation method thereof, and researches the pharmacokinetics of the crystal Form in a rat body, and the result shows that the pharmacokinetic parameters of the crystal Form and the Form 1 crystal Form sold on the market are not obviously different, but other properties of the crystal Form are not researched.

Patent CN103896861A discloses amorphous gefitinib, i.e. Form8 Form and preparation method thereof, but generally can not be selected as medicinal crystal Form due to the physicochemical defect of amorphous substance.

Patent CN104693127B discloses a gefitinib ethylene glycol solvate and a preparation method thereof, but researches have found that the content of ethylene glycol in the crystal is about 300 times (0.062%) of the pharmacopeia limit, and the crystal form is also not suitable for being used as a medicinal crystal form due to the high residual amount of organic solvent.

Patent WO2014016848 mentions that gefitinib and p-hydroxybenzoic acid can form a eutectic, but does not provide a corresponding preparation method, and does not study the properties of the eutectic, and the inventors have not succeeded in obtaining the eutectic of gefitinib and p-hydroxybenzoic acid described in the patent by trying a plurality of methods in research.

Patent WO2015170345 refers to co-crystals of gefitinib and malonic acid, but studies have found that the preparation method is poorly reproducible, and the co-crystals reported in the patent have poor solubility characteristics compared to the existing gefitinib crystal forms.

Patent 201910657224.2 discloses a co-crystal compound of resveratrol and a protein kinase inhibitor and a composition containing the co-crystal compound, wherein the co-crystal compound of resveratrol and gefitinib is formed in a molar ratio of 1.041, and the specification example 3 discloses the preparation of a co-crystal compound of resveratrol and gefitinib: 446.9g of resveratrol and 100g of gefitinib are taken, a screw rod of a hot melt extruder (ZE-16 twin-screw hot melt extruder, ATS (advanced technology systems) Limited) is sequentially divided into modules 1-6 from left (feeding port) to right, and Zone 1-6 represents 6 temperature areas which can be set, and the processes of feeding, transmission, melt mixing and output are sequentially executed. The temperature of the modules 1-6 is 135 ℃, 165 ℃, 215 ℃, 260 ℃, 190-191.4 ℃ in sequence, the rotating speed is 10r/min, and the feeding is carried out at the speed of 3g/min after the temperature is stabilized for 10 min. Collecting the extrudate, grinding the extrudate, and screening the extrudate by using a 82-mesh sieve to obtain 999.793g of white-like solid with the melting point of 170.2-171.5 ℃. Recrystallizing with methanol, and drying to obtain 998.889g of white solid, wherein the melting point is 120-121 ℃, and the R value is 1.041. The experimental feeding is as follows: 446.9g of resveratrol and 100g of gefitinib, but 998.889g of white solid is obtained after recrystallization and drying by methanol, which does not meet the material conservation rule.

Although the existing literature discloses a plurality of gefitinib crystal forms, the systematic research on the crystal forms is still to be perfected, and particularly, the comprehensive research on gefitinib eutectic compounds is not reported. The new salt form of pharmaceutical co-crystal is a supermolecular crystal with fixed stoichiometric ratio formed by introducing a new co-crystal substance (CCF) through proton transfer and self-assembling with Active Pharmaceutical Ingredients (API) under the action of hydrogen bonds. Due to potential advantages in terms of dissolution, permeation, moisture absorption, stability, etc., drug co-crystals are of increasing interest to researchers in the field of drug preparation.

Disclosure of Invention

In view of the defects of the prior art, the invention provides a gefitinib-resveratrol eutectic crystal.

The eutectic formation substance is resveratrol, and the structural formula is as follows:

according to the first aspect of the invention, Cu-Kalpha radiation is used, and an X-ray diffraction spectrum represented by 2 theta has characteristic peaks at 4.23 +/-0.2 degrees, 7.51 +/-0.2 degrees, 8.22 +/-0.2 degrees and 8.67 +/-0.2 degrees.

The gefitinib-resveratrol eutectic crystal uses Cu-Kalpha radiation, and has characteristic peaks at 4.23 +/-0.2 degrees, 7.51 +/-0.2 degrees, 8.22 +/-0.2 degrees, 8.67 +/-0.2 degrees, 13.16 +/-0.2 degrees, 16.07 +/-0.2 degrees, 22.07 +/-0.2 degrees, 22.61 +/-0.2 degrees and 25.54 +/-0.2 degrees in an X-ray diffraction spectrum represented by 2 theta.

Preferably, the gefitinib-resveratrol eutectic crystal uses Cu-Ka radiation, and the X-ray diffraction spectrum expressed by 2 theta is 4.23 +/-0.2 degrees, 7.51 +/-0.2 degrees, 8.22 +/-0.2 degrees, 8.67 +/-0.2 degrees, 13.16 +/-0.2 degrees, 14.41 +/-0.2 degrees, 16.07 +/-0.2 degrees, 16.74 +/-0.2 degrees, 17.66 +/-0.2 degrees, 18.42 +/-0.2 degrees, 22.07 +/-0.2 degrees, 22.61 +/-0.2 degrees, 25.54 +/-0.2 degrees and 29.34 +/-0.2 degrees.

Further preferably, the gefitinib-resveratrol eutectic is radiated by Cu-Ka, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.

Preferably, the gefitinib-resveratrol eutectic has the crystallographic parameters of: triclinic system, space group is P-1; unit cell parameters:

a is 96.1760(10) °, β is 96.9440(10) °, γ is 96.4380(10) °, unit cell volume

The invention provides a preparation method of gefitinib-resveratrol eutectic crystal, which comprises the following steps:

(1) dissolving gefitinib in trifluoroethanol,

(2) dissolving resveratrol in mixed solvent of alcohol solvent and water,

(3) mixing the two solutions in the steps (1) and (2), heating, stirring for reaction,

(4) and filtering, standing the filtrate, controlling the temperature to crystallize, filtering, and drying in vacuum to obtain the gefitinib-resveratrol eutectic.

Preferably, the mass-to-volume ratio of gefitinib to trifluoroethanol in step (1) is 40-55: 1, wherein the mass is in mg and the volume is in mL.

Preferably, the alcohol solvent in step (2) is selected from one of ethanol, methanol, isopropanol, tert-butanol or a combination thereof.

Further preferably, the alcohol solvent in step (2) is selected from one of ethanol and methanol or a combination thereof.

Preferably, in the mixed solvent in the step (2), the volume content of water is 10-20%.

Preferably, the molar ratio of the gefitinib in the step (1) and the resveratrol in the step (2) is 1: 1.0-1.5.

Further preferably, the molar ratio of the gefitinib in the step (1) and the resveratrol in the step (2) is 1: 1.0-1.2.

Preferably, the mass-to-volume ratio of the resveratrol to the mixed solvent in the step (2) is 3-5: 1, wherein the mass is mg and the volume is mL.

Preferably, the heating reaction temperature in the step (3) is 40-60 ℃.

Preferably, the heating reaction time in the step (3) is 3-5 hours.

Preferably, the temperature-controlled crystallization temperature in the step (4) is 15-30 ℃.

Preferably, the crystallization time in the step (4) is 3-5 days.

Preferably, the drying temperature in the step (4) is 40-50 ℃, and the drying time is 8-12 hours.

In a third aspect of the invention, a pharmaceutical composition containing the gefitinib-resveratrol cocrystal is provided.

The preparation method of the pharmaceutical composition of the invention can be as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare useful dosage forms.

The pharmaceutical composition comprises spray, tablets, capsules, powder injections, liquid injections and other pharmaceutically available dosage forms.

In a fourth aspect of the invention, the invention provides an application of gefitinib-resveratrol eutectic serving as an active ingredient in preparing a medicine for treating ineffective or inappropriate chemotherapy for locally advanced or metastatic non-small cell lung cancer.

Confirmation of crystal structure:

the gefitinib-resveratrol eutectic provided by the invention is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffraction instrument and the test conditions related by the invention are as follows: the chemistry XtaLAB Synergy X-ray single crystal diffractometer measures the temperature 293(2) K, uses CuKa radiation, collects data in an omega scanning mode and carries out Lp correction. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.

The crystallographic data obtained by testing and analyzing the gefitinib-resveratrol eutectic crystal prepared by the invention are shown in table 1, and the crystallographic parameters are as follows: triclinic system, space group is P-1; unit cell parameters:

The ORTEP chart of the gefitinib-resveratrol cocrystal prepared by the present invention shows that one molecule of gefitinib is combined with one molecule of resveratrol, as shown in fig. 2.

TABLE 1 Primary crystallographic data for Gefitinib-resveratrol cocrystals

The X-ray powder diffraction test instrument and the test conditions involved in the invention are as follows: x-ray powder diffractometer: PANalytical em copy; Cu-K alpha; a sample stage: a flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40 mA; divergent slit: 1/4, respectively; anti-scattering slit: 1; rope pulling of a slit: 0.04 rad; step length: 0.5 s; scanning range: 3 to 50 degrees.

According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are detailed in FIG. 1 and Table 2.

TABLE 2 PXRD peaks of Gefitinib-resveratrol cocrystals

The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram: METTLER TOLEDO TGA/DSC3 +; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; segment gas N₂(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.

The TGA/DSC test result of the gefitinib-resveratrol eutectic prepared by the method is shown in figure 3, and a DSC test spectrogram shows that the eutectic has an endothermic peak, the temperature range is 204.76-223.44 ℃, and the peak value is 214.76 ℃.

Compared with the gefitinib crystal form reported at present, the gefitinib-resveratrol eutectic crystal prepared by the method has the following advantages:

(1) the solubility is high. The solubility of the gefitinib-resveratrol eutectic in an acetic acid buffer solution with the pH value of 4.5 is as high as 3.17mg/mL, and the solubility of the gefitinib-resveratrol eutectic in a citric acid buffer solution with the pH value of 5 is as high as 16.20 mg/mL.

(2) The stability is good. The gefitinib-resveratrol eutectic crystal has no change in appearance of a sample and almost no reduction in purity after high-temperature and high-humidity tests.

Drawings

FIG. 1: an X-ray powder diffraction pattern of the gefitinib-resveratrol eutectic;

FIG. 2: an ORTEP map of gefitinib-resveratrol co-crystal;

FIG. 3: DSC/TGA chart of gefitinib-resveratrol eutectic.

Detailed Description

The invention will be further described by the following description of specific embodiments, it being properly understood that: the examples of the present invention are provided for illustration only and not for limitation of the present invention. Therefore, simple modifications of the present invention in the process of the present invention are within the scope of the claimed invention.

Example 1

(1) 48.2mg of gefitinib was dissolved in 1mL of trifluoroethanol,

(2) 23.8mg of resveratrol is dissolved in a mixed solvent of 6mL of methanol and 1mL of water,

(3) mixing the two solutions in the steps (1) and (2), heating to 50 ℃, stirring and reacting for 3-5 hours,

(4) and filtering, standing the filtrate, controlling the temperature to be 20-25 ℃ for crystallization for 3-5 days, filtering, and vacuum-drying for 10 hours at 40-50 ℃ to obtain the gefitinib-resveratrol eutectic crystal with the purity of 99.97%.

Example 2

(1) 44.7mg of gefitinib was dissolved in 1.1mL of trifluoroethanol,

(2) dissolving 25.1mg of resveratrol in a mixed solvent of 4mL of ethanol and 1mL of water,

(3) mixing the two solutions in the steps (1) and (2), heating to 40 ℃, stirring and reacting for 3-5 hours,

(4) and (3) filtering, standing the filtrate, controlling the temperature to be 15-20 ℃ for crystallization for 3-5 days, filtering, and vacuum-drying for 8 hours at the temperature of 40-50 ℃ to obtain the gefitinib-resveratrol eutectic crystal with the purity of 99.98%.

Example 3

(1) 44.7mg gefitinib was dissolved in 0.8mL trifluoroethanol,

(2) 27.4mg of resveratrol was dissolved in a mixed solvent of 7.5mL of isopropanol and 1.5mL of water,

(3) mixing the two solutions in the steps (1) and (2), heating to 60 ℃, stirring and reacting for 3-5 hours,

(4) and (3) filtering, standing the filtrate, controlling the temperature to be 25-30 ℃ for crystallization for 3-5 days, filtering, and performing vacuum drying for 12 hours at the temperature of 40-50 ℃ to obtain the gefitinib-resveratrol eutectic crystal with the purity of 99.95%.

Example 4

(1) 44.7mg of gefitinib was dissolved in 1.0mL of trifluoroethanol,

(2) 34.2mg of resveratrol is dissolved in a mixed solvent of 7.0mL of tert-butyl alcohol and 1.5mL of water,

(3) mixing the two solutions in the steps (1) and (2), heating to 55 ℃, stirring and reacting for 3-5 hours,

(4) and (3) filtering, standing the filtrate, controlling the temperature to be 20-25 ℃, crystallizing for 3-5 days, filtering, and vacuum-drying for 12 hours at the temperature of 40-50 ℃ to obtain the gefitinib-resveratrol eutectic crystal with the purity of 99.90%.

Example 5

(1) 44.7mg gefitinib was dissolved in 1.3mL trifluoroethanol,

(2) dissolving 38.8mg of resveratrol in a mixed solvent of 15.0mL of tert-butyl alcohol and 4.0mL of water,

(4) and filtering, standing the filtrate, controlling the temperature to be 10-15 ℃ for crystallization for 3-5 days, filtering, and vacuum-drying for 12 hours at the temperature of 40-50 ℃ to obtain the gefitinib-resveratrol eutectic crystal with the purity of 99.81%.

Example 6

(1) 44.7mg gefitinib was dissolved in 0.7mL trifluoroethanol,

(2) dissolving 20.5mg of resveratrol in a mixed solvent of 2.0mL of ethanol and 1.5mL of water,

(3) mixing the two solutions in the steps (1) and (2), heating to 65 ℃, stirring and reacting for 3-5 hours,

(4) and filtering, standing the filtrate, controlling the temperature to be 10-15 ℃ for crystallization for 3-5 days, filtering, and vacuum-drying at 50-60 ℃ for 10 hours to obtain the gefitinib-resveratrol eutectic crystal with the purity of 99.78%.

Comparative example 1

3.27g of resveratrol and 0.73g of gefitinib are taken, sieved and mixed to obtain a physical mixture. Feeding temperature of a hot melting extruder (Saimeifei Mini-CTW567-209) is 223 ℃, adding 4g of the material at one time through a feeding port, raising temperature to 227 ℃, rotating speed of 30r/min, circularly mixing for 3-5min, extruding the material, collecting, grinding and sieving to obtain a light yellow solid. And degrading the gefitinib through HPLC detection.

1. Solubility test

According to the method of pharmacopoeia, the dosage is reduced in the same proportion for saving materials. Acetic acid buffer solution with pH 4.5 and citric acid buffer solution with pH 5.0 and water are prepared respectively, a proper amount of gefitinib-resveratrol eutectic prepared in examples 1 to 6 is put into a test tube with a plug containing acetic acid buffer solution with pH 4.5, citric acid buffer solution with pH 5.0 and water in sequence, a sample is put into a water bath constant temperature oscillator, the sample is balanced for 24 hours under the conditions of 37 ℃ and 200r/min, the sample is taken, a 0.45 mu m microporous filter membrane is filtered, secondary filtrate is taken, the secondary filtrate is diluted to a linear range by water, the absorbance is measured at the wavelength of 254nm by taking an aqueous solution as a blank solution until the absorbance is not changed any more. The test results are shown in Table 3.

TABLE 3 solubility of Gefitinib-resveratrol cocrystals

All gefitinib-resveratrol cocrystal samples prepared in the examples of the present invention have the same solubility.

The results show that the gefitinib-resveratrol eutectic prepared by the invention has higher solubility in an acetic acid buffer solution with pH value of 4.5, a citric acid buffer solution with pH value of 5.0 and water, wherein the solubility of the gefitinib-resveratrol eutectic in the acetic acid buffer solution with pH value of 4.5 is as high as 3.17mg/mL, and the solubility of the gefitinib-resveratrol eutectic in the citric acid buffer solution with pH value of 5.0 is as high as 16.20 mg/mL.

2. Stability test

(1) High temperature experiment: putting a proper amount of a sample to be tested into a flat weighing bottle, spreading the sample into a thin layer with the thickness less than or equal to 5mm, standing at the temperature of 60 ℃ for 10 days, sampling at the end of 0 day, 5 days and 10 days, observing the color change of the sample, and detecting the purity of the sample by HPLC. The results are shown in Table 4.

TABLE 4 Gefitinib-resveratrol Co-crystal high temperature test

(2) High humidity test: placing a proper amount of a test sample into a flat weighing bottle, spreading the test sample into a thin layer with the thickness of less than or equal to 5mm, placing the test sample for 10 days at 25 ℃ under the condition of 90% +/-5% RH, sampling at the end of 0 day, 5 days and 10 days, observing the color change of the sample, and detecting the purity of the sample by HPLC. The results are shown in Table 5.

TABLE 5 Gefitinib-resveratrol Co-crystal high humidity test

And (4) test conclusion:

from the experimental results shown in tables 4 and 5, it can be known that the gefitinib-resveratrol eutectic disclosed by the invention, especially the crystal forms prepared in examples 1-3, have no obvious change in appearance and purity and good stability effect under the conditions of high temperature (60 ℃) and high humidity (25 ℃ and RH 90% +/-5%), and are suitable for pharmaceutical application.

Claims

1. A gefitinib-resveratrol eutectic crystal is characterized in that Cu-Kalpha radiation is used, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 4.23 +/-0.2 degrees, 7.51 +/-0.2 degrees, 8.22 +/-0.2 degrees and 8.67 +/-0.2 degrees.

2. The gefitinib-resveratrol eutectic crystal of claim 1, wherein an X-ray diffraction spectrum expressed in terms of 2 θ using Cu-ka radiation has characteristic peaks at 4.23 ± 0.2 °, 7.51 ± 0.2 °, 8.22 ± 0.2 °, 8.67 ± 0.2 °, 13.16 ± 0.2 °, 16.07 ± 0.2 °, 22.07 ± 0.2 °, 22.61 ± 0.2 °, 25.54 ± 0.2 °.

3. The gefitinib-resveratrol eutectic crystal of claim 1, wherein an X-ray diffraction spectrum expressed in terms of 2 θ using Cu-ka radiation has characteristic peaks at 4.23 ± 0.2 °, 7.51 ± 0.2 °, 8.22 ± 0.2 °, 8.67 ± 0.2 °, 13.16 ± 0.2 °, 14.41 ± 0.2 °, 16.07 ± 0.2 °, 16.74 ± 0.2 °, 17.66 ± 0.2 °, 18.42 ± 0.2 °, 22.07 ± 0.2 °, 22.61 ± 0.2 °, 25.54 ± 0.2 °, and 29.34 ± 0.2 °.

4. The gefitinib-resveratrol co-crystal of claim 1, characterized in that, using Cu-ka radiation, the characteristic peaks follow the X-ray powder diffraction pattern as shown in figure 1.

5. The gefitinib-resveratrol co-crystal according to any of claims 1-4, having crystallographic parameters of: triclinic system, space group is P-1; the unit cell parameters are:

6. The preparation method of the gefitinib-resveratrol eutectic crystal as claimed in claim 1, which is characterized by comprising the following specific preparation steps:

(1) dissolving gefitinib in trifluoroethanol,

(2) dissolving resveratrol in mixed solvent of alcohol solvent and water,

(4) filtering, standing the filtrate, controlling the temperature to crystallize, filtering, and drying in vacuum to obtain the gefitinib-resveratrol eutectic.

7. The preparation method according to claim 6, wherein the alcohol solvent in step (2) is selected from one or a combination of ethanol, methanol, isopropanol and tert-butanol, preferably from one or a combination of ethanol and methanol.

8. The method according to claim 6, wherein the heating reaction temperature in the step (3) is 40 to 60 ℃.

9. A pharmaceutical composition comprising the gefitinib-resveratrol co-crystal of any one of claims 1-4 and a pharmaceutically acceptable other adjuvant component.

10. Use of gefitinib-resveratrol co-crystal as claimed in any one of claims 1-4 as active ingredient for the preparation of a medicament for treating locally advanced or metastatic non-small cell lung cancer that is ineffective or not amenable to chemotherapy.