CN113754596A

CN113754596A - A co-crystal of gefitinib

Info

Publication number: CN113754596A
Application number: CN202010497426.8A
Authority: CN
Inventors: 翟立海; 夏祥来; 张朝花; 张纪云
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2020-06-01
Filing date: 2020-06-01
Publication date: 2021-12-07
Anticipated expiration: 2040-06-01

Abstract

本发明属于晶型药物分子技术领域，具体涉及一种吉非替尼的共晶体。本发明提供了吉非替尼‑白杨素共晶体、吉非替尼‑酮咯酸共晶体、2‑吲哚甲酸‑吉非替尼共晶体及其制备方法，本发明吉非替尼共晶体的理化性质优良，纯度高、稳定性好，溶解度高，有助于改善吉非替尼生物利用度，提高临床疗效，且制备方法简单高效，适于工业化生产。The invention belongs to the technical field of crystal drug molecules, in particular to a co-crystal of gefitinib. The present invention provides gefitinib-chrysin co-crystal, gefitinib-ketorolac co-crystal, 2-indolecarboxylic acid-gefitinib co-crystal and preparation methods thereof. The gefitinib co-crystal of the present invention provides The gefitinib has excellent physical and chemical properties, high purity, good stability and high solubility, which is helpful for improving the bioavailability of gefitinib and improving the clinical efficacy, and the preparation method is simple and efficient, and is suitable for industrial production.

Description

Gefitinib co-crystal

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a gefitinib co-crystal.

Background

Gefitinib (Gefitinib) is a semisynthetic derivative of camptothecin, developed by Asterazernica, Inc. of England under the trade name GefitinibIressa, chemical name is N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholine-4-propoxy) quinazoline-4-amine, molecular formula is C₂₂H₂₄ClFN₄O₃Molecular weight 446.9, CAS number 184475-35-2, whose chemical structure is shown below:

gefitinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor, and the inhibition of the activity of the selective epidermal growth factor receptor tyrosine kinase can prevent the growth, the metastasis and the angiogenesis of tumors and increase the apoptosis of tumor cells, and is suitable for treating locally advanced or metastatic non-small cell lung cancer which is treated by chemotherapy or is not suitable for chemotherapy.

Gefitinib contains a hydrophobic group in its structure, and is poorly water soluble, sparingly soluble at pH 1, poorly soluble at pH4 to 6, and practically insoluble at pH greater than 7. It is widely recognized that if the water solubility of the medicine is less than 3mg/ml, the dissolution rate of the medicine in vivo will play a limiting role in the absorption process, the water solubility of gefitinib at room temperature is far from the threshold, and the average absorption bioavailability of gefitinib orally taken by lung cancer patients is 59%. Therefore, increasing the solubility of gefitinib becomes one of the bottlenecks in the development of its related formulations.

Because different crystal forms of the medicine can directly influence the solubility, dissolution rate, bioavailability, target effect and the like of the medicine in vivo and further influence the exertion of the medicine effect, in view of the fact that gefitinib has a very important treatment effect and high price, although medicinal gefitinib is on the market for many years, the research report on the advantageous medicinal crystal forms of gefitinib is uninterrupted.

WO2003072108 discloses four crystal forms of Form 1, Form2, Form3 and Form5 of gefitinib, wherein Form 1 is a pure crystal Form, Form2 is a methanol solvate crystal Form of gefitinib, Form3 is a dimethyl sulfoxide solvate crystal Form of gefitinib, and Form5 is a trihydrate crystal Form of gefitinib. The content of methanol in the Form2 crystal Form is about 10 times of the pharmacopeia limit (the pharmacopeia limit is 0.3%), the content of DMSO in the Form3 crystal Form is about 30 times of the pharmacopeia limit (the pharmacopeia limit is 0.5%), excessive solvent residue makes the Form3 crystal Form unsuitable to be used as a medicinal crystal Form, the Form5 trihydrate is only very stable in water, and is suitable for being administrated in a dosage Form of an aqueous suspension, and the application of the Form5 crystal Form is also greatly limited.

WO2006090413 discloses another Form 6 crystal Form of gefitinib, which is a monohydrate crystal Form of gefitinib, has stability lower than Form 1, and also has the problem of limited application similar to the Form5 crystal Form.

CN103896863A discloses Form 7 crystal Form of gefitinib, and CN103319422A discloses alpha crystal Form of gefitinib obtained by anti-solvent crystallization technology, and the possibility of organic solvent residue and overproof colored substances exists.

Crystalline form a of gefitinib is disclosed in CN103910690A, and amorphous form of gefitinib is disclosed in CN103896861A, but generally cannot be selected as a pharmaceutically acceptable crystalline form due to the physicochemical defects of the amorphous form.

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 such high residual amount of organic solvent makes the crystal form unsuitable for being used as a medicinal crystal form.

WO2014016848 discloses co-crystal forms of gefitinib with caffeic acid, P-coumaric acid and ferulic acid.

WO2015170345 discloses co-crystal forms of gefitinib with oxalic acid, succinic acid, glutaric acid, adipic acid, citric acid, terephthalic acid, benzoic acid, and the like.

Among the crystal forms, the crystal Form 1 is the most stable and is the most commonly used crystal Form in clinical application at present, but the preparation reproducibility is poor, the solubility is low, the medicine is sold on the market in the Form of tablets, and due to poor water solubility, effective blood concentration is not easily reached in vivo after oral administration.

Disclosure of Invention

Aiming at the problems of low solubility, poor stability and the like of the existing gefitinib crystal form, the invention explores three new gefitinib co-crystals with excellent physicochemical properties: the gefitinib-chrysin eutectic, the gefitinib-ketorolac eutectic and the 2-indolecarboxylic acid-gefitinib eutectic provide better basis for the application of gefitinib in the aspect of medicament treatment, so that the medicinal value of gefitinib is exerted more efficiently.

In addition, the invention also provides a preparation method for respectively obtaining the eutectic. Based on this finding, the present invention is as follows.

In a first aspect of the present invention, there is provided a co-crystal of gefitinib formed by combining gefitinib with one selected from chrysin, ketorolac, 2-indolecarboxylic acid.

The eutectic is one selected from the following eutectic: gefitinib and chrysin are mixed according to a molar ratio of 1:1 combined to form gefitinib-chrysin co-crystal; gefitinib and ketorolac are mixed according to a molar ratio of 1:1 combined to form a gefitinib-ketorolac co-crystal; gefitinib, 2-indole carboxylic acid, water and methanol are mixed according to a molar ratio of 2: 2: 1: 2 to form 2-indolecarboxylic acid-gefitinib co-crystal.

Gefitinib-chrysin co-crystal:

the Gefitinib-chrysin eutectic disclosed by the invention has characteristic peaks at 5.70 +/-0.2 degrees, 6.94 +/-0.2 degrees, 12.05 +/-0.2 degrees, 13.41 +/-0.2 degrees, 18.46 +/-0.2 degrees and 35.81 +/-0.2 degrees by using Cu-Kalpha radiation and an X-ray diffraction spectrogram expressed by 2 theta.

Preferably, the gefitinib-chrysin co-crystal has characteristic peaks at 5.70 + -0.2 °, 5.96 + -0.2 °, 6.94 + -0.2 °, 12.05 + -0.2 °, 13.41 + -0.2 °, 14.00 + -0.2 °, 15.62 + -0.2 °, 18.46 + -0.2 °, 21.28 + -0.2 ° and 35.81 + -0.2 ° in an X-ray diffraction pattern expressed by 2 θ using Cu-Kalpha radiation.

Preferably, the gefitinib-chrysin co-crystal has characteristic peaks at 5.70 + -0.2 °, 5.96 + -0.2 °, 6.94 + -0.2 °, 11.55 + -0.2 °, 12.05 + -0.2 °, 12.44 + -0.2 °, 13.41 + -0.2 °, 14.00 + -0.2 °, 15.62 + -0.2 °, 16.78 + -0.2 °, 17.13 + -0.2 °, 17.42 + -0.2 °, 18.46 + -0.2 °, 21.28 + -0.2 °, 26.17 + -0.2 °, 26.45 + -0.2 °, 29.54 + -0.2 °, 35.81 + -0.2 °, 44.54 + -0.2 ° and 45.51 + -0.2 ° in an X-ray diffraction spectrum expressed by 2 θ using Cu-Kalpha radiation.

Preferably, the gefitinib-chrysin co-crystal uses Cu-Ka radiation, and the characteristic peak of the gefitinib-chrysin co-crystal accords with an X-ray powder diffraction pattern shown in figure 1.

The Gefitinib-chrysin co-crystal has the crystallographic parameters as follows: monoclinic system, space group is P21/c; the unit cell parameters are:

α is 90 °, β is 93.4583(10 °), γ is 90 °, unit cell volume

The gefitinib-chrysin co-crystal has a TGA/DSC (thermo-gravimetric analysis/DSC) spectrum as shown in figure 2, wherein the DSC spectrum has an endothermic peak within the temperature range of 182.93-209.63 ℃, and the peak value corresponding to the endothermic peak is 195.11 ℃.

Gefitinib-ketorolac co-crystal:

the Gefitinib-ketorolac eutectic disclosed by the invention uses Cu-Kalpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 6.31 +/-0.2 degrees, 7.00 +/-0.2 degrees, 11.64 +/-0.2 degrees, 12.83 +/-0.2 degrees, 20.12 +/-0.2 degrees, and 24.81 +/-0.2 degrees.

Preferably, the gefitinib-ketorolac eutectic has an X-ray diffraction spectrum expressed by 2 theta with Cu-Ka radiation having characteristic peaks at 6.31 +/-0.2 degrees, 7.00 +/-0.2 degrees, 8.86 +/-0.2 degrees, 11.64 +/-0.2 degrees, 12.83 +/-0.2 degrees, 16.53 +/-0.2 degrees, 17.66 +/-0.2 degrees, 19.47 +/-0.2 degrees, 20.12 +/-0.2 degrees, 23.56 +/-0.2 degrees, 24.81 +/-0.2 degrees, 27.67 +/-0.2 degrees.

Preferably, the gefitinib-ketorolac co-crystal uses Cu-Ka radiation, and the characteristic peak of the gefitinib-ketorolac co-crystal accords with an X-ray powder diffraction pattern shown in figure 5.

Preferably, the gefitinib-ketorolac eutectic has a TGA/DSC pattern as shown in figure 6, and an endothermic melting peak appears around 184.88 ℃.

The Gefitinib-ketorolac eutectic has the crystallographic parameters of: a crystal system of a triclinic type,the space group is P-1; the unit cell parameters are:

a is 82.3790(9) °, β is 86.4683(10) °, γ is 88.9412(10) °, unit cell volume

2-indolecarboxylic acid-gefitinib co-crystal:

according to the 2-indolecarboxylic acid-gefitinib co-crystal, Cu-Ka radiation is used, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.09 +/-0.2 degrees, 6.32 +/-0.2 degrees, 6.89 +/-0.2 degrees, 7.30 +/-0.2 degrees and 8.26 +/-0.2 degrees, or has characteristic peaks at 6.09 +/-0.2 degrees, 6.89 +/-0.2 degrees, 7.30 +/-0.2 degrees and 8.26 +/-0.2 degrees, or has characteristic peaks at 6.32 +/-0.2 degrees, 6.89 +/-0.2 degrees, 7.30 +/-0.2 degrees and 8.26 +/-0.2 degrees.

Preferably, the 2-indolecarboxylic acid-gefitinib co-crystal has an X-ray diffraction spectrum shown by 2 theta with Cu-Ka radiation having characteristic peaks at 6.09 + -0.2 degrees, 6.32 + -0.2 degrees, 6.89 + -0.2 degrees, 7.30 + -0.2 degrees, 8.26 + -0.2 degrees, 11.64 + -0.2 degrees, 12.10 + -0.2 degrees, 17.38 + -0.2 degrees, 17.98 + -0.2 degrees, 19.51 + -0.2 degrees, 21.22 + -0.2 degrees, 21.39 + -0.2 degrees, or having characteristic peaks at 6.09 + -0.2 degrees, 6.32 + -0.2 degrees, 6.89 + -0.2 degrees, 7.30 + -0.2 degrees, 8.26 + -0.2 degrees, 11.64 + -0.2 degrees, 12.10 + -0.2 degrees, 17.38 degrees, 0.2 + -0.2 degrees, 6.2 + -0.2 degrees, 7.2 + -0.2 degrees, 2 + -0.2 degrees, 9 + -0.2 degrees, 2 degrees, 6.2 + -0.2 degrees, 6.2 degrees, 6 + -0.2 degrees, 2 + -0.2 degrees, 6 + -0.2 degrees, 2 degrees, 6 + -0.2 degrees, 2 degrees, 6.2 + -0.2 degrees, 9 + -0.2 degrees, 6 + -0.2 degrees, 2 degrees, 6.2 degrees, 2 degrees, 9 + -0.2 degrees, 2 degrees, 9 + -0.2 degrees, 6.2 degrees, 2 degrees, 9 + -0.2 degrees, 2 degrees, 6.2 degrees, 2 degrees, 6.2 degrees, 9 + -0.2 degrees, 6.2 degrees, 2 degrees, 9 degrees, 6 + -0.2 degrees, 2 degrees, 9 + -0.2 degrees, 2 degrees, 9 + -0.2 degrees, 2 degrees, 6.2 degrees, 2 degrees, 9 degrees, 2 degrees, 9 degrees, 2 degrees, 6.2 degrees, 2 degrees, 11.64 +/-0.2 degrees, 12.10 +/-0.2 degrees, 17.38 +/-0.2 degrees, 17.98 +/-0.2 degrees, 19.51 +/-0.2 degrees, 21.22 +/-0.2 degrees, 21.39 +/-0.2 degrees, or 6.32 +/-0.2 degrees, 6.89 +/-0.2 degrees, 7.30 +/-0.2 degrees, 8.26 +/-0.2 degrees, 11.64 +/-0.2 degrees, 12.10 +/-0.2 degrees, 17.38 +/-0.2 degrees, 17.98 +/-0.2 degrees, 19.51 +/-0.2 degrees, 21.22 +/-0.2 degrees, 21.39 +/-0.2 degrees, or 6.09 +/-0.2 degrees, 6.89 +/-0.2 degrees, 7.30 +/-0.2 degrees, 8.26 +/-0.2 degrees, 11.64 +/-0.2 degrees, 12.10 +/-0.2.2 degrees, 17.2.2 degrees, 17 +/-0.2 degrees, 17.2.2 degrees, 6.2 degrees, 2.2 degrees, 2 degrees, 2.2 degrees, 2 +/-0.2 degrees, 2.2 degrees, 2 degrees, 2.2 degrees, 2 degrees, 2.2.2 degrees, 2 degrees, 2.2 degrees, 2 degrees, 2.2.2 degrees, 2 degrees, 2.2 degrees, 2 degrees, 2.2 degrees, 2 degrees, 2 degrees, 2, the characteristic peak is at 17.98 + -0.2 deg., 19.51 + -0.2 deg., 21.22 + -0.2 deg., or at 6.32 + -0.2 deg., 6.89 + -0.2 deg., 7.30 + -0.2 deg., 8.26 + -0.2 deg., 11.64 + -0.2 deg., 12.10 + -0.2 deg., 17.38 + -0.2 deg., 17.98 + -0.2 deg., 19.51 + -0.2 deg., 21.39 + -0.2 deg..

Preferably, the 2-indolecarboxylic acid-gefitinib co-crystal, using Cu-ka radiation, has characteristic peaks according to the X-ray powder diffraction pattern shown in fig. 9.

The 2-indolecarboxylic acid-gefitinib co-crystal has a TGA/DSC pattern as shown in figure 10.

The crystallography parameters of the 2-indolecarboxylic acid-gefitinib co-crystal are as follows: triclinic, space group P-1; the unit cell parameters are:

a is 62.0080(10) °, β is 71.5030(10) °, γ is 75.1180(10) °, unit cell volume

In a second aspect of the present invention, there are provided methods for preparing gefitinib-chrysin co-crystal, gefitinib-ketorolac co-crystal and 2-indolecarboxylic acid-gefitinib co-crystal.

The preparation method of the gefitinib-chrysin co-crystal comprises the following steps:

the gefitinib-chrysin co-crystal can be prepared by, for example, dissolving gefitinib in an organic solvent A to prepare a gefitinib solution, adding chrysin powder into the solution, heating, mixing and stirring, filtering, standing at room temperature for volatilization and crystallization, filtering and drying to obtain the gefitinib-chrysin co-crystal.

Preferably, the organic solvent a is selected from one or more of methyl isobutyl ketone, methanol, ethyl acetate, acetone, ethanol, isopropyl acetate and acetonitrile, and particularly preferably a mixed solvent of acetonitrile and acetone.

Preferably, the mass-to-volume ratio of the gefitinib to the organic solvent A is 80-200 mg/ml; further preferably 160, mg/ml.

Preferably, the molar ratio of gefitinib to chrysin is 1: 0.9 to 1.3, preferably 1:1.

preferably, the heating temperature is 30-60 ℃, and preferably 50 ℃.

Preferably, the stirring time is 12-36 h, preferably 24 h.

The preparation method of the gefitinib-ketorolac eutectic comprises the following steps:

the gefitinib-ketorolac eutectic can be prepared by, for example, adding gefitinib and ketorolac into an organic solvent B, heating for dissolving, filtering, standing, volatilizing for crystallization, filtering, and drying.

Preferably, the method for preparing the gefitinib-ketorolac co-crystal specifically comprises the following steps: adding gefitinib and ketorolac into the organic solvent B, heating and stirring in a water bath, filtering when the solid is completely dissolved, putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking the hole, standing for crystallization, filtering and drying to obtain the gefitinib-ketorolac solid.

Preferably, the molar ratio of gefitinib to ketorolac is 1: 1.0-2.0; further preferably, the molar ratio of gefitinib to ketorolac is 1: 1.0-1.5.

Preferably, the dosage ratio of the gefitinib to the organic solvent B is 5-15: 1 mg/ml; further preferably, the dosage ratio of the gefitinib to the organic solvent B is 10:1 and mg/ml.

Preferably, the organic solvent B is selected from one of methanol, acetone, ethanol, isopropanol and acetonitrile; more preferably, the organic solvent B is one of methanol and ethanol.

Preferably, the heating temperature is 40-75 ℃.

Preferably, the crystallization time is 20-24 h.

Preferably, the drying temperature is 40-50 ℃, and the drying time is 8-10 h.

The preparation method of the 2-indolecarboxylic acid-gefitinib co-crystal comprises the following steps:

the 2-indolecarboxylic acid-gefitinib co-crystal can be prepared by the following method, for example, adding gefitinib and 2-indolecarboxylic acid into a mixed solution of water and methanol, heating for reaction, filtering, standing the filtrate for crystallization, filtering, and drying in vacuum to obtain the 2-indolecarboxylic acid-gefitinib co-crystal.

Preferably, the volume ratio of the methanol to the water is 6-10: 1.

Preferably, the molar ratio of gefitinib to 2-indolecarboxylic acid is 1: 0.95 to 1.25.

Further preferably, the molar ratio of gefitinib to 2-indolecarboxylic acid is 1:1.

Preferably, the heating reaction temperature is 45-65 ℃.

Preferably, in the method, the mass-to-volume ratio of gefitinib to methanol is 8-15: 1, mg/ml.

Preferably, the heating reaction time is 3-5 h.

Preferably, the temperature for standing crystallization is room temperature.

Preferably, the standing crystallization mode is solvent volatilization crystallization.

In a third aspect of the present invention, there is provided an application of gefitinib-chrysin co-crystal, gefitinib-ketorolac co-crystal and 2-indolecarboxylic acid-gefitinib co-crystal as active ingredients in the preparation of a medicament for treating non-small cell lung cancer.

In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising the co-crystal of gefitinib and other pharmaceutically acceptable components.

Preferably, the preparation method of the pharmaceutical composition comprises the following steps: the co-crystals of gefitinib 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.

Further, the dosage form of the pharmaceutical composition includes, but is not limited to, tablets, capsules, granules, pills, injections, patches and the like.

Confirmation of crystal structure

(1) X-ray single crystal diffraction test

The X-ray single crystal diffraction instrument and the test conditions used by the gefitinib co-crystal of the invention are as follows: the chemistry XtalaBSynergy 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-chrysin co-crystal prepared by the invention are as follows: monoclinic system, space group is P21/c; the unit cell parameters are:

α is 90 °, β is 93.4583(10 °), γ is 90 °, unit cell volume

Molecular formula C₃₇H₃₃ClFN₄O₇The molecular weight is 700.12. Specific results are shown in table 1.

TABLE 1 Primary crystallographic data for Gefitinib-chrysin cocrystals

The ORTEP plot of the gefitinib-chrysin co-crystal of the present invention shows that the crystalline form contains one molecule of gefitinib and one molecule of chrysin, as shown in figure 3. The hydrogen bond diagram of the gefitinib-chrysin eutectic is shown in the attached figure 4.

Test and analysis bookThe prepared gefitinib-ketorolac eutectic has the following crystallographic data: triclinic system, space group is P-1; the unit cell parameters are:

The molecular formula is: c₃₇H₃₇ClFN₅O₆The molecular weight is: 702.16. the specific results are shown in Table 2.

TABLE 2 Primary crystallographic data for Gefitinib-ketorolac cocrystals

The ORTEP diagram of the gefitinib-ketorolac co-crystal of the present invention shows that the crystalline form contains one molecule of gefitinib and one molecule of ketorolac, as shown in fig. 7. The hydrogen bond diagram of the gefitinib-ketorolac eutectic is shown in figure 8.

Testing and analyzing the crystallography data of the 2-indolecarboxylic acid-gefitinib co-crystal prepared by the invention: triclinic, space group P-1; the unit cell parameters are:

Molecular formula C₆₄H₇₂Cl₂F₂N₁₀O₁₃And the molecular weight is 1298.21. The specific results are shown in Table 3.

TABLE 32 Primary crystallographic data for indolecarboxylic acid-Gefitinib cocrystals

The ORTEP plot of the 2-indolecarboxylic acid-gefitinib co-crystal of the present invention shows that two molecules of gefitinib bind two molecules of 2-indolecarboxylic acid, two molecules of methanol and one molecule of water as shown in figure 11.

(2) X-ray powder diffraction detection

The invention discloses an X-ray powder diffraction test instrument and test conditions for gefitinib eutectic, which 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 degrees; anti-scattering slit: 1 degree; rope pulling of a slit: 0.04 rad; step length: 0.5 s; scanning range: 3 to 50 degrees.

The main X-ray powder diffraction characteristic peaks of the gefitinib-chrysin co-crystal are shown in table 4.

TABLE 4 major X-ray powder diffraction characteristic peaks of Gefitinib-chrysin cocrystals

The main X-ray powder diffraction characteristic peaks of the gefitinib-ketorolac co-crystal are shown in table 5.

TABLE 5 major X-ray powder diffraction characteristic peaks of gefitinib-ketorolac cocrystals

The main X-ray powder diffraction characteristic peaks of the 2-indolecarboxylic acid-gefitinib co-crystal are shown in Table 6.

TABLE 62 major X-ray powder diffraction characteristic peaks of the indolecarboxylic acid-gefitinib cocrystal

(3) TGA/DSC analysis

The TGA/DSC thermal analyzer used by the gefitinib eutectic and the test conditions are as follows: mettler-toledo TGA/DSC thermogram (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 results of the gefitinib-chrysin eutectic, the gefitinib-ketorolac eutectic and the 2-indolecarboxylic acid-gefitinib eutectic of the present invention are shown in fig. 2, fig. 6 and fig. 10, respectively.

Compared with the prior art, the gefitinib co-crystal has the following advantages:

(1) the gefitinib eutectic has higher solubility, wherein the solubility of the gefitinib-ketorolac eutectic in hydrochloric acid solution with the pH value of 2.0 is up to 23.86mg/ml, and the solubility of the gefitinib-chrysin eutectic in 6.8 phosphoric acid buffer solution is up to 0.071mg/ml, thereby being beneficial to improving the bioavailability and clinical curative effect of gefitinib;

(2) the gefitinib-chrysin eutectic, the gefitinib-ketorolac eutectic and the 2-indolecarboxylic acid-gefitinib eutectic have good stability and small hygroscopicity, and are suitable for manufacturing and long-term storage of pharmaceutical preparations;

(3) the gefitinib co-crystal of the invention has simple preparation process and good repeatability, and is suitable for industrial production.

Drawings

FIG. 1: a PXRD spectrogram of the gefitinib-chrysin co-crystal;

FIG. 2: TGA/DSC profile of gefitinib-chrysin co-crystal;

FIG. 3: an ORTEP map of gefitinib-chrysin co-crystals;

FIG. 4: a hydrogen bond diagram of gefitinib-chrysin co-crystal;

FIG. 5: a PXRD spectrogram of the gefitinib-ketorolac eutectic;

FIG. 6: a TGA/DSC profile of gefitinib-ketorolac co-crystal;

FIG. 7: an ORTEP map of gefitinib-ketorolac co-crystal;

FIG. 8: a hydrogen bond diagram for the gefitinib-ketorolac cocrystal;

FIG. 9: a PXRD spectrogram of the 2-indolecarboxylic acid-gefitinib co-crystal;

FIG. 10: TGA/DSC of 2-indolecarboxylic acid-gefitinib co-crystal;

FIG. 11: ORTEP diagram of 2-indolecarboxylic acid-gefitinib co-crystal.

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.

The gefitinib-chrysin co-crystal obtained in the embodiment of the invention has diffraction peaks shown in figure 1 through X-ray powder diffraction test, the gefitinib-ketorolac co-crystal has diffraction peaks shown in figure 5, and the 2-indolecarboxylic acid-gefitinib co-crystal has diffraction peaks shown in figure 9.

Preparation of gefitinib-chrysin co-crystal

Example 1

Adding 48g of gefitinib into 300mL of a mixed solution of acetonitrile and acetone (the volume ratio is 2: 1), stirring and dissolving to obtain a gefitinib solution (the concentration is 160mg/mL), grinding and crushing chrysin (27.3g), slowly adding the ground gefitinib solution into the gefitinib solution, heating to 50 ℃, stirring at a constant temperature for 24 hours, filtering and collecting filtrate, standing at room temperature for volatilization and crystallization for 48 hours, filtering and drying to obtain 67.8g of gefitinib-chrysin eutectic crystal, and performing HPLC: 99.96 percent.

Example 2

Adding 54g of gefitinib into 300mL of a mixed solution of acetonitrile and acetone (the volume ratio is 2: 1), stirring and dissolving to obtain a gefitinib solution (the concentration is 180mg/mL), grinding and crushing chrysin (39.5g), slowly adding the ground gefitinib solution into the gefitinib solution, heating to 60 ℃, stirring at a constant temperature for 24 hours, filtering and collecting filtrate, standing at room temperature for volatilization and crystallization for 48 hours, filtering and drying to obtain 74.55g of gefitinib-chrysin eutectic crystal, and performing HPLC: 99.93 percent.

Example 3

Adding 30g of gefitinib into 300mL of a mixed solution of acetonitrile and acetone (the volume ratio is 2: 1), stirring and dissolving to obtain a gefitinib solution (the concentration is 100mg/mL), grinding and crushing chrysin (15.4g), slowly adding the ground gefitinib solution into the gefitinib solution, heating to 50 ℃, stirring at a constant temperature for 24 hours, filtering and collecting filtrate, standing at room temperature for volatilization and crystallization for 48 hours, filtering and drying to obtain 37.4g of gefitinib-chrysin eutectic crystal, and performing HPLC: 99.92 percent.

Example 4

Adding 60g of gefitinib into 300mL of a mixed solution of acetonitrile and methyl isobutyl ketone (the volume ratio is 2: 1), stirring and dissolving to obtain a gefitinib solution (the concentration is 200mg/mL), grinding and crushing chrysin (51.2g), slowly adding the ground gefitinib solution into the gefitinib solution, heating to 50 ℃, stirring at constant temperature for 12 hours, filtering and collecting filtrate, standing at room temperature for volatilization and crystallization for 48 hours, filtering and drying to obtain 73.4g of gefitinib-chrysin eutectic crystal, and performing HPLC: 99.82 percent.

Example 5

Adding 24g of gefitinib into 300mL of a mixed solution of methanol and ethyl acetate (the volume ratio is 2: 1), stirring and dissolving to obtain a gefitinib solution (the concentration is 80mg/mL), grinding and crushing chrysin (14.3g), slowly adding the ground gefitinib solution into the gefitinib solution, heating to 50 ℃, stirring at a constant temperature for 36 hours, filtering and collecting filtrate, standing at room temperature for volatilization and crystallization for 48 hours, filtering and drying to obtain 27.1g of gefitinib-chrysin eutectic crystal, and performing HPLC: 99.79 percent.

Preparation of gefitinib-ketorolac eutectic

Example 6

Placing 100.00mg of gefitinib and 69.87mg of ketorolac in a 50ml single-mouth bottle, adding 10ml of ethanol, heating and stirring in a water bath at 65 ℃, filtering when the solid is completely dissolved, placing the filtrate in a beaker, covering the cup mouth with a sealing film, pricking, standing and crystallizing for 24h, filtering, and drying at 45 ℃ for 9h to obtain the gefitinib-ketorolac eutectic. The yield was 96.12% and the HPLC purity was 99.96%.

Example 7

Placing 100.00mg of gefitinib and 58.22mg of ketorolac in a 50ml single-mouth bottle, adding 8ml of methanol, heating and stirring in a water bath at 60 ℃, filtering when the solid is completely dissolved, placing the filtrate in a beaker, covering the cup mouth with a sealing film, pricking, standing and crystallizing for 22h, filtering, and drying at 45 ℃ for 8h to obtain the gefitinib ketorolac eutectic crystal. The yield was 94.58%, the HPLC purity was 99.90%.

Example 8

Placing 100.00mg of gefitinib and 87.33mg of ketorolac in a 50ml single-mouth bottle, adding 20ml of isopropanol, heating and stirring in water bath at 40 ℃, filtering when the solid is completely dissolved, placing the filtrate in a beaker, covering the cup mouth with a sealing film, pricking, standing and crystallizing for 20h, filtering, and drying for 8h at 50 ℃ to obtain the gefitinib-ketorolac eutectic. The yield was 95.40%, HPLC purity was 99.88%.

Example 9

Placing 100.00mg of gefitinib and 116.45mg of ketorolac in a 50ml single-mouth bottle, adding 7ml of acetone, heating and stirring in a water bath at 50 ℃, filtering when the solid is completely dissolved, placing the filtrate in a beaker, covering the cup mouth with a sealing film, pricking, standing and crystallizing for 24h, filtering, and drying at 40 ℃ for 10h to obtain the gefitinib-ketorolac eutectic. The yield was 93.52%, HPLC purity was 99.91%.

Example 10

Placing 100.00mg of gefitinib and 69.87mg of ketorolac in a 50ml single-mouth bottle, adding 7ml of acetonitrile, heating and stirring in a water bath at 75 ℃, filtering when the solid is completely dissolved, placing the filtrate in a beaker, covering the cup mouth with a sealing film, pricking, standing and crystallizing for 24h, filtering, and drying at 50 ℃ for 9h to obtain the gefitinib-ketorolac eutectic. The yield was 95.13% and the HPLC purity was 99.95%.

Example 11

Placing 100.00mg of gefitinib and 174.66mg of ketorolac in a 50ml single-mouth bottle, adding 25ml of ethanol, heating and stirring in a water bath at 45 ℃, filtering when the solid is completely dissolved, placing the filtrate in a beaker, covering the cup mouth with a sealing film, pricking, standing and crystallizing for 24h, filtering, and drying at 45 ℃ for 9h to obtain the gefitinib-ketorolac eutectic. The yield was 89.71%, with an HPLC purity of 99.84%.

Example 12

Placing 100.00mg of gefitinib and 69.87mg of ketorolac in a 50ml single-mouth bottle, adding 10ml of tetrahydrofuran, heating and stirring in a water bath at 60 ℃, filtering when the solid is completely dissolved, placing the filtrate in a beaker, covering the cup mouth with a sealing film, pricking, standing and crystallizing for 24h, filtering, and drying for 9h at 45 ℃ to obtain the gefitinib-ketorolac eutectic. The yield was 84.24%, the HPLC purity was 99.81%.

Preparation of 2-indolecarboxylic acid-gefitinib co-crystal

Example 13

Adding 44.6mg of gefitinib and 16.1mg of 2-indolecarboxylic acid into a single-neck round-bottom flask, adding 4mL of methanol and 0.5mL of purified water, heating to 50 ℃, reacting for 4h, filtering, placing in a small glass bottle, sealing by using a sealing film, pricking a plurality of holes, volatilizing, crystallizing, filtering, drying under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib eutectic crystal with HPLC purity: 99.98 percent.

Example 14

Adding 44.6mg of gefitinib and 15.3mg of 2-indolecarboxylic acid into a single-neck round-bottom flask, adding 3.7mL of methanol and 0.5mL of purified water, heating to 45 ℃, reacting for 3h, filtering, placing in a small glass bottle, sealing by using a sealing film, pricking a plurality of holes, volatilizing, crystallizing, filtering, drying under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib eutectic crystal with HPLC purity: 99.96 percent.

Example 15

Adding 44.6mg of gefitinib and 20.1mg of 2-indolecarboxylic acid into a single-neck round-bottom flask, adding 5.5mL of methanol and 0.9mL of purified water, heating to 65 ℃, reacting for 3 hours, filtering, placing into a small glass bottle, sealing by using a sealing film, pricking a plurality of holes, volatilizing, crystallizing, filtering, drying under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib eutectic crystal with HPLC purity: 99.93 percent.

Example 16

Adding 44.6mg of gefitinib and 22.5mg of 2-indolecarboxylic acid into a single-neck round-bottom flask, adding 7.5mL of methanol and 0.5mL of purified water, heating to 40 ℃, reacting for 4 hours, filtering, placing into a small glass bottle, sealing by using a sealing film, pricking a plurality of holes, volatilizing, crystallizing, filtering, drying under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib eutectic crystal with HPLC purity: 99.90 percent.

Example 17

Adding 44.6mg of gefitinib and 14.5mg of 2-indolecarboxylic acid into a single-neck round-bottom flask, adding 3mL of methanol and 0.2mL of purified water, heating to 50 ℃, reacting for 4h, filtering, placing in a small glass bottle, sealing by using a sealing film, pricking a plurality of holes, volatilizing, crystallizing, filtering, drying under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib eutectic crystal with HPLC purity: 99.85 percent.

Verification example 1 accelerated stability test

1. Test materials: the gefitinib-chrysin eutectic, the gefitinib-ketorolac eutectic, the 2-indolecarboxylic acid-gefitinib eutectic and the gefitinib Form 1 crystal forms prepared by the embodiment of the invention.

2. The test method comprises the following steps: the test is carried out according to the method of appendix <9001 guidelines for stability test of raw material medicaments and preparations in the fourth part of the Chinese pharmacopoeia (2015 edition). Three batches of gefitinib crystals are respectively taken and packaged according to the market, and are placed for 6 months under the conditions of constant temperature and constant humidity of 40 +/-2 ℃ and 75 +/-5% RH. Samples were taken at the end of the month of 1, 2, 3, 6 months during the test period and examined by stability stress.

3. And (3) test results: the test results are shown in Table 7.

TABLE 7 accelerated stability test results

Tests prove that the three gefitinib co-crystals prepared by the invention have high purity, and the purity of the samples is changed slightly after accelerated tests, so that the gefitinib co-crystals have remarkable stability.

Verification example 2 hygroscopicity test

2. The test method comprises the following steps: the gefitinib-chrysin eutectic, the gefitinib-ketorolac eutectic, the 2-indolecarboxylic acid-gefitinib eutectic and the Form 1 crystal Form are respectively taken for 10mg, and the respective hygroscopicity is tested by a dynamic moisture adsorption (DVS) instrument. Three replicates were run and the results averaged.

Description of hygroscopicity characteristics and definition of hygroscopicity increase (guidance of hygroscopicity test in appendix XIX J, 2010 edition of Chinese pharmacopoeia, experimental conditions: 25 ℃. + -. 1 ℃, 80%. + -. 2% relative humidity): deliquescence: sufficient water is absorbed to form a liquid. Has the characteristics of moisture absorption: the moisture-drawing weight gain is not less than 15%. Moisture absorption: the moisture-inducing weight gain is less than 15% but not less than 2%. Slightly hygroscopic: the moisture-inducing weight gain is less than 2% but not less than 0.2%. No or almost no hygroscopicity: the moisture-drawing weight gain is less than 0.2 percent.

3. And (3) test results: the results of the hygroscopicity test are shown in Table 8.

TABLE 8 hygroscopicity test results

Sample (I)	80% relative humidity gain (%)
		Gefitinib-chrysin eutectic crystal	1.34
Gefitinib-ketorolac eutectic crystal	0.53
		2-indolecarboxylic acid-gefitinib co-crystal	0.86
Gefitinib Form 1 crystal Form	3.21

Tests prove that the gefitinib-chrysin eutectic, the gefitinib-ketorolac eutectic and the 2-indolecarboxylic acid-gefitinib eutectic respectively increase the weight by 1.34%, 0.53% and 0.86% after being balanced under the humidity of 80%, and are all lower than Form 1 crystal forms.

Verification example 3 solubility test

1. Test materials: the gefitinib-chrysin eutectic, the gefitinib-ketorolac eutectic and the 2-indolecarboxylic acid-gefitinib eutectic are prepared by the embodiment of the invention.

2. The test method comprises the following steps: the solubility test is referred to the contents of the Chinese pharmacopoeia (2015 edition). Respectively weighing 900ml of medium (pH7.0 water, pH2.0 hydrochloric acid solution, pH4.0 acetate buffer solution) into a penicillin bottle, adding excessive medicine, sealing the penicillin bottle, stirring in 37 deg.C water bath at constant temperature for 1 hr, filtering with 0.2 μm filter membrane, measuring absorbance of the filtrate at 247nm wavelength, and measuring the absorbance of standard control to calculate its solubility. Three replicates were run and the results averaged.

3. And (3) test results: the results of the solubility test are shown in Table 9.

TABLE 9 solubility of gefitinib co-crystals in different media

Tests prove that the gefitinib co-crystal prepared by the invention has better solubility in the three media, wherein the solubility of the gefitinib-ketorolac eutectic in hydrochloric acid solution with the pH value of 2.0 is as high as 23.86mg/ml, which is beneficial to improving the bioavailability of gefitinib.

Claims

1. A co-crystal of gefitinib, characterized in that, the co-crystal is formed by combining gefitinib and a kind of selected from chrysin, ketorolac, and 2-indolecarboxylic acid.

2. the co-crystal of gefitinib as claimed in claim 1, is characterized in that, described co-crystal is a kind of in the following co-crystal selected from:

Gefitinib-chrysin co-crystal formed by combining gefitinib and chrysin in a molar ratio of 1:1;

Gefitinib-ketorolac co-crystal formed by combining gefitinib and ketorolac in a molar ratio of 1:1;

A 2-indolecarboxylic acid-gefitinib co-crystal formed by combining gefitinib with 2-indolecarboxylic acid, water, and methanol in a molar ratio of 2:2:1:2.

3. the co-crystal of gefitinib as claimed in claim 2, is characterized in that, described co-crystal is a kind of in the following co-crystal selected from:

Gefitinib-chrysin co-crystal, using Cu-Kα radiation, X-ray diffraction pattern in 2θ at 5.70±0.2°, 6.94±0.2°, 12.05±0.2°, 13.41±0.2°, 18.46±0.2° , There are characteristic peaks at 35.81±0.2°;

Gefitinib-ketorolac co-crystal, using Cu-Kα radiation, X-ray diffraction pattern in 2θ at 6.31±0.2°, 7.00±0.2°, 11.64±0.2°, 12.83±0.2°, 20.12±0.2 °, there is a characteristic peak at 24.81±0.2°;

2-Indolecarboxylic acid-Gefitinib co-crystal, using Cu-Kα radiation, X-ray diffraction pattern in 2θ at 6.09±0.2°, 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26 Characteristic peaks at ±0.2°, or characteristic peaks at 6.09±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, or 6.32±0.2°, 6.89±0.2°, 7.30±0.2° , there is a characteristic peak at 8.26±0.2°.

4. the co-crystal of gefitinib as claimed in claim 3, is characterized in that, described co-crystal is a kind of in the following co-crystal selected from:

Gefitinib-chrysin co-crystal, using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 1;

Gefitinib-ketorolac co-crystal, using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 5;

The 2-indolecarboxylic acid-gefitinib co-crystal was irradiated with Cu-Kα, and its characteristic peaks were consistent with the X-ray powder diffraction pattern shown in FIG. 9 .

5. The co-crystal of gefitinib according to any one of claims 1 to 4, wherein the preparation of the gefitinib-chrysin co-crystal comprises the following steps: Dissolve in organic solvent A to prepare a gefitinib solution, add chrysin powder to the solution, heat, mix and stir, filter, stand at room temperature for volatilization and crystallization, filter and dry to obtain.

6. The co-crystal of gefitinib according to any one of claims 1 to 4, wherein the preparation of the gefitinib-ketorolac co-crystal comprises the following steps: Ni and ketorolac are added to the organic solvent B, heated to dissolve, filtered, cooled and left to stand, volatilized and crystallized, filtered, and dried to obtain.

7. The co-crystal of gefitinib according to any one of claims 1 to 4, wherein the preparation of the 2-indolecarboxylic acid-gefitinib co-crystal comprises the following steps: Fetinib and 2-indolecarboxylic acid are added to the mixed solution of water and methanol, heated for reaction, filtered, the filtrate is left to stand for crystallization, filtered, and dried in vacuo to obtain.

8. The application of the co-crystal of gefitinib according to any one of claims 1 to 4 as an active ingredient for preparing a medicine for treating non-small cell lung cancer.

9 . A pharmaceutical composition, characterized in that it comprises the co-crystal of gefitinib according to any one of claims 1 to 4 and other pharmaceutically acceptable components. 10 .