A co-crystal of gefitinib

Abstract

The present invention belongs to the technical field of crystalline drug molecules, and specifically relates to a co-crystal of gefitinib. The present invention provides a gefitinib-chrysin co-crystal, a gefitinib-ketorolac co-crystal, a 2-indolecarboxylic acid-gefitinib co-crystal and a preparation method thereof. The gefitinib co-crystal of the present invention has excellent physical and chemical properties, high purity, good stability, and high solubility, and is helpful to improve the bioavailability of gefitinib and improve clinical efficacy. The preparation method is simple and efficient, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a co-crystal of gefitinib. Background Art

[0002] Gefitinib is a semi-synthetic derivative of camptothecin, developed by AstraZeneca Ltd. in the UK. Its trade name is Iressa, its chemical name is N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine-4-propoxy)quinazolin-4-amine, and its molecular formula is C 22 H 24 ClFN4O3, molecular weight 446.9, CAS number 184475-35-2, its chemical structure is as follows:

[0003]

[0004] Gefitinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor. The inhibition of selective epidermal growth factor receptor tyrosine kinase activity can hinder tumor growth, metastasis and angiogenesis, and increase tumor cell apoptosis. It is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer that has previously received chemotherapy or is not suitable for chemotherapy.

[0005] Gefitinib contains hydrophobic groups in its structure, and its water solubility is poor. It is slightly soluble at pH = 1, poorly soluble at pH = 4-6, and almost insoluble when the pH is greater than 7. It is generally recognized that if the water solubility of a drug is less than 3 mg / ml, the dissolution rate of in vivo administration will play a rate-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 taken orally by lung cancer patients is 59%. Therefore, improving the solubility of gefitinib has become one of the bottlenecks in the development of its related preparations.

[0006] Since different crystal forms of drugs will directly affect the solubility, dissolution, bioavailability, interaction with the target, etc. of the drug in the body, and thus affect the efficacy of the drug, in view of the important therapeutic effects and high price of gefitinib, although the pharmaceutical gefitinib has been on the market for many years, research reports on its superior pharmaceutical crystal form have never stopped.

[0007] WO2003072108 discloses four crystal forms of gefitinib, namely Form 1, Form 2, Form 3 and Form 5, wherein Form 1 is a pure crystalline form, Form 2 is a methanol solvate crystal form of gefitinib, Form 3 is a dimethyl sulfoxide solvate crystal form of gefitinib, and Form 5 is a trihydrate crystal form of gefitinib. The methanol content in the Form 2 crystal form is about 10 times the pharmacopoeia limit (the pharmacopoeia limit is 0.3%), and the DMSO content in the Form 3 crystal form is about 30 times the pharmacopoeia limit (the pharmacopoeia limit is 0.5%). Excessive solvent residues make it unsuitable as a pharmaceutical crystal form. The Form 5 trihydrate is only very stable in water and is suitable for administration in the form of an aqueous suspension, which greatly limits the application of the Form 5 crystal form.

[0008] WO2006090413 discloses another Form 6 crystal form of gefitinib, which is a monohydrate crystal form of gefitinib and has lower stability than Form 1. It also has the same application limitation problem as Form 5 crystal form.

[0009] CN103896863A discloses the Form 7 crystal form of gefitinib, and CN103319422A discloses an α crystal form of gefitinib obtained by anti-solvent crystallization technology, which may contain excessive organic solvents and colored substances.

[0010] CN103910690A discloses the crystal form A of gefitinib, and CN103896861A discloses the amorphous form of gefitinib. However, due to the physical and chemical defects of the amorphous form, it is generally not selected as a pharmaceutical crystal form.

[0011] CN104693127B discloses a gefitinib ethylene glycol solvate and a preparation method thereof. However, studies have found that the content of ethylene glycol in the crystal is about 300 times the pharmacopoeia limit (0.062%). Such a high residual amount of organic solvent makes the crystal form unsuitable as a pharmaceutical crystal form.

[0012] WO2014016848 discloses a co-crystal form of gefitinib with caffeic acid, p-coumaric acid and ferulic acid.

[0013] WO2015170345 discloses a co-crystal form of gefitinib with oxalic acid, succinic acid, glutaric acid, adipic acid, citric acid, terephthalic acid, benzoic acid, and the like.

[0014] Among the above-mentioned crystal forms, Form 1 is the most stable and is also the most commonly used crystal form in clinical applications. However, its preparation reproducibility is poor and its solubility is low. The drug is marketed in the form of tablets. Due to its poor water solubility, it is difficult to reach an effective blood drug concentration in the body after oral administration. Summary of the invention

[0015] In view of the problems of low solubility and poor stability of existing gefitinib crystal forms, the present invention explores and obtains three new gefitinib co-crystals with excellent physical and chemical properties: gefitinib-chrysin co-crystal, gefitinib-ketorolac co-crystal and 2-indolecarboxylic acid-gefitinib co-crystal, which provide a better basis for the application of gefitinib in drug treatment, thereby more efficiently exerting the medicinal value of gefitinib.

[0016] In addition, the present invention also provides methods for preparing these co-crystals. Based on this discovery, the present invention is as follows.

[0017] In a first aspect, the present invention provides a co-crystal of gefitinib, wherein the co-crystal is formed by combining gefitinib and one selected from chrysin, ketorolac, and 2-indolecarboxylic acid.

[0018] The co-crystal is one selected from the following co-crystals: a gefitinib-chrysin co-crystal formed by combining gefitinib and chrysin in a molar ratio of 1:1; a gefitinib-ketorolac co-crystal formed by combining gefitinib and ketorolac in a molar ratio of 1:1; and a 2-indolecarboxylic acid-gefitinib co-crystal formed by combining gefitinib and 2-indolecarboxylic acid, water and methanol in a molar ratio of 2:2:1:2.

[0019] Gefitinib-chrysin cocrystals:

[0020] The gefitinib-chrysin cocrystal of the present invention uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at 5.70±0.2°, 6.94±0.2°, 12.05±0.2°, 13.41±0.2°, 18.46±0.2°, and 35.81±0.2°.

[0021] Preferably, the gefitinib-chrysin cocrystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ 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°.

[0022] Preferably, the gefitinib-chrysin cocrystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ is 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 There are characteristic peaks at ±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°.

[0023] Preferably, the characteristic peaks of the gefitinib-chrysin co-crystal, when irradiated with Cu-Kα, meet the following conditions: Figure 1 The X-ray powder diffraction pattern is shown.

[0024] The crystallographic parameters of the gefitinib-chrysin co-crystal are: monoclinic system, space group P21 / c; unit cell parameters are: α=90°、β=93.4583(10)°、γ=90°,unit cell volume

[0025] The gefitinib-chrysin co-crystal has Figure 2 The TGA / DSC spectrum shown in the DSC spectrum shows an endothermic peak in the range of 182.93-209.63°C, and the corresponding peak value of the endothermic peak is 195.11°C.

[0026] Gefitinib-ketorolac cocrystal:

[0027] The gefitinib-ketorolac cocrystal of the present invention uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at 6.31±0.2°, 7.00±0.2°, 11.64±0.2°, 12.83±0.2°, 20.12±0.2°, and 24.81±0.2°.

[0028] Preferably, the gefitinib-ketorolac cocrystal has characteristic peaks at 6.31±0.2°, 7.00±0.2°, 8.86±0.2°, 11.64±0.2°, 12.83±0.2°, 16.53±0.2°, 17.66±0.2°, 19.47±0.2°, 20.12±0.2°, 23.56±0.2°, 24.81±0.2°, and 27.67±0.2° in an X-ray diffraction spectrum expressed as 2θ using Cu-Kα radiation.

[0029] Preferably, the characteristic peaks of the gefitinib-ketorolac cocrystal, when irradiated with Cu-Kα, conform to the following Figure 5 The X-ray powder diffraction pattern is shown.

[0030] Preferably, the gefitinib-ketorolac cocrystal has Figure 6 The TGA / DSC spectrum shown shows an endothermic melting peak at around 184.88°C.

[0031] The crystallographic parameters of the gefitinib-ketorolac cocrystal are: triclinic system, space group P-1; unit cell parameters are: α=82.3790(9)°,β=86.4683(10)°,γ=88.9412(10)°,unit cell volume

[0032] 2-Indolecarboxylic acid-gefitinib cocrystal:

[0033] The 2-indolecarboxylic acid-gefitinib co-crystal of the present invention uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at 6.09±0.2°, 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, and 8.26±0.2°, or has characteristic peaks at 6.09±0.2°, 6.89±0.2°, 7.30±0.2°, and 8.26±0.2°, or has characteristic peaks at 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, and 8.26±0.2°.

[0034] Preferably, the 2-indolecarboxylic acid-gefitinib cocrystal has a characteristic peak at 6.09±0.2°, 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2°, 17.38±0.2°, 17.98±0.2°, 19.51±0.2°, 21.22±0.2°, and 21.39±0.2°, or at 6.09±0.2°, 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2° , 17.38±0.2°, 17.98±0.2°, 19.51±0.2°, 21.22±0.2°, or characteristic peaks at 6.09±0.2°, 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2°, 1 There are characteristic peaks at 7.38±0.2°, 17.98±0.2°, 19.51±0.2°, and 21.39±0.2°, or at 6.09±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2°, 17.38±0.2°, 17 .98±0.2°, 19.51±0.2°, 21.22±0.2°, 21.39±0.2°, or have characteristic peaks at 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2°, 17.38±0.2°, 17. There are characteristic peaks at 98±0.2°, 19.51±0.2°, 21.22±0.2°, 21.39±0.2°, or at 6.09±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2°, 17.38±0.2°, 17.9 8±0.2°, 19.51±0.2°, 21.22±0.2°, or at 6.09±0.2°, 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2°, 17.38±0.2°, 17.98± 0.2°, 19.51±0.2°, 21.39±0.2°, or characteristic peaks at 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2°, 17.38±0.2°, 17.98±0.2°, 19.51±0.2°, 21.22±0.2°, or 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2°, 17.38±0.2°, 17.98±0.2°, 19.51±0.2°, 21.39±0.2°. .

[0035] Preferably, the characteristic peaks of the 2-indolecarboxylic acid-gefitinib co-crystal, when irradiated with Cu-Kα, meet the following conditions: Fig. 9 The X-ray powder diffraction pattern is shown.

[0036] The 2-indolecarboxylic acid-gefitinib co-crystal has Fig.10 TGA / DSC spectra shown.

[0037] The crystallographic parameters of the 2-indolecarboxylic acid-gefitinib co-crystal are: triclinic system, space group P-1; unit cell parameters are: α=62.0080(10)°,β=71.5030(10)°,γ=75.1180(10)°,unit cell volume

[0038] In a second aspect, the present invention provides methods for preparing gefitinib-chrysin co-crystals, gefitinib-ketorolac co-crystals and 2-indolecarboxylic acid-gefitinib co-crystals.

[0039] Preparation method of gefitinib-chrysin co-crystal:

[0040] The gefitinib-chrysin co-crystal of the present invention can be prepared by the following method, for example, dissolving gefitinib in an organic solvent A to prepare a gefitinib solution, adding chrysin powder to 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.

[0041] 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 is particularly preferably a mixed solvent of acetonitrile and acetone.

[0042] Preferably, the mass volume ratio of gefitinib to organic solvent A is 80-200 mg / ml; more preferably 160 mg / ml.

[0043] Preferably, the molar ratio of gefitinib to chrysin is 1:0.9-1.3, preferably 1:1.

[0044] Preferably, the heating temperature is 30-60°C, preferably 50°C.

[0045] Preferably, the stirring time is 12 to 36 hours, preferably 24 hours.

[0046] Preparation method of gefitinib-ketorolac cocrystal:

[0047] The gefitinib-ketorolac cocrystal of the present invention can be prepared by the following method, for example, adding gefitinib and ketorolac into an organic solvent B, heating to dissolve, filtering, standing, volatilizing and crystallizing, filtering, and drying to obtain the cocrystal.

[0048] Preferably, the method for preparing the gefitinib-ketorolac cocrystal specifically comprises the following steps: adding gefitinib and ketorolac to an organic solvent B, heating and stirring in a water bath, filtering while hot after all the solids are dissolved, placing the filtrate in a beaker, sealing with a sealing film, piercing holes, standing for crystallization, filtering, and drying to obtain the cocrystal.

[0049] 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.

[0050] Preferably, the dosage ratio of gefitinib to organic solvent B is 5 to 15:1, mg / ml; further preferably, the dosage ratio of gefitinib to organic solvent B is 10:1, mg / ml.

[0051] Preferably, the organic solvent B is selected from one of methanol, acetone, ethanol, isopropanol and acetonitrile; further preferably, the organic solvent B is one of methanol and ethanol.

[0052] Preferably, the heating temperature is 40-75°C.

[0053] Preferably, the crystallization time is 20 to 24 hours.

[0054] Preferably, the drying temperature is 40-50° C., and the drying time is 8-10 hours.

[0055] Preparation method of 2-indolecarboxylic acid-gefitinib cocrystal:

[0056] The 2-indolecarboxylic acid-gefitinib co-crystal of the present invention can be prepared by the following method, for example, adding gefitinib and 2-indolecarboxylic acid to a mixed solution of water and methanol, heating for reaction, filtering, allowing the filtrate to stand for crystallization, filtering, and vacuum drying to obtain 2-indolecarboxylic acid-gefitinib co-crystal.

[0057] Preferably, the volume ratio of methanol to water is 6 to 10:1.

[0058] Preferably, the molar ratio of gefitinib to 2-indolecarboxylic acid is 1:0.95-1.25.

[0059] Further preferably, the molar ratio of gefitinib to 2-indolecarboxylic acid is 1:1.

[0060] Preferably, the heating reaction temperature is 45-65°C.

[0061] Preferably, in the method, the mass volume ratio of gefitinib to methanol is 8 to 15:1, mg / ml.

[0062] Preferably, the heating reaction time is 3 to 5 hours.

[0063] Preferably, the temperature of the static crystallization is room temperature.

[0064] Preferably, the static crystallization method is solvent evaporation crystallization.

[0065] In a third aspect, the present invention provides the use of gefitinib-chrysin cocrystal, gefitinib-ketorolac cocrystal and 2-indolecarboxylic acid-gefitinib cocrystal as active ingredients for preparing drugs for treating non-small cell lung cancer.

[0066] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the co-crystal of gefitinib and other pharmaceutically acceptable components.

[0067] Preferably, the pharmaceutical composition is prepared by combining the gefitinib co-crystal of the present invention with a pharmaceutically acceptable solid or liquid carrier using standard and conventional techniques, and optionally combining it with pharmaceutically acceptable adjuvants and excipients to prepare a usable dosage form.

[0068] Furthermore, the dosage form of the pharmaceutical composition includes but is not limited to tablets, capsules, granules, pills, injections and patches.

[0069] Crystal structure confirmation

[0070] (1) X-ray single crystal diffraction test

[0071] The X-ray single crystal diffraction instrument and test conditions used for the gefitinib co-crystal of the present invention are: Rigaku XtaLab Synergy X-ray single crystal diffractometer, test temperature 293 (2) K, CuKa radiation, ω scanning mode data collection and Lp correction. The structure is analyzed by direct method, the difference Fourier method is used to find all non-hydrogen atoms, all hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the least square method is used to refine the structure.

[0072] The crystallographic data obtained by testing and analyzing the gefitinib-chrysin co-crystal prepared by the present invention are: monoclinic system, space group is P21 / c; unit cell parameters are: α=90°、β=93.4583(10)°、γ=90°,unit cell volume The molecular formula is C 37 H 33 ClFN4O7, molecular weight is 700.12. Specific results are shown in Table 1.

[0073] Table 1 Main crystallographic data of gefitinib-chrysin co-crystals

[0074]

[0075]

[0076] The ORTEP diagram 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. Figure 3 The hydrogen bond diagram of the gefitinib-chrysin co-crystal of the present invention is shown in the attached Figure 4 shown.

[0077] The crystallographic data obtained by testing and analyzing the gefitinib-ketorolac cocrystal prepared by the present invention are: triclinic system, space group is P-1; unit cell parameters are: α=82.3790(9)°,β=86.4683(10)°,γ=88.9412(10)°,unit cell volume The molecular formula is: C 37 H 37 ClFN5O6, molecular weight: 702.16. Specific results are shown in Table 2.

[0078] Table 2 Main crystallographic data of gefitinib-ketorolac cocrystals

[0079]

[0080]

[0081] 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 the attached Figure 7 The hydrogen bonding diagram of the gefitinib-ketorolac co-crystal of the present invention is shown in the attached Figure 8 shown.

[0082] The crystallographic data obtained by testing and analyzing the 2-indolecarboxylic acid-gefitinib co-crystal prepared by the present invention are: triclinic system, space group P-1; the unit cell parameters are: α=62.0080(10)°,β=71.5030(10)°,γ=75.1180(10)°,unit cell volume The molecular formula is C 64 H 72 Cl2F2N 10 O13 , the molecular weight is 1298.21. The specific results are shown in Table 3.

[0083] Table 3 Main crystallographic data of 2-indolecarboxylic acid-gefitinib co-crystals

[0084]

[0085]

[0086] The ORTEP diagram of the 2-indolecarboxylic acid-gefitinib cocrystal of the present invention shows that two molecules of gefitinib are combined with two molecules of 2-indolecarboxylic acid, two molecules of methanol and one molecule of water. Fig.11 shown.

[0087] (2) X-ray powder diffraction detection

[0088] The X-ray powder diffraction test instrument and test conditions used for the gefitinib co-crystal of the present invention are as follows: X-ray powder diffractometer: PANalytical EMPYREAN; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv, current 40mA; divergence slit: 1 / 4°; anti-scattering slit: 1°; Soller slit: 0.04rad; step length: 0.5s; scanning range: 3-50°.

[0089] The main X-ray powder diffraction characteristic peaks of gefitinib-chrysin co-crystals are shown in Table 4.

[0090] Table 4 Main X-ray powder diffraction characteristic peaks of gefitinib-chrysin cocrystals

[0091]

[0092]

[0093] The main X-ray powder diffraction characteristic peaks of gefitinib-ketorolac cocrystals are shown in Table 5.

[0094] Table 5 Main X-ray powder diffraction characteristic peaks of gefitinib-ketorolac cocrystals

[0095]

[0096] The main X-ray powder diffraction characteristic peaks of 2-indolecarboxylic acid-gefitinib co-crystals are shown in Table 6.

[0097] Table 6 Main X-ray powder diffraction characteristic peaks of 2-indolecarboxylic acid-gefitinib cocrystals

[0098]

[0099]

[0100] (3) TGA / DSC analysis

[0101] The TGA / DSC thermal analysis instrument and test conditions used for the gefitinib co-crystal of the present invention are: Mettler-Toledo TGA / DSC thermal analyzer (TGA / DSC3+); dynamic temperature section: 30-300°C; heating rate: 10°C / min; program section gas N2; gas flow rate: 50ml / min; crucible: aluminum crucible 40μl.

[0102] The TGA / DSC test results of the gefitinib-chrysin cocrystal, gefitinib-ketorolac cocrystal and 2-indolecarboxylic acid-gefitinib cocrystal of the present invention are as follows: Figure 2 , Figure 6 , Fig.10 shown.

[0103] Compared with the prior art, the gefitinib co-crystal of the present invention has the following advantages:

[0104] (1) The gefitinib cocrystal of the present invention has a high solubility, wherein the solubility of the gefitinib-ketorolac cocrystal in a pH 2.0 hydrochloric acid solution is as high as 23.86 mg / ml, and the solubility of the gefitinib-chrysin cocrystal in a 6.8 phosphate buffer solution is as high as 0.071 mg / ml, which helps to improve the bioavailability and clinical efficacy of gefitinib;

[0105] (2) The gefitinib-chrysin cocrystal, gefitinib-ketorolac cocrystal, and 2-indolecarboxylic acid-gefitinib cocrystal of the present invention have good stability and low hygroscopicity, and are suitable for the manufacture and long-term storage of pharmaceutical preparations;

[0106] (3) The preparation process of the gefitinib co-crystal of the present invention is simple, has good reproducibility, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0107] Figure 1 : PXRD spectrum of gefitinib-chrysin cocrystal;

[0108] Figure 2 : TGA / DSC diagram of gefitinib-chrysin cocrystal;

[0109] Figure 3 : ORTEP image of gefitinib-chrysin cocrystal;

[0110] Figure 4 : Hydrogen bond diagram of gefitinib-chrysin cocrystal;

[0111] Figure 5 : PXRD spectrum of gefitinib-ketorolac cocrystal;

[0112] Figure 6 : TGA / DSC diagram of gefitinib-ketorolac cocrystal;

[0113] Figure 7 : ORTEP diagram of gefitinib-ketorolac cocrystal;

[0114] Figure 8 : Hydrogen bonding diagram of gefitinib-ketorolac cocrystal;

[0115] Fig. 9 : PXRD spectrum of 2-indolecarboxylic acid-gefitinib cocrystal;

[0116] Fig.10 : TGA / DSC diagram of 2-indolecarboxylic acid-gefitinib cocrystal;

[0117] Fig.11 : ORTEP diagram of 2-indolecarboxylic acid-gefitinib cocrystal. DETAILED DESCRIPTION

[0118] The present invention is further described below by describing specific embodiments. It should be correctly understood that the embodiments of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all belong to the scope of protection claimed in the present invention.

[0119] The gefitinib-chrysin co-crystals obtained in the present invention were tested by X-ray powder diffraction, and all had Figure 1 The diffraction peaks shown in FIG. 1 and FIG. 2 are all present in the gefitinib-ketorolac cocrystals. Figure 5 The diffraction peaks shown in the figure, the obtained 2-indolecarboxylic acid-gefitinib co-crystals all have Fig. 9 Diffraction peaks shown.

[0120] Preparation of Gefitinib-Chrysin Cocrystals

[0121] Example 1

[0122] 48 g of gefitinib was added to a mixed solution of 300 mL of acetonitrile and acetone (volume ratio of 2:1), stirred and dissolved to obtain a gefitinib solution (concentration of 160 mg / mL), chrysin (27.3 g) was ground and slowly added to the gefitinib solution, heated to 50°C and stirred at constant temperature for 24 hours, the filtrate was collected by filtration, and allowed to stand at room temperature for 48 hours for volatilization and crystallization, and filtered and dried to obtain 67.8 g of gefitinib-chrysin cocrystal, HPLC: 99.96%.

[0123] Example 2

[0124] 54 g of gefitinib was added to a mixed solution of 300 mL of acetonitrile and acetone (volume ratio of 2:1), stirred and dissolved to obtain a gefitinib solution (concentration of 180 mg / mL), chrysin (39.5 g) was ground and slowly added to the gefitinib solution, heated to 60°C and stirred at constant temperature for 24 hours, the filtrate was collected by filtration, and allowed to stand at room temperature for 48 hours for volatilization and crystallization, and filtered and dried to obtain 74.55 g of gefitinib-chrysin cocrystal, HPLC: 99.93%.

[0125] Example 3

[0126] 30 g of gefitinib was added to a mixed solution of 300 mL of acetonitrile and acetone (volume ratio of 2:1), stirred and dissolved to obtain a gefitinib solution (concentration of 100 mg / mL), chrysin (15.4 g) was ground and slowly added to the gefitinib solution, heated to 50°C and stirred at constant temperature for 24 hours, the filtrate was collected by filtration, and allowed to stand at room temperature for 48 hours for volatilization and crystallization, and filtered and dried to obtain 37.4 g of gefitinib-chrysin cocrystal, HPLC: 99.92%.

[0127] Example 4

[0128] 60 g of gefitinib was added to a mixed solution of 300 mL of acetonitrile and methyl isobutyl ketone (volume ratio of 2:1), stirred and dissolved to obtain a gefitinib solution (concentration of 200 mg / mL), chrysin (51.2 g) was ground and slowly added to the gefitinib solution, heated to 50°C and stirred at constant temperature for 12 h, the filtrate was collected by filtration, and allowed to stand at room temperature for 48 h for volatilization and crystallization, and filtered and dried to obtain 73.4 g of gefitinib-chrysin cocrystal, HPLC: 99.82%.

[0129] Example 5

[0130] 24 g of gefitinib was added to a mixed solution of 300 mL of methanol and ethyl acetate (volume ratio of 2:1), stirred and dissolved to obtain a gefitinib solution (concentration of 80 mg / mL), chrysin (14.3 g) was ground and slowly added to the gefitinib solution, heated to 50°C and stirred at a constant temperature for 36 hours, the filtrate was collected by filtration, and allowed to stand at room temperature for 48 hours for evaporation and crystallization, filtered and dried to obtain 27.1 g of gefitinib-chrysin cocrystal, HPLC: 99.79%.

[0131] Preparation of Gefitinib-Ketorolac Cocrystal

[0132] Example 6

[0133] 100.00 mg of gefitinib and 69.87 mg of ketorolac were placed in a 50 ml single-mouth bottle, 10 ml of ethanol was added, and the mixture was heated in a water bath at 65°C with stirring. After the solid was completely dissolved, it was filtered while hot, and the filtrate was placed in a beaker, the mouth of the beaker was covered with a sealing film, and a hole was made. The mixture was allowed to stand for crystallization for 24 hours, filtered, and dried at 45°C for 9 hours to obtain gefitinib-ketorolac cocrystal. The yield was 96.12%, and the HPLC purity was 99.96%.

[0134] Example 7

[0135] Place 100.00 mg of gefitinib and 58.22 mg of ketorolac in a 50 ml single-mouth bottle, add 8 ml of methanol, heat and stir in a 60°C water bath, filter while hot after all the solids are dissolved, place the filtrate in a beaker, cover the beaker mouth with a sealing film, pierce a hole, let stand for crystallization for 22 hours, filter, and dry at 45°C for 8 hours to obtain gefitinid ketorolac cocrystals. The yield is 94.58%, and the HPLC purity is 99.90%.

[0136] Example 8

[0137] 100.00 mg of gefitinib and 87.33 mg of ketorolac were placed in a 50 ml single-mouth bottle, 20 ml of isopropanol was added, and the mixture was heated in a 40°C water bath with stirring. After the solid was completely dissolved, it was filtered while hot, and the filtrate was placed in a beaker, the beaker was covered with a sealing film, and a hole was made. The mixture was allowed to stand for crystallization for 20 hours, filtered, and dried at 50°C for 8 hours to obtain gefitinib-ketorolac cocrystal. The yield was 95.40%, and the HPLC purity was 99.88%.

[0138] Example 9

[0139] 100.00 mg of gefitinib and 116.45 mg of ketorolac were placed in a 50 ml single-mouth bottle, 7 ml of acetone was added, and the mixture was heated in a 50°C water bath with stirring. After the solid was completely dissolved, it was filtered while hot, and the filtrate was placed in a beaker, the mouth of the beaker was covered with a sealing film, and a hole was made. The mixture was allowed to stand for crystallization for 24 hours, filtered, and dried at 40°C for 10 hours to obtain gefitinib-ketorolac cocrystal. The yield was 93.52%, and the HPLC purity was 99.91%.

[0140] Example 10

[0141] 100.00 mg of gefitinib and 69.87 mg of ketorolac were placed in a 50 ml single-mouth bottle, 7 ml of acetonitrile was added, and the mixture was heated in a 75°C water bath with stirring. After the solid was completely dissolved, it was filtered while hot, and the filtrate was placed in a beaker, the mouth of the beaker was covered with a sealing film, and a hole was made. The mixture was allowed to stand for crystallization for 24 hours, filtered, and dried at 50°C for 9 hours to obtain gefitinib-ketorolac cocrystal. The yield was 95.13%, and the HPLC purity was 99.95%.

[0142] Embodiment 11

[0143] 100.00 mg of gefitinib and 174.66 mg of ketorolac were placed in a 50 ml single-mouth bottle, 25 ml of ethanol was added, and the mixture was heated in a water bath at 45°C with stirring. After the solid was completely dissolved, it was filtered while hot, and the filtrate was placed in a beaker, the mouth of the beaker was covered with a sealing film, and a hole was made. The mixture was allowed to stand for crystallization for 24 hours, filtered, and dried at 45°C for 9 hours to obtain gefitinib-ketorolac cocrystal. The yield was 89.71%, and the HPLC purity was 99.84%.

[0144] Example 12

[0145] 100.00 mg of gefitinib and 69.87 mg of ketorolac were placed in a 50 ml single-mouth bottle, 10 ml of tetrahydrofuran was added, and the mixture was heated in a water bath at 60°C with stirring. After the solid was completely dissolved, it was filtered while hot, and the filtrate was placed in a beaker, the mouth of the beaker was covered with a sealing film, and a hole was made. The mixture was allowed to stand for crystallization for 24 hours, filtered, and dried at 45°C for 9 hours to obtain gefitinib-ketorolac cocrystal. The yield was 84.24%, and the HPLC purity was 99.81%.

[0146] Preparation of 2-Indolecarboxylic Acid-Gefitinib Cocrystal

[0147] Embodiment 13

[0148] Add 44.6 mg of gefitinib and 16.1 mg of 2-indolecarboxylic acid into a single-mouth round-bottom flask, add 4 mL of methanol and 0.5 mL of purified water, heat to 50°C, react for 4 hours, filter, place in a small glass bottle, seal with a sealing film, pierce several holes, evaporate, crystallize, filter, and dry under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib cocrystal, HPLC purity: 99.98%.

[0149] Embodiment 14

[0150] Add 44.6 mg of gefitinib and 15.3 mg of 2-indolecarboxylic acid into a single-mouth round-bottom flask, add 3.7 mL of methanol and 0.5 mL of purified water, heat to 45°C, react for 3 hours, filter, place in a small glass bottle, seal with a sealing film, pierce several holes, evaporate, crystallize, filter, and dry under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib cocrystal, HPLC purity: 99.96%.

[0151] Embodiment 15

[0152] Add 44.6 mg of gefitinib and 20.1 mg of 2-indolecarboxylic acid into a single-mouth round-bottom flask, add 5.5 mL of methanol and 0.9 mL of purified water, heat to 65°C, react for 3 hours, filter, place in a small glass bottle, seal with a sealing film, pierce several holes, evaporate, crystallize, filter, and dry under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib cocrystal, HPLC purity: 99.93%.

[0153] Example 16

[0154] Add 44.6 mg of gefitinib and 22.5 mg of 2-indolecarboxylic acid into a single-mouth round-bottom flask, add 7.5 mL of methanol and 0.5 mL of purified water, heat to 40°C, react for 4 hours, filter, place in a small glass bottle, seal with a sealing film, pierce several holes, evaporate, crystallize, filter, and dry under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib cocrystal, HPLC purity: 99.90%.

[0155] Embodiment 17

[0156] Add 44.6 mg of gefitinib and 14.5 mg of 2-indolecarboxylic acid into a single-mouth round-bottom flask, add 3 mL of methanol and 0.2 mL of purified water, heat to 50°C, react for 4 hours, filter, place in a small glass bottle, seal with a sealing film, pierce several holes, evaporate, crystallize, filter, and dry under reduced pressure to obtain 2-indolecarboxylic acid-gefitinib cocrystal, HPLC purity: 99.85%.

[0157] Verification Example 1 Accelerated Stability Test

[0158] 1. Experimental materials: gefitinib-chrysin cocrystal, gefitinib-ketorolac cocrystal, 2-indolecarboxylic acid-gefitinib cocrystal and gefitinib Form 1 crystal prepared in the examples of the present invention.

[0159] 2. Test method: The test was conducted in accordance with the method in Appendix 9001 Stability Test Guidelines for Drug Substances and Preparations of Part IV of the Chinese Pharmacopoeia (2015 edition). Three batches of gefitinib crystals were taken and placed in a constant temperature and humidity condition of 40°C ± 2°C and 75% RH ± 5% for 6 months according to the commercial packaging. Samples were taken at the end of the 1st, 2nd, 3rd, and 6th month during the test period and tested according to the key stability inspection items.

[0160] 3. Test results: The test results are shown in Table 7.

[0161] Table 7 Accelerated stability test results

[0162]

[0163] The tests showed that the three gefitinib co-crystals prepared by the present invention had high purity, and the purity of the samples changed little after the accelerated test, showing significant stability.

[0164] Verification Example 2 Moisture Absorption Test

[0165] 1. Experimental materials: gefitinib-chrysin cocrystal, gefitinib-ketorolac cocrystal, 2-indolecarboxylic acid-gefitinib cocrystal and gefitinib Form 1 crystal prepared in the examples of the present invention.

[0166] 2. Test method: 10 mg of each of the gefitinib-chrysin cocrystal, gefitinib-ketorolac cocrystal, 2-indolecarboxylic acid-gefitinib cocrystal, and Form 1 crystal of the present invention were taken, and their hygroscopicity was tested using a dynamic moisture sorption (DVS) instrument. Three parallel tests were performed, and the results were averaged.

[0167] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Appendix XIX J of the 2010 edition of the Chinese Pharmacopoeia, Guiding Principles for Drug Hygroscopicity Test, experimental conditions: 25℃±1℃, 80%±2% relative humidity): Deliquesce: Absorb enough water to form a liquid. Very hygroscopic: Hygroscopic weight gain is not less than 15%. Hygroscopic: Hygroscopic weight gain is less than 15% but not less than 2%. Slightly hygroscopic: Hygroscopic weight gain is less than 2% but not less than 0.2%. No or almost no hygroscopicity: Hygroscopic weight gain is less than 0.2%.

[0168] 3. Test results: The results of the moisture absorption test are shown in Table 8.

[0169] Table 8 Moisture absorption test results

[0170] sample 80% relative humidity weight gain (%) Gefitinib-chrysin cocrystal 1.34 Gefitinib-ketorolac cocrystal 0.53 2-Indolecarboxylic acid-Gefitinib cocrystal 0.86 Gefitinib Form 1 3.21

[0171] After testing, the gefitinib-chrysin cocrystal, gefitinib-ketorolac cocrystal and 2-indolecarboxylic acid-gefitinib cocrystal of the present invention gained weight by 1.34%, 0.53% and 0.86% respectively after equilibrium at 80% humidity, which were all lower than Form 1 crystal.

[0172] Verification Example 3 Solubility Test

[0173] 1. Experimental materials: gefitinib-chrysin cocrystal, gefitinib-ketorolac cocrystal, and 2-indolecarboxylic acid-gefitinib cocrystal prepared in the examples of the present invention.

[0174] 2. Test method: The solubility test refers to the relevant content of the "Chinese Pharmacopoeia" (2015 edition). Measure 900 ml of the medium (pH 7.0 water, pH 2.0 hydrochloric acid solution, pH 4.0 acetate buffer) in the vial, add an excess of the drug, seal the vial and place it in a 37°C water bath for constant temperature stirring for 1 hour, filter through a 0.2μm filter membrane, take the filtrate and measure the absorbance at a wavelength of 247nm, and calculate its solubility by testing the absorbance of the standard reference substance. Perform three parallel tests and take the average of the results.

[0175] 3. Test results: The solubility test results are shown in Table 9.

[0176] Table 9 Solubility of gefitinib cocrystals in different media

[0177]

[0178]

[0179] The experiments showed that the gefitinib cocrystal prepared by the present invention has good solubility in the above three media, among which the solubility of gefitinib-ketorolac cocrystal in pH 2.0 hydrochloric acid solution is as high as 23.86 mg / ml, which helps to improve the bioavailability of gefitinib.

Claims

1. A co-crystal of gefitinib, characterized in that: The co-crystal is 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. The co-crystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ is 6.09±0.2°, 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11. There are characteristic peaks at 64±0.2°, 12.10±0.2°, 17.38±0.2°, 17.98±0.2°, 19.51±0.2°, and 21.22±0.2°, or at 6.09±0.2°, 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10± 0.2°, 17.38±0.2°, 17.98±0.2°, 19.51±0.2°, and 21.39±0.2°.

2. The co-crystal of gefitinib according to claim 1, characterized in that The co-crystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 6.09±0.2°, 6.32±0.2°, 6.89±0.2°, 7.30±0.2°, 8.26±0.2°, 11.64±0.2°, 12.10±0.2°, 17.38±0.2°, 17.98±0.2°, 19.51±0.2°, 21.22±0.2°, and 21.39±0.2°.

3. The co-crystal of gefitinib according to claim 1, characterized in that: The co-crystal uses Cu-Kα radiation, and its characteristic peaks conform to the X-ray powder diffraction pattern shown in FIG9 .

4. A method for preparing a co-crystal of gefitinib according to any one of claims 1 to 3, characterized in that: The preparation of the 2-indolecarboxylic acid-gefitinib co-crystal comprises the following steps: adding gefitinib and 2-indolecarboxylic acid to a mixed solution of water and methanol, heating for reaction, filtering, allowing the filtrate to stand for crystallization, filtering, and vacuum drying to obtain the 2-indolecarboxylic acid-gefitinib co-crystal; the volume ratio of the methanol to water is 6 to 10:1; the molar ratio of gefitinib to 2-indolecarboxylic acid is 1:0.95 to 1.25; the mass-to-volume ratio of gefitinib to methanol is 8 to 15:1, mg / ml.

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