A pharmaceutical co-crystal of gefitinib

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and relates to a gefitinib pharmaceutical co-crystal and a preparation method thereof. The application specifically provides a co-crystal formed by gefitinib and malonic acid in a molar ratio of 1:2. The gefitinib pharmaceutical co-crystal provided by the application has high solubility and good solubility, is helpful to improve the bioavailability, and has important value for optimization and development of gefitinib preparations.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to gefitinib drug cocrystals and their preparation methods. Background Technology

[0002] Gefitinib, marketed as Iressa, with the chemical name 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by AstraZeneca. It is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has not responded to or is unsuitable for chemotherapy following prior treatment with platinum-based antitumor drugs and docetaxel. It was the first small molecule protein tyrosine kinase inhibitor targeted anticancer drug approved for the treatment of solid tumors and was officially launched in China in February 2005.

[0003] Currently, many studies have reported on the polymorphism of gefitinib. Since different crystal forms of a drug can directly affect its solubility, dissolution rate, and interaction with the target in vivo, thus affecting its efficacy, given the importance of gefitinib's therapeutic effect and its high price, although gefitinib has been on the market for many years, research reports on its preferred pharmaceutical crystal forms have never stopped.

[0004] Patent WO9633980A1 first disclosed a method for preparing gefitinib compounds, but the patent did not specifically disclose whether the prepared compound was crystalline or amorphous, nor did it specifically disclose whether the compound could exist in a solvated form.

[0005] Patent CN100404032C discloses four polymorphs of gefitinib: Form 1 (polymorph), Form 2 (methanol solvate), Form 3 (DMSO solvate), and Form 5 (trihydrate), along with their preparation methods. This patent indicates that Form 1 polymorph can be obtained by washing Form 3, Form 2, or Form 5 with a solvent or solvent mixture, followed by separation. Studies have shown that Form 1 has good stability and is suitable for solid dosage forms of gefitinib, such as tablets and capsules. However, in actual preparation, the reproducibility of obtaining Form 1 is poor. The stability of Form 2 (methanol solvate) and Form 3 (DMSO solvate) is lower than that of Form 1. Furthermore, the methanol content in Form 2 is approximately 10 times the pharmacopoeia limit (0.3%), and the DMSO content in Form 3 is approximately 30 times the pharmacopoeia limit (0.5%). It is evident that Form 2 and Form 3 polymorphs are also relatively easy to prepare, but the excessive solvent residue makes them unsuitable as pharmaceutical polymorphs. Form 5 trihydrate is also less stable than Form 1, being very stable only in water, making it suitable for administration as an aqueous suspension. This greatly limits the application of the Form 5 crystal form.

[0006] Patent WO2006090413A1 discloses the gefitinib Form 6 crystal form and its preparation method. The preparation method involves mixing anhydrous gefitinib with water, stirring at ambient temperature for 18-20 hours, filtering and drying with air to obtain Form 6. This crystal form is a monohydrate crystal form, which has lower stability than Form 1 and also suffers from application limitations similar to those of Form 5 crystal form.

[0007] Patent CN103896863B discloses a new crystalline form of gefitinib, Form 7, and its preparation method. The pharmacokinetics of this crystalline form in rats were also studied. The results showed that the pharmacokinetic parameters of this crystalline form were not significantly different from those of the commercially available Form 1 crystalline form. However, other properties of this crystalline form were not studied.

[0008] Patent application CN103896861A discloses amorphous gefitinib, i.e., Form 8, and its preparation method. However, due to the physicochemical defects inherent in amorphous materials, it is generally not selected as a pharmaceutical crystal form. Patent CN104693127B discloses a gefitinib ethylene glycol solvate and its preparation method. However, studies have found that the ethylene glycol content in the crystals is approximately 300 times (0.062%) above the pharmacopoeia limit. Such a high residual amount of organic solvent makes this crystal form unsuitable as a pharmaceutical crystal form as well.

[0009] Although patent WO2014016848 mentions that gefitinib and p-hydroxybenzoic acid can form a co-crystal, it does not provide a corresponding preparation method, nor does it study the properties of the co-crystal. The inventors tried various methods in their research but failed to obtain the gefitinib and p-hydroxybenzoic acid co-crystal described in the patent.

[0010] Patent WO2015170345 mentions a co-crystal of gefitinib and malonic acid, but studies have found that its preparation method has poor reproducibility, and the co-crystal reported in this patent has poor solubility characteristics compared to existing gefitinib crystal forms.

[0011] Although numerous crystal forms of gefitinib have been published in existing literature, systematic research on its crystal forms still needs improvement, especially comprehensive studies on gefitinib cocrystal compounds, which are yet to be reported. Novel drug cocrystal salts refer to supramolecular crystals with fixed stoichiometric ratios formed by the self-assembly of a new cocrystal material (CCF) with the active pharmaceutical ingredient (API) under hydrogen bonding, introduced through proton transfer. Due to their potential advantages in dissolution, permeation, hygroscopicity, and stability, drug cocrystals have attracted increasing interest from researchers in the field of drug preparation. Summary of the Invention

[0012] In view of the shortcomings of the prior art, the present invention provides a gefitinib drug cocrystal, a method for preparing such cocrystals, and a composition comprising a cocrystal.

[0013] In a first aspect, the present invention provides a gefitinib drug cocrystal, the cocrystal being composed of gefitinib and a cocrystal formation selected from malonic acid, succinic acid, and emodin.

[0014] For ease of reference, the different cocrystals described herein are consistently referred to throughout this application as a cocrystal composed of gefitinib and malonic acid in a molar ratio of 1:2, a cocrystal composed of gefitinib and succinic acid in a molar ratio of 4:1, and a cocrystal composed of gefitinib, emodin, and methanol in a molar ratio of 1:2:1.

[0015] A co-crystal of gefitinib and malonic acid in a molar ratio of 1:2

[0016] In one embodiment, the present invention relates to a co-crystal formed by combining gefitinib and malonic acid, specifically a co-crystal formed by gefitinib and malonic acid in a molar ratio of 1:2, referred to herein as a co-crystal formed by gefitinib and malonic acid in a molar ratio of 1:2. Based on its physical properties, the co-crystal formed by gefitinib and malonic acid in a molar ratio of 1:2 is a crystal form.

[0017] The eutectic of gefitinib and malonic acid in a molar ratio of 1:2 can be characterized as having one or more of the following physical characteristics:

[0018] (a) Having X-ray diffraction peaks at 2θ including 6.26±0.2°, 7.59±0.2°, 7.83±0.2°, 11.57±0.2°, 19.05±0.2°, 25.64±0.2°, or having X-ray diffraction peaks at 2θ including 6.26±0.2°, 7.59±0.2°, 11.57±0.2°, 19.05±0.2°, 25.64±0.2°, or having X-ray diffraction peaks at 2θ including 6.26±0.2°, 7.83 ... 19.05±0.2°, 25.64±0.2°, 19.05±0.2°, 25.64±0.2°, 19.05 X-ray diffraction peaks at 2θ (using Cu-Kα radiation, X-ray diffraction pattern expressed in 2θ) at 2°, 19.05±0.2°, and 25.64±0.2°; preferably, including peaks selected from 6.26±0.2°, 7.59±0.2°, 7.83±0.2°, 11.57±0.2°, 14.18±0.2°, 16.15±0.2°, 19.05±0.2°, 19.99±0.2°, 21.48±0.2°, 24.22±0.2°, and 25.64±0.2°. Five or more diffraction peaks selected from the diffraction peaks at 4±0.2°, 26.74±0.2°, and 27.04±0.2°, or including diffraction peaks selected from the diffraction peaks at 6.26±0.2°, 7.59±0.2°, 7.83±0.2°, 11.57±0.2°, 14.18±0.2°, 16.15±0.2°, 19.05±0.2°, 19.99±0.2°, 21.48±0.2°, 24.22±0.2°, 25.64±0.2°, and 27.04±0.2°. The diffraction peaks at 6.26±0.2°, 7.59±0.2°, 7.83±0.2°, 11.57±0.2°, 14.18±0.2°, 16.15±0.2°, 19.05±0.2°, 19.99±0.2°, 21.48±0.2°, 24.22±0.2°, 25.64±0.2°, and 26.74±0.2° are selected as the ... Figure 1 The X-ray powder diffraction pattern shown;

[0019] (b) Its crystallographic parameters are: triclinic system, space group P-1; unit cell parameters are: α = 64.4281(18)°, β = 77.124(3)°, γ = 79.788(2)°, cell volume ;

[0020] (c) A differential scanning calorimeter with an endothermic peak in the temperature range of 187.25 to 200.68 °C and a peak value of 189.62 °C.

[0021] A eutectic of gefitinib and succinic acid in a molar ratio of 4:1

[0022] In one embodiment, the present invention relates to a cocrystal formed by combining gefitinib and succinic acid, specifically a cocrystal formed by gefitinib and succinic acid in a molar ratio of 4:1, referred to herein as a cocrystal formed by gefitinib and succinic acid in a molar ratio of 4:1. Based on its physical properties, the cocrystal formed by gefitinib and succinic acid in a molar ratio of 4:1 is a crystal form.

[0023] The eutectic of gefitinib and succinic acid in a molar ratio of 4:1 can be characterized as having one or more of the following physical characteristics:

[0024] (a) Having X-ray diffraction peaks at 2θ (using Cu-Kα radiation, X-ray diffraction pattern expressed in 2θ) including peaks at 5.85±0.2°, 6.46±0.2°, 9.99±0.2°, 13.07±0.2°, and 18.39±0.2°, preferably including five or more diffraction peaks selected from peaks at 5.85±0.2°, 6.46±0.2°, 7.85±0.2°, 9.99±0.2°, 13.07±0.2°, 18.39±0.2°, 19.32±0.2°, 21.72±0.2°, 24.82±0.2°, and 26.59±0.2°, more preferably having... Figure 2 The X-ray powder diffraction pattern shown;

[0025] (b) Its crystallographic parameters are: triclinic system, space group P-1; unit cell parameters are: α = 91.5500(10)°, β = 109.8010(10)°, γ = 95.9810(10)°, cell volume ;

[0026] (c) Differential scanning calorimetry spectrum with an endothermic peak in the temperature range of 191.50 to 213.36 °C and a peak value of 194.21 °C.

[0027] A co-crystal formed by combining gefitinib with emodin and methanol in a molar ratio of 1:2:1

[0028] In one embodiment, the present invention relates to a co-crystal formed by combining gefitinib with emodin and methanol, referred herein as a co-crystal formed by combining gefitinib with emodin and methanol in a molar ratio of 1:2:1. Based on its physical properties, the co-crystal formed by combining gefitinib with emodin and methanol in a molar ratio of 1:2:1 is a crystalline form.

[0029] The cocrystal formed by combining gefitinib with emodin and methanol in a molar ratio of 1:2:1 can be characterized as having one or more of the following physical characteristics:

[0030] (a) Having X-ray diffraction peaks at 2θ including 4.83±0.2°, 6.10±0.2°, 7.05±0.2°, 8.33±0.2°, 8.86±0.2°, 9.33±0.2°, 9.70±0.2°, and 17.81±0.2° (X-ray diffraction pattern expressed in 2θ using Cu-Kα radiation), preferably including those selected from 4.83±0.2°, 6.10±0.2°, 7.05±0.2°, 8.33±0.2°, 8.86±0.2°, 9.33±0.2°, 9.70±0.2°, and 17.81±0.2°, preferably including those selected from 4.83±0.2°, 6.10±0.2°, 7.05±0.2°, 8.33±0.2°, 8.86±0.2°, 9.33±0.2°, 9.70±0.2°, and 17.81±0.2°. Five or more diffraction peaks selected from the diffraction peaks at 91±0.2°, 13.18±0.2°, 14.16±0.2°, 14.76±0.2°, 16.74±0.2°, 17.81±0.2°, 19.60±0.2°, 23.12±0.2°, 24.66±0.2°, 25.10±0.2°, 25.58±0.2°, and 26.25±0.2°, or including diffraction peaks selected from 4.83±0.2°, 6.10±0.2°, 7.05±0.2°, 8.33±0.2°, 8.86±0.2°, and 9.33. Five or more diffraction peaks selected from the following values: ±0.2°, 9.70±0.2°, 10.91±0.2°, 13.18±0.2°, 14.16±0.2°, 14.76±0.2°, 16.74±0.2°, 17.81±0.2°, 19.60±0.2°, 23.12±0.2°, 24.66±0.2°, 25.10±0.2°, 25.58±0.2°, and 26.79±0.2°; or including diffraction peaks selected from the following values: 4.83±0.2°, 6.10±0.2°, 7.05±0.2°, and 8.33°. Five or more diffraction peaks are formed by diffraction peaks at ±0.2°, 8.86±0.2°, 9.33±0.2°, 9.70±0.2°, 10.91±0.2°, 13.18±0.2°, 14.16±0.2°, 14.76±0.2°, 16.74±0.2°, 17.81±0.2°, 19.60±0.2°, 23.12±0.2°, 24.66±0.2°, 25.10±0.2°, 25.58±0.2°, 26.25±0.2°, and 26.79±0.2°. More preferably, the diffraction peaks have the following characteristics: Figure 3 The X-ray powder diffraction pattern shown;

[0031] (b) Its crystallographic parameters are: monoclinic system, space group P21 / c; unit cell parameters are: α = 90°, β = 96.3038(6)°, γ = 90°, cell volume ;

[0032] (c) Differential scanning calorimetry spectrum with two sets of endothermic peaks in the temperature ranges of 145.52–172.11 °C and 184.09–202.94 °C.

[0033] Preparation and characterization of gefitinib cocrystal

[0034] Gefitinib can be synthesized using various methods or obtained commercially. A representative method for synthesizing gefitinib is described in patent CN1882569B.

[0035] Methods for preparing gefitinib cocrystals are described in Examples 1-9, wherein Examples 1-3 describe the preparation method of a cocrystal composed of gefitinib and malonic acid in a molar ratio of 1:2, Examples 4-6 describe the preparation method of a cocrystal composed of gefitinib and succinic acid in a molar ratio of 4:1, and Examples 7-9 describe the preparation method of a cocrystal composed of gefitinib, emodin, and methanol in a molar ratio of 1:2:1.

[0036] Various experiments were performed to physically characterize the gefitinib drug cocrystals, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Methods used to test the solubility of the gefitinib drug cocrystals are described in Examples 10-11.

[0037] A co-crystal of gefitinib and malonic acid in a molar ratio of 1:2

[0038] A cocrystal of gefitinib and malonic acid in a molar ratio of 1:2 can be prepared by using various solvents and crystallizing under various crystallization conditions during polymorph screening (e.g., fast and slow evaporation, cooling of saturated solutions, grinding, addition of solvents and antisolvents). Examples 1-3 summarize a method for preparing a cocrystal of gefitinib and malonic acid in a molar ratio of 1:2. For example, gefitinib and malonic acid are placed in a mortar, organic solvent A is added, and the mixture is ground until a white powder is formed. Then, organic solvent A is added again, and the mixture is ground until dissolved. The mixture is allowed to stand and crystallize under controlled temperature, filtered, and vacuum dried to obtain the final product.

[0039] Preferably, the organic solvent A is selected from one or a combination of ethanol, acetone, methanol, and isopropanol.

[0040] More preferably, the organic solvent A is one of ethanol, methanol, or a combination thereof.

[0041] Preferably, the mass-to-volume ratio of gefitinib to organic solvent A required for the first milling is 50-80:1, where mass is expressed in mg and volume in ml.

[0042] Preferably, the molar ratio of gefitinib to malonic acid is 1:1.95 to 2.5.

[0043] More preferably, the molar ratio of gefitinib to malonic acid is 1:2.0 to 2.2.

[0044] Preferably, the first grinding time is 20 to 50 minutes.

[0045] Preferably, the volume ratio of organic solvent A required for the first grinding to that required for the second grinding is 1:3 to 10.

[0046] Preferably, the temperature for controlled crystallization is 0–10°C.

[0047] More preferably, the temperature for controlled crystallization is 0–5°C.

[0048] Preferably, the crystallization time is 48 to 72 hours.

[0049] Preferably, the drying temperature is 50-60°C and the drying time is 8-10 hours.

[0050] The co-crystal of gefitinib and malonic acid in a molar ratio of 1:2 was characterized by XRPD, TGA, and DSC.

[0051] Figure 1 The characteristic XRPD spectrum (CuKα) of the eutectic composed of gefitinib and malonic acid in a molar ratio of 1:2 is shown. The XRPD pattern confirmed that the eutectic of gefitinib and malonic acid in a molar ratio of 1:2 is crystalline. The main X-ray diffraction patterns, represented as 2θ, and their relative intensities are summarized in Table 1.

[0052] Table 1. Characteristic XRPD peaks (CuKα) of the eutectic composed of gefitinib and malonic acid in a molar ratio of 1:2.

[0053]

[0054]

[0055]

[0056] The set of XRPD peak positions mentioned above, or a subset thereof, can be used to identify the cocrystal of gefitinib and malonic acid in a molar ratio of 1:2.

[0057] Figure 4The image shows the DSC / TGA spectrum of a eutectic composed of gefitinib and malonic acid in a molar ratio of 1:2. TGA analysis indicates that the eutectic of gefitinib and malonic acid in a molar ratio of 1:2 exhibits a significant weight loss from 148.91 to 212.69 °C, suggesting that the eutectic of gefitinib and malonic acid in a molar ratio of 1:2 decomposes during melting. The DSC spectrum shows an endothermic peak in this eutectic, with a temperature range of 187.25–200.68 °C and a peak value of 189.62 °C.

[0058] A eutectic of gefitinib and succinic acid in a molar ratio of 4:1

[0059] A cocrystal of gefitinib and succinic acid in a molar ratio of 4:1 can be prepared by using various solvents and crystallizing under various crystallization conditions during polymorph screening (e.g., fast and slow evaporation, cooling of saturated solutions, addition of solvents and antisolvents). Examples 4-6 summarize a method for preparing a cocrystal of gefitinib and succinic acid in a molar ratio of 4:1. For example, gefitinib and succinic acid are dissolved in a mixed solvent of methanol and organic solvent B, ultrasonically heated until the solid is completely dissolved, allowed to stand to crystallize, filtered, and dried to obtain the final product.

[0060] Preferably, the organic solvent B is selected from one or more of acetone, ethanol, isopropanol, acetonitrile, and water.

[0061] Preferably, the volume fraction of methanol in the mixed solvent is 11% to 100%.

[0062] Preferably, the molar ratio of gefitinib to succinic acid is 3.5 to 4.2:1.

[0063] More preferably, the molar ratio of gefitinib to succinic acid is 3.9 to 4.1:1.

[0064] Preferably, the heating temperature is 40–60°C.

[0065] Preferably, the mass-to-volume ratio of gefitinib to the mixed solvent is 8 to 20:1, wherein the mass is expressed in mg and the volume in mL.

[0066] More preferably, the mass-to-volume ratio of gefitinib to the mixed solvent is 10-15:1; wherein the mass is expressed in mg and the volume in mL.

[0067] Preferably, the crystallization time is 24 to 72 hours.

[0068] Preferably, the crystallization temperature is 15–40°C.

[0069] Preferably, the drying temperature is 26–55°C and the drying time is 8–24 hours.

[0070] The following details the preparation method of the eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1 according to the present invention:

[0071] Gefitinib and succinic acid in a molar ratio of 3.9–4.1:1 were dissolved in a mixed solvent of methanol and organic solvent B. The solution was heated to 40–60°C by sonication. After the gefitinib and succinic acid dissolved, the solution was filtered. The filtrate was allowed to stand to crystallize. The crystals were then filtered and dried for 8–24 hours to obtain the final product.

[0072] Preferably, the organic solvent B is selected from one or more of water, ethanol, acetone and acetonitrile.

[0073] Figure 2 The characteristic XRPD spectrum (CuKα) of the eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1 is shown. The XRPD pattern confirmed that the eutectic of gefitinib and succinic acid in a molar ratio of 4:1 is crystalline. The main X-ray diffraction patterns, represented as 2θ, and their relative intensities are summarized in Table 2.

[0074] Table 2. Characteristic XRPD peaks (CuKα) of the eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1.

[0075]

[0076]

[0077] The set of XRPD peak positions mentioned above, or a subset thereof, can be used to identify the cocrystal of gefitinib and succinic acid in a molar ratio of 4:1.

[0078] Figure 5 The image shows the DSC / TGA spectrum of a eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1. TGA analysis indicates that the eutectic of gefitinib and succinic acid in a molar ratio of 4:1 exhibits a significant weight loss in the temperature range of 185.2–300.97 °C, indicating that the eutectic of gefitinib and succinic acid in a molar ratio of 4:1 decomposes during melting. The DSC spectrum shows an endothermic peak in this eutectic, with a temperature range of 191.50–213.36 °C and a peak value of 194.21 °C.

[0079] A co-crystal formed by combining gefitinib with emodin and methanol in a molar ratio of 1:2:1

[0080] A cocrystal of gefitinib, emodin, and methanol in a molar ratio of 1:2:1 can be prepared by crystallization under various solvents and crystallization conditions used in polymorph screening processes (e.g., fast and slow evaporation, cooling of saturated solutions, addition of solvents and antisolvents). Examples 7-9 summarize a method for preparing a cocrystal of gefitinib, emodin, and methanol in a molar ratio of 1:2:1. For example, gefitinib and emodin are added to methanol, heated to react, filtered, the filtrate is allowed to stand to crystallize, filtered again, and vacuum dried to obtain the cocrystal.

[0081] Preferably, the molar ratio of gefitinib to emodin is 1:0.9 to 1.5.

[0082] More preferably, the molar ratio of gefitinib to emodin is 1:1.

[0083] The mass-to-volume ratio of gefitinib to methanol in the system is 5–10:1, where mass is expressed in mg and volume in ml.

[0084] The heating temperature is 45–60°C.

[0085] The heating reaction takes 3 to 5 hours.

[0086] The temperature at which the crystals are allowed to settle is room temperature.

[0087] Preferably, the static crystallization method is solvent evaporation crystallization.

[0088] Figure 3 The characteristic XRPD spectrum (CuKα) of the cocrystal formed by combining gefitinib with emodin and methanol in a molar ratio of 1:2:1 is shown. The XRPD pattern confirmed that the cocrystal formed by gefitinib, emodin, and methanol in a molar ratio of 1:2:1 was indeed crystalline. The principal X-ray diffraction patterns, expressed as 2θ, and their relative intensities are summarized in Table 3.

[0089] Table 3. Main XRD peaks of the cocrystal formed by gefitinib combined with emodin and methanol in a molar ratio of 1:2:1

[0090]

[0091]

[0092] The set of XRPD peak positions mentioned above, or a subset thereof, can be used to identify the cocrystal formed by the combination of gefitinib with emodin and methanol in a molar ratio of 1:2:1.

[0093] Figure 6The image shows the DSC / TGA plot of the eutectic formed by combining gefitinib with emodin and methanol in a molar ratio of 1:2:1. It has two sets of endothermic peaks with temperature ranges of 145.52–172.11℃ and 184.09–202.94℃, with peak values ​​of 157.99℃ and 190.11℃, respectively.

[0094] In a third aspect, the present invention provides a pharmaceutical composition comprising the gefitinib drug cocrystal described herein.

[0095] The pharmaceutical composition of the present invention can be prepared as follows: using standard and conventional techniques, the gefitinib drug cocrystal of the present invention is combined with a pharmaceutically acceptable solid or liquid carrier, and then arbitrarily combined with pharmaceutically acceptable excipients and formulations to prepare a usable dosage form.

[0096] The pharmaceutical compositions of the present invention include sprays, tablets, capsules, powder for injection, liquid injections and other pharmaceutically available dosage forms.

[0097] In a fourth aspect, the present invention provides the use of gefitinib drug cocrystal as an active ingredient in the preparation of a drug for treating locally advanced or metastatic non-small cell lung cancer that is ineffective or unsuitable for chemotherapy.

[0098] Confirmation of the cocrystal structure of gefitinib:

[0099] The gefitinib drug cocrystal provided by this invention was subjected to X-ray single-crystal diffraction analysis. The X-ray single-crystal diffraction instrument and testing conditions involved in this invention are: Rigaku XtaLAB Synergy X-ray single-crystal diffractometer, testing temperature 293(2)K or 102.63(10)K, CuKa radiation, data collection in ω-scan mode and Lp correction. The structure was resolved by direct method, all non-hydrogen atoms were identified by difference Fourier method, all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least squares method.

[0100] The crystallographic data obtained from the testing and analysis of the eutectic of gefitinib and malonic acid prepared in this invention at a molar ratio of 1:2 are shown in Table 4. Its crystallographic parameters are: triclinic system, space group P-1; cell parameters are: α = 64.4281(18)°, β = 77.124(3)°, γ = 79.788(2)°, cell volume The ORTEP diagram of the eutectic gefitinib and malonic acid combination in this invention shows that one molecule of gefitinib binds to two molecules of malonic acid, as... Figure 7 As shown, the packing diagram of the eutectic formed by gefitinib and malonic acid in a molar ratio of 1:2 in this invention is as follows. Figure 10As shown.

[0101] Table 4. Key crystallographic data of the eutectic composed of gefitinib and malonic acid in a molar ratio of 1:2.

[0102]

[0103]

[0104]

[0105] The crystallographic data obtained from the testing and analysis of the eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1 prepared in this invention are shown in Table 5. Its crystallographic parameters are: triclinic system, space group P-1; cell parameters are: α = 91.5500(10)°, β = 109.8010(10)°, γ = 95.9810(10)°, cell volume The ORTEP diagram of the eutectic gefitinib and succinic acid combination in this invention shows that four molecules of gefitinib are combined with one molecule of succinic acid, as... Figure 8 As shown, the packing diagram of the eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1 in this invention is as follows. Figure 11 As shown.

[0106] Table 5. Main crystallographic data of the eutectic formed by gefitinib and succinic acid in a molar ratio of 4:1.

[0107]

[0108]

[0109] The crystallographic data obtained from the testing and analysis of the eutectic formed by the combination of gefitinib, emodin, and methanol in a molar ratio of 1:2:1 prepared in this invention are shown in Table 6. Its crystallographic parameters are: monoclinic system, space group P21 / c; cell parameters are: α = 90°, β = 96.3038(6)°, γ = 90°, cell volume The ORTEP diagram of the cocrystallization of gefitinib with emodin and methanol in this invention shows that one molecule of gefitinib binds to two molecules of emodin and one molecule of methanol, as shown in the figure. Figure 9 As shown.

[0110] Table 6. Main crystallographic data of the cocrystal formed by gefitinib combined with emodin and methanol in a molar ratio of 1:2:1

[0111]

[0112]

[0113] The X-ray powder diffraction testing instrument and testing conditions involved in this 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; Solar slit: 0.04rad; step size: 0.5s; scanning range: 3~50°.

[0114] The gefitinib cocrystal prepared by the method described in this invention has the following advantages over currently reported gefitinib crystal forms:

[0115] (1) High solubility. The cocrystal of gefitinib and malonic acid in a molar ratio of 1:2 has high solubility in water, hydrochloric acid at pH 1.2, and phosphate buffer at pH 6.8. The cocrystal of gefitinib and succinic acid in a molar ratio of 4:1 has a solubility of up to 27.41 mg / ml in hydrochloric acid solution at pH 1.2.

[0116] (2) Good solubility. The cocrystal of gefitinib and malonic acid in a molar ratio of 1:2 and the cocrystal of gefitinib and succinic acid in a molar ratio of 4:1 have high solubility and uniform release in hydrochloric acid solution at pH=3, and the solubility rate is stable, making them suitable for preparation into formulations. Attached Figure Description

[0117] Figure 1 X-ray powder diffraction pattern of a eutectic of gefitinib and malonic acid in a molar ratio of 1:2;

[0118] Figure 2 X-ray powder diffraction pattern of a eutectic of gefitinib and succinic acid in a molar ratio of 4:1;

[0119] Figure 3 X-ray powder diffraction pattern of a eutectic composed of gefitinib, emodin, and methanol in a molar ratio of 1:2:1.

[0120] Figure 4 DSC / TGA plot of a eutectic of gefitinib and malonic acid in a molar ratio of 1:2;

[0121] Figure 5 DSC / TGA image of a eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1;

[0122] Figure 6 DSC / TGA image of the cocrystal formed by gefitinib combined with emodin and methanol in a molar ratio of 1:2:1.

[0123] Figure 7 ORTEP diagram of a eutectic composed of gefitinib and malonic acid in a molar ratio of 1:2;

[0124] Figure 8 ORTEP diagram of a eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1;

[0125] Figure 9 ORTEP diagram of the cocrystal formed by gefitinib combined with emodin and methanol in a molar ratio of 1:2:1;

[0126] Figure 10 Packing diagram of a eutectic composed of gefitinib and malonic acid in a molar ratio of 1:2;

[0127] Figure 11 Packing diagram of a eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1;

[0128] Figure 12 : Packing diagram of the eutectic formed by gefitinib combined with emodin and methanol in a molar ratio of 1:2:1. Detailed Implementation

[0129] The present invention will be further described below through specific embodiments. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0130] I. Preparation method of eutectic composed of gefitinib and malonic acid in a molar ratio of 1:2:

[0131] Example 1

[0132] 60.0 mg gefitinib and 27.9 mg malonic acid were placed in a mortar, and 1 mL of methanol was added dropwise. The mixture was ground thoroughly for 35 min, and then 5 mL of methanol was added and the mixture was ground for another 15 min to obtain a clear solution. The solution was allowed to stand at 0–5 °C for 48 hours to crystallize. After filtration, the solution was dried under vacuum at 50.5 °C for 8 h to obtain a co-crystal of gefitinib and malonic acid in a molar ratio of 1:2, with a yield of 94.32% and an HPLC purity of 99.96%.

[0133] Example 2

[0134] 50.0 mg of gefitinib and 23.9 mg of malonic acid were placed in a mortar, and 1 mL of ethanol was added dropwise. The mixture was ground thoroughly for 30 min, and then 3 mL of ethanol was added and the mixture was ground for another 10 min to obtain a clear solution. The solution was allowed to stand at 5–10 °C for 52 hours to crystallize, filtered, and dried under vacuum at 55 °C for 10 h to obtain a co-crystal of gefitinib and malonic acid in a molar ratio of 1:2, with a yield of 95.76% and an HPLC purity of 99.97%.

[0135] Example 3

[0136] 80.0 mg gefitinib and 41.0 mg malonic acid were placed in a mortar, and 1 mL of methanol was added dropwise. The mixture was ground thoroughly for 50 min, and then 10 mL of ethanol was added and the mixture was ground for another 20 min to obtain a clear solution. The solution was allowed to stand at 0–5 °C for 72 hours to crystallize. After filtration, the solution was dried under vacuum at 60 °C for 9 h to obtain a co-crystal of gefitinib and malonic acid in a molar ratio of 1:2, with a yield of 94.14% and an HPLC purity of 99.95%.

[0137] II. Preparation method of eutectic composed of gefitinib and succinic acid in a molar ratio of 4:1:

[0138] Example 4

[0139] Gefitinib 178.8 mg and succinic acid 11.8 mg were dissolved in 15 mL of a mixed solvent (10 mL methanol + 2 mL purified water + 3 mL acetone), and ultrasonically heated to 50 °C until the solid dissolved. The solution was filtered, and the filtrate was allowed to crystallize at 15–20 °C for 40–45 hours. After filtration, the solution was dried at 26–30 °C for 10 hours to obtain a co-crystal of gefitinib and succinic acid in a molar ratio of 4:1. The yield was 94.48%, and the HPLC purity was 99.96%.

[0140] Example 5

[0141] Gefitinib 178.8 mg and succinic acid 11.5 mg were dissolved in 18 mL of a mixed solvent (10 mL methanol + 4 mL purified water + 4 mL ethanol), and ultrasonically heated to 40 °C until the solid dissolved. The solution was filtered, and the filtrate was allowed to crystallize at 20–25 °C for 45–50 hours. After filtration, the solution was dried at 30–35 °C for 15 hours to obtain a co-crystal of gefitinib and succinic acid in a molar ratio of 4:1. The yield was 94.12%, and the HPLC purity was 99.93%.

[0142] Example 6

[0143] Gefitinib 178.8 mg and succinic acid 12.1 mg were dissolved in 12 mL of a mixed solvent (6 mL methanol + 6 mL purified water), and ultrasonically heated to 60 °C until the solid dissolved. The solution was filtered, and the filtrate was allowed to crystallize at 25–30 °C for 50–55 hours. After filtration, the solution was dried at 35–40 °C for 8 hours to obtain a co-crystal of gefitinib and succinic acid in a molar ratio of 4:1. The yield was 93.75%, and the HPLC purity was 99.90%.

[0144] III. Preparation method of co-crystal formed by combining gefitinib with emodin and methanol in a molar ratio of 1:2:1

[0145] Example 7

[0146] 44.6 mg of gefitinib and 27.0 mg of emodin were added to a single-necked round-bottom flask, followed by 6.0 mL of methanol. The mixture was heated to 50 °C and reacted for 4 h. After filtration, the mixture was placed in a small glass bottle, sealed with sealing film, and several holes were punched in the bottle. The mixture was then allowed to evaporate, crystallize, filter, and dry under reduced pressure to obtain a co-crystal composed of gefitinib, emodin, and methanol in a molar ratio of 1:2:1. The HPLC purity was 99.98%.

[0147] Example 8

[0148] 44.6 mg of gefitinib and 24.3 mg of emodin were added to a single-necked round-bottom flask, along with 5.0 mL of methanol. The mixture was heated to 60 °C and reacted for 3 h. After filtration, the mixture was placed in a small glass bottle, sealed with sealing film, and several holes were punched in the bottle. The mixture was then allowed to evaporate, crystallize, filter, and dry under reduced pressure to obtain a co-crystal composed of gefitinib, emodin, and methanol in a molar ratio of 1:2:1. The HPLC purity was 99.96%.

[0149] Example 9

[0150] 44.6 mg of gefitinib and 40.5 mg of emodin were added to a single-necked round-bottom flask, followed by 9.0 mL of methanol. The mixture was heated to 45 °C and reacted for 5 h. After filtration, the mixture was placed in a small glass bottle, sealed with sealing film, and several holes were punched in the bottle. The mixture was allowed to evaporate, crystallize, filter, and dry under reduced pressure to obtain a co-crystal composed of gefitinib, emodin, and methanol in a molar ratio of 1:2:1. The HPLC purity was 99.94%.

[0151] Example 10: Solubility Test

[0152] Following the pharmacopoeia method, to conserve materials and proportionally reduce dosage, hydrochloric acid solution with pH 1.2, phosphate buffer solution with pH 6.8, and water were prepared. Appropriate amounts of cocrystals composed of gefitinib and malonic acid in a molar ratio of 1:2, gefitinib and succinic acid in a molar ratio of 4:1, and gefitinib and emodin and methanol in a molar ratio of 1:2:1 were sequentially placed into stoppered test tubes containing water, hydrochloric acid solution (pH 1.2), and phosphate buffer solution (pH 6.8). The samples were placed in a water bath at 37°C and 200 rpm for 24 hours to equilibrate. Samples were taken at designated times, filtered through a 0.45 μm microporous membrane, and the filtrate was diluted with water to the linear range. Using the aqueous solution as a blank, the absorbance was measured at a wavelength of 254 nm until the absorbance no longer changed. All experimental results are based on the measured equilibrium solubility of gefitinib. The experimental results are shown in Table 7.

[0153] Table 7 Solubility of Gefitinib Cocrystal

[0154]

[0155] The results showed that the cocrystal of gefitinib and malonic acid in a molar ratio of 1:2 prepared in this invention had high solubility in water, hydrochloric acid solution at pH 1.2, and phosphate buffer solution at pH 6.8; the cocrystal of gefitinib and succinic acid in a molar ratio of 4:1 had a solubility of up to 27.41 mg / ml in hydrochloric acid solution at pH 1.2; and the cocrystal of gefitinib combined with emodin and methanol in a molar ratio of 1:2:1 had high solubility in water and phosphate buffer solution at pH 6.8.

[0156] Example 11: Characteristic Dissolution Rate Test

[0157] The characteristic dissolution rates of gefitinib cocrystals (1:2 molar ratio with malonic acid), gefitinib cocrystals (4:1 molar ratio with succinic acid), and gefitinib cocrystals (1:2:1 molar ratio with emodin and methanol) were investigated using a USP-certified Electrolab TDL-08 tablet dissolution analyzer at 37°C and 50 rpm in HCl solution at pH 3. Aliquots (1 mL) were taken at specific time intervals and replenished with an equal volume of fresh pH solution to maintain a constant volume. These aliquots were analyzed at 254 nm using a UV spectrophotometer (UV-1601PC, Shimadzu Scientific Instrument) and compared with a standard calibration curve. The results are shown in Table 8.

[0158] Table 8 Results of the characteristic dissolution rate test

[0159]

[0160] All cocrystals of the same type of gefitinib prepared in this invention have the same solubility properties.

[0161] The results show that the cocrystals of gefitinib and malonic acid in a molar ratio of 1:2 and gefitinib and succinic acid in a molar ratio of 4:1 prepared by the present invention are uniformly released and have a stable dissolution rate in hydrochloric acid solution with pH=3, and are suitable for preparation into formulations.

Claims

1. A co-crystal of gefitinib and malonic acid, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, shows characteristic peaks at 6.26±0.2°, 7.59±0.2°, 7.83±0.2°, 11.57±0.2°, 14.18±0.2°, 16.15±0.2°, 19.05±0.2°, 19.99±0.2°, 21.48±0.2°, 24.22±0.2°, 25.64±0.2°, and 27.04±0.2°; the cocrystal is a cocrystal composed of gefitinib and malonic acid in a molar ratio of 1:

2.

2. The cocrystal of gefitinib and malonic acid according to claim 1, characterized in that, Using Cu-Kα radiation, the characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 1.

3. A method for preparing the co-crystal of gefitinib and malonic acid according to any one of claims 1-2, characterized in that, The specific steps of the preparation method include: placing gefitinib and malonic acid in a mortar, adding organic solvent A and grinding until a white powder is formed, then adding organic solvent A and grinding until dissolved, allowing to stand and crystallize under controlled temperature, filtering, and vacuum drying to obtain the final product.

4. A pharmaceutical composition comprising a cocrystal of gefitinib and malonic acid as described in any one of claims 1-2, and comprising other pharmaceutically acceptable excipient components.

5. The cocrystal of gefitinib and malonic acid as described in any one of claims 1-2 is used as an active ingredient in the preparation of a drug for treating locally advanced or metastatic non-small cell lung cancer that is ineffective or unsuitable for chemotherapy.

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