Acid addition salt of gefitinib
By forming gefitinib with acid addition salts of sulfamic acid, glycolic acid and phthalic acid, the problems of low solubility and poor stability of existing crystal forms are solved, high solubility and low moisture-induced properties are achieved, and the drugs are improved bioavailability and safety.
Patent Information
- Application Number
- CN202010609136.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2020-06-29
- Publication Date
- 2024-12-17
- Estimated Expiration
- 2040-06-29
AI Technical Summary
The existing crystal forms of gefitinib have problems such as low solubility, poor stability, poor reproducibility during preparation and excessive organic solvent residues, which affect its efficacy and safety.
A gefitinib acid addition salt was developed to form eutectics with sulfamic acid, glycolic acid and phthalic acid, and to improve solubility and stability by using the formation of acid addition salts to avoid polycrystalline phenomena and solvents. Remaining.
The acid addition salt of gefitinib has higher solubility and chemical stability than a single drug component, low humidity, significantly improves its solubility and stability in the body, and reduces the risk of gastrointestinal side effects.
Smart Images
Figure BDA0002560254740000011 
Figure BDA0002560254740000061 
Figure BDA0002560254740000071
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an acid addition salt of gefitinib. Background Art
[0002] Gefitinib, chemical name 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline, has a structure as shown in Formula I, and its trade name is Iressa. It is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by AstraZeneca. It is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has been ineffective or unsuitable for chemotherapy with platinum-based anti-tumor drugs and docetaxel chemotherapy. It is the first small molecule protein tyrosine kinase inhibitor targeted anticancer drug for the treatment of solid tumors. It was officially approved for marketing in China in February 2005. Its structural formula is shown in Formula I:
[0003]
[0004] Gefitinib contains more than two hydrophobic groups in its structure, making it a poorly soluble drug; the molecule contains two weakly basic groups, aliphatic tertiary amine and aromatic secondary amine, which makes its solubility in water pH-dependent. It is slightly soluble in water at pH = 1, and its solubility becomes poor at pH = 4-6. It is almost insoluble in water when the pH is greater than 7. The results of an experiment on healthy volunteers showed that when the pH value was maintained above 5, the absorption of gefitinib decreased by 47%. Since gefitinib is poorly soluble in water at pH 6 or above, it has brought great difficulties to the research on gefitinib preparations. Therefore, improving the solubility of gefitinib has become one of the bottlenecks in the development of its related preparations.
[0005] 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.
[0006] Patent WO9633980 discloses for the first time a method for preparing a gefitinib compound, but the patent does not specifically disclose whether the prepared compound is crystalline or amorphous, nor does it specifically disclose whether the compound can exist in a solvated form.
[0007] Patent CN100404032C discloses four crystal forms of gefitinib Form 1 (polymorph), Form 2 (methanol solvate), Form 3 (DMSO solvate), and Form 5 (trihydrate) and their preparation methods. The patent points out that after washing Form 3, Form 2 or Form 5 with a solvent or a solvent mixture, Form 1 polymorph can be obtained by separation. The stability of Form 2 methanol solvate and Form 3 DMSO solvate are both lower than Form 1, and the content of methanol in the Form 2 crystal form is about 10 times the pharmacopoeia limit (pharmacopoeia limit is 0.3%). The content of DMSO in the Form 3 crystal form is about 30 times the pharmacopoeia limit (pharmacopoeia limit is 0.5%). It can be seen that the crystal forms of Form 2 and Form 3 are also relatively easy to prepare, but too much solvent residue makes it unsuitable as a pharmaceutical crystal form. The stability of Form 5 trihydrate is also not as good as Form 1. It is only very stable in water and is suitable for administration in the form of an aqueous suspension, which also greatly limits the application of Form 5 crystal form.
[0008] Patent WO2006090413A1 discloses Gefitinib Form 6 crystal form and preparation method, wherein the preparation method comprises mixing anhydrous Gefitinib with water, stirring at ambient temperature for 18-20 hours, filtering air and drying to obtain Form 6, which is a monohydrate crystal form with lower stability than Form 1 and also has the same application limitation problem as Form 5 crystal form.
[0009] Patent CN103896863B discloses a new crystal form of gefitinib Form 7 and its preparation method, and studies the pharmacokinetics of the crystal form in rats. The results show that the pharmacokinetic parameters of the crystal form are not significantly different from those of the commercially available Form 1 crystal form, but other properties of the crystal form have not been studied.
[0010] Patent CN103319422A discloses an α-crystal form of gefitinib obtained by anti-solvent crystallization technology, the yield of the obtained crystal form is 85%, and defective products exist after being made into tablets.
[0011] Patent CN106083739 discloses a new crystalline form β of gefitinib and its preparation method based on supercritical anti-solvent technology. Both crystalline forms may have excessive organic solvent residues and colored substances. Patent CN103910690A discloses crystalline form A of gefitinib.
[0012] Patent CN103896861A discloses amorphous gefitinib, i.e. Form 8, and its preparation method. However, due to the physical and chemical defects of amorphous form, it is generally not selected as a pharmaceutical crystal form.
[0013] Among the above-mentioned crystal forms, Form 1 is the most stable and the most commonly used crystal form in clinical applications. It is suitable for solid preparations of gefitinib such as tablets and capsules. However, the reproducibility of its preparation is poor, which may be due to the polymorphism of crystals in this form. In addition, Form 1 has a low solubility, and its solubility in high-purity water at pH = 7 is only 2.55μg / mL. 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, and the dosage is large, causing serious gastrointestinal reactions and other toxic side effects.
[0014] Patent 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 organic solvent content makes the crystal form unsuitable as a pharmaceutical crystal form.
[0015] Although many gefitinib crystal forms have been disclosed in existing literature, the systematic study of its crystal forms still needs to be improved, especially the comprehensive study of gefitinib cocrystal compounds has not been reported. The new salt form of drug cocrystal refers to the introduction of a new cocrystal substance (CCF) through proton transfer, which self-assembles with the active pharmaceutical ingredient (APT) under the action of hydrogen bonds to form a supramolecular crystal with a fixed stoichiometric ratio. The drug cocrystal does not change the chemical structure of the drug molecule, and can effectively improve the drugability of the drug molecule through the hydrogen bonding between molecules, thus becoming a highly valued drug crystal form. Due to its potential advantages in dissolution, permeability, moisture absorption and stability, the new salt form of drug cocrystal has attracted the interest of more and more researchers in the field of drug preparation.
[0016] WO2005 / 028469 discloses pharmaceutically acceptable salts of gefitinib, including hydrochloric acid, sulfuric acid, citrate and the like. The water solubility of the sulfuric acid addition salt is not ideal, and the stability of the citric acid and hydrochloric acid addition salts needs to be improved.
[0017] WO2009 / 138781 discloses a fumarate salt form of a gefitinib analog, which has good solubility but poor stability. CN103172576B discloses a malic acid addition salt of gefitinib, the effects of which need to be improved.
[0018] 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 have tried many methods in their research but have not successfully obtained the co-crystal of gefitinib and p-hydroxybenzoic acid described in the patent.
[0019] Patent WO2015170345 also mentions the co-crystal of gefitinib and benzoic acid, but studies have found that its method is not universal, and the benzoic acid co-crystal prepared by this patent does not have outstanding properties compared to the existing gefitinib crystal form.
[0020] CN110128356A discloses a co-crystal of gefitinib and 3-hydroxybenzoic acid, CN110156700A discloses a co-crystal of gefitinib and salicylic acid, and CN110283131A discloses a co-crystal of gefitinib and vanillic acid methanol solvate and a preparation method thereof. Although the solubility is improved, the solubility still needs to be improved. Summary of the invention
[0021] In view of the problems of low solubility, poor stability, poor reproducibility in the preparation process and excessive organic solvent residue in the existing gefitinib crystal form, the present invention aims to provide an acid addition salt of gefitinib that can replace the existing crystal form. The acid addition salt of gefitinib has good chemical stability and a solubility higher than that of conventional stable crystals composed of a single drug component. In addition, the formation of the acid addition salt effectively avoids the polymorphism and solvent residue problems of the existing crystal form.
[0022] The second aspect of the present invention is to provide a method for preparing gefitinib acid addition salt.
[0023] The third aspect of the present invention is to provide a pharmaceutical composition, which optionally comprises one or more pharmaceutically acceptable carriers and / or diluents in the gefitinib acid addition salt of the present application.
[0024] For ease of reference, the various acid addition salts described herein are consistently indicated in this application as gefitinib with sulfamic acid addition salt, gefitinib with phthalic acid addition salt, gefitinib with glycolic acid addition salt.
[0025] Gefitinib and aminosulfonic acid addition salt
[0026] In one embodiment, the present invention relates to a gefitinib and aminosulfonic acid addition salt, specifically a salt formed by combining gefitinib and aminosulfonic acid in a molar ratio of 1:1, referred to herein as a gefitinib and aminosulfonic acid addition salt. Based on its physical properties, the gefitinib and aminosulfonic acid addition salt is a crystalline form.
[0027] The addition salt of gefitinib and aminosulfonic acid can be characterized as having one or more of the following physical characteristics:
[0028] (a) having an X-ray diffraction peak at 2θ of 9.77±0.2°, 15.08±0.2°, 20.27±0.2°, 20.80±0.2°, 22.23±0.2°, 22.76±0.2°, 27.82±0.2°; preferably, comprising an X-ray diffraction peak selected from 9.77±0.2°, 14.31±0.2°, 15.08±0.2°, 1 6.34±0.2°, 17.60±0.2°, 18.73±0.2°, 20.27±0.2°, 20.80±0.2°, 22.23±0.2°, 22.76±0.2°, 27.43±0.2°, 27.82±0.2°, and five or more diffraction peaks at 36.42±0.2°; further preferably, having the following diffraction peaks: Figure 1 The X-ray powder diffraction pattern shown;
[0029] (b) has the following crystallographic parameters: monoclinic system, space group P21 / c; unit cell parameters: α=90°,β=112.9170(17)°,γ=90°,unit cell volume The unit cell structure of
[0030] (c) A differential scanning calorimetry spectrum having an endothermic peak in the temperature range of 225.57-236.52°C and a peak value at 233.41°C.
[0031] Gefitinib glycolic acid addition salt
[0032] In one embodiment, the present invention relates to a gefitinib and glycolic acid addition salt, specifically a salt formed by combining gefitinib and glycolic acid in a molar ratio of 1:1, referred to herein as a gefitinib and glycolic acid addition salt. Based on its physical properties, the gefitinib and glycolic acid addition salt is a crystalline form.
[0033] The addition salt of gefitinib with glycolic acid can be characterized as having one or more of the following physical characteristics:
[0034] (a) having an X-ray diffraction peak at 2θ of 20.29±0.2°, 20.67±0.2°, 21.55±0.2°, 23.05±0.2°, 23.77±0.2°, 24.74±0.2°, 27.89±0.2°; preferably, comprising an X-ray diffraction peak selected from 14.52±0.2°, 15.20±0.2°, 18.81±0.2°, 20.29±0.2°, 20.67±0.2°, 21.55±0.2°, 23.05±0.2°, 23.77±0.2°, 24.74±0.2°, 26.13±0.2°, 27.89±0.2°, 28.27±0.2°, and five or more diffraction peaks composed of diffraction peaks at 29.46±0.2°; further preferably, having Figure 2 The X-ray powder diffraction pattern shown;
[0035] (b) has the crystallographic parameters: monoclinic system, space group P21 / c, unit cell parameters: α=90°、β=94.2394(8)°、γ=90°,unit cell volume The unit cell structure.
[0036] Gefitinib and phthalic acid addition salt
[0037] In one embodiment, the present invention relates to a phthalic acid addition salt of gefitinib, specifically a salt formed by combining gefitinib with phthalic acid and water in a molar ratio of 2:3:4, referred to herein as a phthalic acid addition salt of gefitinib. Based on its physical properties, the phthalic acid addition salt of gefitinib is a crystalline form.
[0038] The phthalic acid addition salt of gefitinib can be characterized as having one or more of the following physical characteristics:
[0039] (a) having an X-ray diffraction peak at 2θ of 4.66±0.2°, 5.34±0.2°, 6.28±0.2°, 7.17±0.2°, 16.20±0.2°; preferably, comprising a peak selected from 4.66±0.2°, 5.34±0.2°, 6.28±0.2°, 7.17±0.2°, 12.66±0.2°, 16.20±0.2°, 21.45±0.2°, 22. 50±0.2°, 26.96±0.2°, or five or more diffraction peaks selected from 4.66±0.2°, 5.34±0.2°, 6.28±0.2°, 7.17±0.2°, 8.56±0.2°, 9.01±0.2°, 12.66±0.2°, 16.20±0.2°, 21.45±0.2°, 22.50±0.2°, 26.96±0.2° or five or more diffraction peaks selected from the group consisting of diffraction peaks at 4.66±0.2°, 5.34±0.2°, 6.28±0.2°, 7.17±0.2°, 8.56±0.2°, 9.39±0.2°, 12.66±0.2°, 16.20±0.2°, 21.45±0.2°, 22.50±0.2°, and 26.96±0.2°, or Five or more diffraction peaks selected from the group consisting of 4.66±0.2°, 5.34±0.2°, 6.28±0.2°, 7.17±0.2°, 8.56±0.2°, 9.01±0.2°, 9.39±0.2°, 12.66±0.2°, 16.20±0.2°, 21.45±0.2°, 22.50±0.2°, and 26.96±0.2°; further preferably, having Figure 3 The X-ray powder diffraction pattern shown;
[0040] (b) The crystallographic parameters are: triclinic system, space group is P-1; unit cell parameters are: α=99.7360(10)°,β=95.5340(10)°,γ=91.4650(10)°,unit cell volume The unit cell structure of
[0041] (c) Differential scanning calorimetry spectrum with two endothermic peaks in the temperature ranges of 66.50-108.76°C and 166.73-185.54°C, respectively.
[0042] Preparation and characterization of acid addition salts of gefitinib
[0043] Gefitinib can be synthesized by various methods or obtained commercially. A representative method for synthesizing gefitinib is shown in patent CN1882569B.
[0044] The methods that can be used to prepare the acid addition salts of gefitinib are described in Examples 1-9, wherein Examples 1-3 describe the preparation method of the addition salt of gefitinib with aminosulfonic acid, Examples 4-6 describe the preparation method of the addition salt of gefitinib with glycolic acid, and Examples 7-9 describe the preparation method of the addition salt of gefitinib with phthalic acid.
[0045] A variety of tests were performed to physically characterize the acid addition salt of gefitinib, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA). The method used to test the solubility of gefitinib acid addition salt is described in Validation Example 1, and the method used to test the hygroscopicity of gefitinib acid addition salt is described in Validation Example 2.
[0046] Preparation method of gefitinib and aminosulfonic acid addition salt
[0047] In one embodiment, the addition salt of gefitinib and aminosulfonic acid is prepared by the following method: adding gefitinib and aminosulfonic acid to a solvent, heating for reaction, cooling for crystallization, filtering and drying to obtain the salt.
[0048] Preferably, the preparation of the addition salt of gefitinib and aminosulfonic acid comprises the following steps:
[0049] Gefitinib and aminosulfonic acid are added to solvent A, subjected to ultrasonication, and heated until the solid is completely dissolved. The mixture is allowed to stand at room temperature for crystallization, filtered, and dried to obtain an addition salt of gefitinib and aminosulfonic acid.
[0050] Further preferably, the following contents are included:
[0051] The solvent A is a mixed solvent of methanol and water;
[0052] The volume percentage of water in the solvent A is 11%-90%;
[0053] The molar ratio of gefitinib to aminosulfonic acid is 1:1.0-2.6;
[0054] The crystallization time is 12 to 72 hours;
[0055] The drying temperature is 26-55° C., and the drying time is 8-15 hours.
[0056] More preferably, it includes the following:
[0057] The volume percentage of water in the solvent A is 25%-80%;
[0058] The molar ratio of gefitinib to aminosulfonic acid is 1:1.8-2.0;
[0059] The crystallization time is 15 to 24 hours;
[0060] The mass volume ratio of gefitinib to solvent A is 10-50:1, wherein the mass is measured in mg and the volume is measured in mL;
[0061] The drying temperature is 25-35° C., and the drying time is 10-12 hours.
[0062] The addition salt of gefitinib and aminosulfonic acid was characterized by XRPD, TGA and DSC.
[0063] Figure 1 The characteristic XRPD spectrum of gefitinib and aminosulfonic acid addition salt is shown The XRPD pattern confirmed that the addition salt of gefitinib with aminosulfonic acid was crystalline. The main X-ray diffraction patterns and their relative intensities expressed as 2θ are summarized in Table 1.
[0064] Table 1 PXRD peaks of gefitinib and aminosulfonic acid addition salt
[0065]
[0066]
[0067] The above set of XRPD peak positions or a subset thereof can be used to identify the aminosulfonic acid addition salt of gefitinib.
[0068] Confirmation of the crystal structure of gefitinib and aminosulfonic acid addition salt:
[0069] The X-ray crystal data in the test of gefitinib and aminosulfonic acid addition salt described in the present invention were collected on a Rigaku XtaLABSynergy instrument of Japan, with a test temperature of 293 (2) K, using CuKa radiation, collecting data in ω scanning mode and performing Lp correction. The structure was analyzed by direct method, all non-hydrogen atoms were found by difference Fourier method, all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least square method.
[0070] The crystallographic data of the gefitinib and aminosulfonic acid addition salt prepared by the present invention are shown in Table 2: Its crystallographic parameters are: monoclinic system, space group is P21 / c; unit cell parameters are: α=90°,β=112.9170(17)°,γ=90°,unit cell volume
[0071] Table 2 Main crystallographic data of gefitinib and aminosulfonic acid addition salt
[0072]
[0073] ORTEP diagram of gefitinib and aminosulfonic acid addition salt of the present invention ( Figure 4 ) shows that one molecule of gefitinib is combined with one molecule of aminosulfonic acid. The stacking diagram of gefitinib and aminosulfonic acid addition salt of the present invention ( Figure 5 ) showed that gefitinib and aminosulfonic acid were connected into a three-dimensional structure through intermolecular hydrogen bonds.
[0074] Preparation method of gefitinib and glycolic acid addition salt
[0075] In one embodiment, the addition salt of gefitinib and glycolic acid is prepared by the following method: adding gefitinib and glycolic acid into a solvent, heating for reaction, cooling for crystallization, filtering and drying to obtain the salt.
[0076] Preferably, the method comprises the following steps: adding gefitinib and glycolic acid into an organic solvent C, heating and stirring, refluxing, filtering, standing at room temperature, volatilizing and crystallizing, filtering, and drying to obtain the product.
[0077] Preferably, the organic solvent C is one of methanol, acetone, ethyl acetate, acetonitrile or a combination thereof.
[0078] Preferably, the molar ratio of gefitinib to glycolic acid is 1:0.8-2.
[0079] More preferably, the molar ratio of gefitinib to glycolic acid is 1:1.
[0080] Preferably, the mass-to-volume ratio of gefitinib to the organic solvent C is 8-12:1, wherein the mass is measured in mg and the volume is measured in ml.
[0081] Preferably, the heating temperature is 40-55°C.
[0082] Preferably, the reflux reaction time is 1 to 3 hours.
[0083] The addition salt of gefitinib with glycolic acid was characterized by XRPD, TGA and DSC.
[0084] Figure 2 The characteristic XRPD spectrum of gefitinib and glycolic acid addition salt is shown The XRPD pattern confirmed that the addition salt of gefitinib with glycolic acid was crystalline. The main X-ray diffraction patterns and their relative intensities expressed as 2θ are summarized in Table 3.
[0085] Table 3. Characteristic XRPD peaks of gefitinib and glycolic acid addition salt (CuKα)
[0086]
[0087]
[0088] The above set of XRPD peak positions or a subset thereof can be used to identify the glycolic acid addition salt of gefitinib.
[0089] Confirmation of the crystal structure of gefitinib and glycolic acid addition salt:
[0090] The X-ray crystal data in the test of gefitinib and glycolic acid addition salt described in the present invention were collected on a Rigaku XtaLABSynergy instrument of Japan, with a test temperature of 100.00 (10) K, using CuKa radiation, collecting data in ω scanning mode and performing Lp correction. The structure was analyzed by direct method, all non-hydrogen atoms were found by difference Fourier method, all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least square method.
[0091] Test and analysis The crystallographic data of the gefitinib and glycolic acid addition salt prepared by the present invention are shown in Table 4. Its crystallographic parameters are: monoclinic system, space group is P21 / c, and unit cell parameters are: α=90°、β=94.2394(8)°、γ=90°,unit cell volume
[0092] Table 4 Main crystallographic data of gefitinib and glycolic acid addition salt
[0093]
[0094]
[0095] ORTEP diagram of gefitinib and glycolic acid addition salt of the present invention (attached Figure 6 ) shows that the gefitinib and glycolic acid addition salt molecule contains one gefitinib molecule and one glycolic acid molecule. The stacking diagram of the gefitinib glycolate of the present invention is shown in the attached figure. Figure 7 shown.
[0096] Preparation method of gefitinib and phthalic acid addition salt
[0097] In one embodiment, the addition salt of gefitinib and phthalic acid is prepared by the following method: adding gefitinib and phthalic acid into a solvent, heating for reaction, cooling for crystallization, filtering and drying to obtain the salt.
[0098] Preferably, the preparation method of the addition salt of gefitinib and phthalic acid comprises the following specific preparation steps: adding gefitinib and phthalic acid to a mixed solvent of water and an alcohol solvent, heating for reaction, filtering, allowing the filtrate to stand for crystallization, filtering, and vacuum drying to obtain the addition salt of gefitinib and phthalic acid.
[0099] Preferably, the alcohol solvent is a combination of methanol and ethanol.
[0100] More preferably, the volume ratio of methanol to ethanol in the alcohol solvent is 2-6:8-4.
[0101] Preferably, the volume ratio of water to alcohol solvent is 1:15-25.
[0102] Preferably, the molar ratio of gefitinib to phthalic acid is 1:0.9-1.5.
[0103] More preferably, the molar ratio of gefitinib to phthalic acid is 1:1.
[0104] The mass-to-volume ratio of gefitinib to the alcohol solvent in the system is 4-7:1, wherein the mass is measured in mg and the volume is measured in ml.
[0105] The heating temperature is 45-60°C.
[0106] The heating reaction time is 3 to 5 hours.
[0107] The temperature of the static crystallization is room temperature.
[0108] Preferably, the static crystallization method is solvent evaporation crystallization.
[0109] The phthalic acid addition salt of gefitinib was characterized by XRPD, TGA and DSC.
[0110] Figure 3 The characteristic XRPD spectrum of gefitinib and phthalic acid addition salt is shown The XRPD pattern confirmed that the addition salt of gefitinib with phthalic acid was crystalline. The main X-ray diffraction patterns and their relative intensities expressed as 2θ are summarized in Table 5.
[0111] The X-ray powder diffraction test instrument and test conditions in the test of gefitinib and phthalic acid addition salt described in the present invention are: PANalytical Empyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction light path: PLXCEL, voltage 45KV, current 40mA, divergence slit of 1 / 4°, anti-scattering slit of 1°, Soller slit of 0.04rad, counting time per step of 0.5s, scanning range of 3-50°.
[0112] Table 5 Main XRD peaks of gefitinib and phthalic acid addition salt
[0113]
[0114]
[0115] The above set of XRPD peak positions or a subset thereof can be used to identify the phthalic acid addition salt of gefitinib.
[0116] Confirmation of the crystal structure of gefitinib and phthalic acid addition salt:
[0117] The gefitinib and phthalic acid addition salt provided by the present invention is subjected to X-ray single crystal diffraction test and analysis. The X-ray single crystal diffraction instrument and test conditions involved 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.
[0118] The crystallographic data of the gefitinib and phthalic acid addition salt prepared by the present invention are shown in Table 6. The crystallographic parameters are: triclinic system, space group P-1; unit cell parameters are: α=99.7360(10)°,β=95.5340(10)°,γ=91.4650(10)°,unit cell volume
[0119] Table 6 Main crystallographic data of gefitinib and phthalic acid addition salt
[0120]
[0121]
[0122] The ORTEP diagram of the gefitinib phthalate addition salt of the present invention shows that two molecules of gefitinib are combined with three molecules of phthalic acid and four molecules of water, such as Figure 8 shown.
[0123] The third aspect of the present invention provides a pharmaceutical composition comprising the acid addition salt of gefitinib and other pharmaceutically acceptable components.
[0124] Preferably, the pharmaceutical composition is prepared by combining the compound 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.
[0125] Preferably, the available dosage form of the pharmaceutical composition is selected from one of spray, tablet, capsule, powder injection, liquid injection, lyophilized powder injection or other pharmaceutically usable dosage forms.
[0126] The gefitinib acid addition salt prepared by the method of the present invention has the following advantages over the currently reported gefitinib crystal forms:
[0127] (1) High solubility. The solubility of gefitinib and aminosulfonic acid addition salt in hydrochloric acid at pH = 1 is as high as 35.26 mg / ml, and the solubility of gefitinib and phthalic acid addition salt in water and phosphate buffer at pH = 6.8 is as high as 0.063 mg / ml and 0.085 mg / ml respectively.
[0128] (2) Low hygroscopicity and good stability. The weight gains of gefitinib and phthalic acid addition salt, gefitinib and glycolic acid addition salt, and gefitinib and aminosulfonic acid addition salt after equilibrium at 80% humidity were 0.73%, 2.19%, and 0.51%, respectively, which were lower than the hygroscopicity of Form 1. BRIEF DESCRIPTION OF THE DRAWINGS
[0129] Figure 1 : X-ray powder diffraction pattern of gefitinib and aminosulfonic acid addition salt;
[0130] Figure 2 : X-ray powder diffraction pattern of gefitinib and glycolic acid addition salt;
[0131] Figure 3 : X-ray powder diffraction pattern of gefitinib and phthalic acid addition salt;
[0132] Figure 4 : ORTEP diagram of gefitinib and aminosulfonic acid addition salt;
[0133] Figure 5 : Stacking diagram of gefitinib and aminosulfonic acid addition salt;
[0134] Figure 6 : ORTEP diagram of gefitinib and glycolic acid addition salt;
[0135] Figure 7 : Stacking diagram of gefitinib and glycolic acid addition salt;
[0136] Figure 8 : ORTEP diagram of gefitinib and phthalic acid addition salt; DETAILED DESCRIPTION
[0137] The present invention is further illustrated by the following examples. It should be correctly understood that the examples 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 based on the method of the present invention are all within the scope of protection claimed by the present invention.
[0138] Preparation of gefitinib and aminosulfonic acid addition salt:
[0139] Example 1
[0140] Dissolve 100.0 mg of gefitinib and 39.1 mg of aminosulfonic acid in 2.0 mL of a mixed solvent (0.2 mL of methanol + 1.8 mL of water), and heat with ultrasound until the solid is completely dissolved. Continue ultrasound for 10 min, filter, and allow to stand at room temperature for crystallization for 20 h. Filter and dry under vacuum at 30° C. for 10 h to obtain an addition salt of gefitinib and aminosulfonic acid with a yield of 93.69% and a purity of 99.94%.
[0141] Example 2
[0142] Dissolve 100.0 mg of gefitinib and 43.5 mg of aminosulfonic acid in 10 mL of a mixed solvent (9 mL of methanol + 1 mL of water), and heat by ultrasonication until the solid is completely dissolved. Continue ultrasonication for 10 min, filter, and allow to stand at room temperature for crystallization for 15 h. Filter and dry under vacuum at 25 °C for 12 h to obtain an addition salt of gefitinib and aminosulfonic acid with a yield of 94.14% and a purity of 99.91%.
[0143] Example 3
[0144] Dissolve 100 mg of gefitinib and 41.3 mg of aminosulfonic acid in 4 mL of a mixed solvent (2 mL of methanol + 2 mL of water), and heat with ultrasound until the solid is completely dissolved. Continue ultrasound for 10 min, filter, and allow to stand at room temperature for crystallization for 24 h. Filter and dry under vacuum at 35 °C for 11 h to obtain an addition salt of gefitinib and aminosulfonic acid with a yield of 95.06% and a purity of 99.89%.
[0145] Preparation of digefitinib and glycolic acid addition salt:
[0146] Example 4
[0147] 446.9 mg of gefitinib and 76.0 mg of glycolic acid were added to 50 ml of acetone, heated and stirred in a water bath at 50°C, heated under reflux for 1 hour, filtered, allowed to stand at room temperature, evaporated and crystallized to obtain gefitinib and glycolic acid addition salt. The yield was 95.64% and the HPLC purity was 99.95%.
[0148] Example 5
[0149] 446.9 mg of gefitinib and 60.8 mg of glycolic acid were added to 37 ml of methanol, heated and stirred in a water bath at 40°C, heated under reflux for 2 h, filtered, allowed to stand at room temperature, evaporated and crystallized to obtain gefitinib and glycolic acid addition salt, with a yield of 93.78% and a HPLC purity of 99.90%.
[0150] Example 6
[0151] 446.9 mg of gefitinib and 152.0 mg of glycolic acid were added to 56 ml of ethyl acetate, heated and stirred in a water bath at 55°C, heated under reflux for 3 hours, allowed to stand at room temperature, evaporated and crystallized to obtain gefitinib and glycolic acid addition salt, with a yield of 94.03% and a HPLC purity of 99.86%.
[0152] Preparation of gefitinib and phthalic acid addition salt
[0153] Example 7
[0154] Add 44.6 mg of gefitinib and 16.6 mg of phthalic acid into a single-necked round-bottom flask, add 5 mL of methanol, 5 mL of ethanol 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 gefitinib and phthalic acid addition salt, HPLC purity: 99.98%.
[0155] Example 8
[0156] Add 44.6 mg of gefitinib and 14.9 mg of phthalic acid into a single-mouth round-bottom flask, add 2 mL of methanol, 8 mL of ethanol and 0.4 mL of purified water, heat to 60°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 gefitinib and phthalic acid addition salt, HPLC purity: 99.96%.
[0157] Example 9
[0158] Add 44.6 mg of gefitinib and 24.9 mg of phthalic acid into a single-necked round-bottom flask, add 3.8 mL of methanol, 2.6 mL of ethanol and 0.4 mL of purified water, heat to 45°C, react for 5 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 gefitinib and phthalic acid addition salt, HPLC purity: 99.95%.
[0159] Verification Example 1, Solubility Test
[0160] Refer to the method of the pharmacopoeia, in order to save materials, reduce the dosage in the same proportion. Prepare hydrochloric acid solution with a pH value of 1.0, phosphate buffer with a pH value of 6.8 and water, respectively, take appropriate amounts of gefitinib and phthalic acid addition salt, gefitinib and glycolic acid addition salt, gefitinib and aminosulfonic acid addition salt, respectively, and put them into stoppered test tubes with water, hydrochloric acid solution with a pH of 1.0, and phosphate buffer with a pH of 6.8, respectively, put the samples into a water bath constant temperature oscillator, balance at 37°C, 200r / min for 24h, take samples at the specified time, filter with a 0.45μm microporous membrane, take the filtrate, dilute with water to the linear range, use the aqueous solution as the blank solution, and measure the absorbance at 254nm until the absorbance no longer changes. The test results are shown in Table 7.
[0161] Table 7 Solubility of gefitinib acid addition salt in different solutions
[0162]
[0163] The results showed that the solubility of the addition salt of gefitinib and aminosulfonic acid in hydrochloric acid at pH = 1 was as high as 35.26 mg / ml, and the solubility of the addition salt of gefitinib and phthalic acid in water and phosphate buffer at pH = 6.8 was as high as 0.063 mg / ml and 0.085 mg / ml, respectively.
[0164] Verification Example 2, Moisture Absorption Test
[0165] Hygroscopicity test of gefitinib and phthalic acid addition salt, gefitinib and glycolic acid addition salt, gefitinib and aminosulfonic acid addition salt, Form 1 crystal form:
[0166] About 10 mg of the gefitinib phthalic acid addition salt, gefitinib glycolic acid addition salt, gefitinib aminosulfonic acid addition salt, and Form 1 crystal form of the present invention were taken and tested for their hygroscopicity using a dynamic moisture sorption (DVS) instrument. The experimental results are shown in Table 8.
[0167] Table 8 Hygroscopicity test results of different gefitinib crystal forms
[0168]
[0169] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Appendix XIX J of the Chinese Pharmacopoeia 2010 Edition, Guidelines for Drug Hygroscopicity Test, experimental conditions: 25℃±1℃, 80%±2% relative humidity):
[0170] Deliquescent: Absorbs sufficient water to form a liquid.
[0171] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%.
[0172] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%.
[0173] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%.
[0174] No or almost no hygroscopicity: moisture gain is less than 0.2%.
[0175] The results show that the weight gain of the gefitinib and phthalic acid addition salt, gefitinib and glycolic acid addition salt, and gefitinib and aminosulfonic acid addition salt of the present invention after equilibrium at 80% humidity is 0.73%, 2.19%, and 0.51%, respectively, and the Form 1 crystal form after equilibrium at 80% humidity is 3.21%, respectively, which is higher than the hygroscopic weight gain of the gefitinib and phthalic acid addition salt, gefitinib and glycolic acid addition salt, and gefitinib and aminosulfonic acid addition salt of the present invention. The gefitinib acid addition salt prepared by the present invention has low hygroscopicity and good stability.
Claims
1. An acid addition salt of gefitinib and an acid selected from the group consisting of sulfamic acid, glycolic acid, and phthalic acid, characterized in that: The acid addition salt formed by gefitinib and aminosulfonic acid has the following crystallographic parameters: monoclinic system, space group P21 / c; unit cell parameters: a =10.89450(16)Å, b =19.36830(17)Å, c =12.60508(18)Å, α=90°, β=112.9170(17)°, γ=90°, unit cell volume V =2249.84(6)Å 3 The acid addition salt of gefitinib and glycolic acid has the following crystallographic parameters: monoclinic system, space group P21 / c; unit cell parameters: a =5.64179(5)Å, b =19.1666(2)Å, c =21.52254(19)Å, α=90°, β=94.2394(8)°, γ=90°, unit cell volume V =2320.95(4)Å 3 The acid addition salt of gefitinib and phthalic acid has the following crystallographic parameters: triclinic system, space group P-1; unit cell parameters: a =13.79500(10)Å, b =15.27090(10)Å, c =16.6542(2)Å, α=99.7360(10)°, β=95.5340(10)°, γ=91.4650(10)°, unit cell volume V =3438.62(5)Å 3 .
2. The acid addition salt according to claim 1, characterized in that The molar ratio of gefitinib to acid is 1:1.0-1.
5.
3. The acid addition salt according to claim 2, characterized in that The molar ratio of gefitinib to aminosulfonic acid in the gefitinib and aminosulfonic acid addition salt is 1:
1.
4. The acid addition salt according to claim 2, characterized in that The molar ratio of gefitinib to glycolic acid in the gefitinib and glycolic acid addition salt is 1:
1.
5. The acid addition salt according to claim 2, characterized in that The gefitinib and phthalic acid addition salt is in the form of a hydrate, and the molar ratio of gefitinib to phthalic acid and water is 2:3:
4.
6. The acid addition salt according to claim 3, characterized in that The gefitinib and aminosulfonic acid addition salt uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at 9.77±0.2°, 14.31±0.2°, 15.08±0.2°, 16.34±0.2°, 17.60±0.2°, 18.73±0.2°, 20.27±0.2°, 20.80±0.2°, 22.23±0.2°, 22.76±0.2°, 27.43±0.2°, 27.82±0.2°, and 36.42±0.2°.
7. The acid addition salt according to claim 3, characterized in that Using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in FIG1 .
8. The acid addition salt according to claim 4, characterized in that The gefitinib and glycolic acid addition salt uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at 14.52±0.2°, 15.20±0.2°, 18.81±0.2°, 20.29±0.2°, 20.67±0.2°, 21.55±0.2°, 23.05±0.2°, 23.77±0.2°, 24.74±0.2°, 26.13±0.2°, 27.89±0.2°, 28.27±0.2°, and 29.46±0.2°.
9. The acid addition salt according to claim 4, characterized in that Using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in FIG2 .
10. The acid addition salt according to claim 5, characterized in that The gefitinib and phthalic acid addition salt uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at 4.66±0.2°, 5.34±0.2°, 6.28±0.2°, 7.17±0.2°, 8.56±0.2°, 9.01±0.2°, 9.39±0.2°, 12.66±0.2°, 16.20±0.2°, 21.45±0.2°, 22.50±0.2°, and 26.96±0.2°.
11. The acid addition salt according to claim 5, characterized in that Using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in FIG3 .
12. A method for preparing an acid addition salt according to any one of claims 1 to 11, characterized in that Gefitinib and acid are added to a solvent, heated for reaction, cooled for crystallization, filtered and dried to obtain the product.
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, optionally in combination with one or more pharmaceutically acceptable carriers and / or diluents.