CN112047892B - Gefitinib and 3-hydroxybenzoic acid eutectic - Google Patents
Gefitinib and 3-hydroxybenzoic acid eutectic Download PDFInfo
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Abstract
The invention provides a co-crystal of gefitinib and 3-hydroxybenzoic acid, a preparation method thereof and application thereof in preparing medicines for treating diseases. The X-ray diffraction spectrum of the co-crystal of gefitinib and 3-hydroxybenzoic acid, which is expressed by 2 theta, has characteristic peaks at 7.06+/-0.2 degrees, 14.08+/-0.2 degrees, 15.92+/-0.2 degrees, 24.66+/-0.2 degrees, 25.06+/-0.2 degrees and 28.33+/-0.2 degrees, so that the co-crystal has better chemical stability, high solubility of Yu Jifei tinib crystal or solvate thereof and better bioavailability; and the eutectic can be obtained by a simple grinding method, the operation is simple and convenient, and the yield is stable.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a gefitinib and 3-hydroxybenzoic acid eutectic, and a preparation method and application thereof.
Background
Gefitinib, with the trade name of easy-to-run sand (Iressa), with the chemical name of 4- (3-chloro-4-fluorophenylamino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline, is a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor developed by the company of Abilikang, is suitable for treating local advanced or metastatic non-small cell lung cancer (NSCLC) which is not effective in the prior platinum anti-tumor drug and docetaxel chemotherapy or is not suitable for chemotherapy, is a1 st small molecular protein tyrosine kinase inhibitor targeted anti-cancer drug for treating solid tumor, and is formally marketed in China in 2005 2 menstrual approval.
At present, a lot of documents report that gefitinib has a polymorphic problem, as different crystal forms of the medicine can directly influence the solubility, dissolution rate, action with a target point and the like of the medicine in vivo so as to influence the exertion of the medicine effect, and in view of the importance of the therapeutic action of the gefitinib and the price of the gefitinib, although the gefitinib which can be used for medicine is marketed for many years, the research report on the dominant crystal forms of the gefitinib is never interrupted.
Patent WO9633980 discloses for the first time a process for the preparation of gefitinib compounds, but does not disclose in particular whether the compound prepared is crystalline or amorphous, nor whether the compound may exist in solvated form.
Patent CN100404032C discloses four crystalline forms of gefitinib Form 1 (polymorph), form 2 (methanol solvate), form 3 (DMSO solvate), form 5 (trihydrate) and methods of making the same. The patent teaches that Form 1 polymorphs can be obtained by separation after washing Form 3, form 2 or Form 5 with a solvent or solvent mixture, and studies have found that Form 1 has good stability and is suitable for solid formulations of gefitinib such as tablets and capsules, but in the actual preparation process, the Form 1 is obtained with poor reproducibility, possibly due to the polymorphic Form of the crystals of this Form. The stability of both Form 2 methanol solvate and Form 3DMSO solvate is lower than Form 1, and the methanol content in Form 2 forms is about 10 times the pharmacopoeial limit (0.3% pharmacopoeial limit), the DMSO content in Form 3 forms is about 30 times the pharmacopoeial limit (0.5% pharmacopoeial limit), it is seen that forms of Form 2 and Form 3 are also relatively easy to prepare, but too much solvent residue makes it unsuitable as a pharmaceutical Form. Form 5 trihydrate is also not as stable as Form 1, is only very stable in water, is suitable for administration in the Form of an aqueous suspension, and also greatly limits the use of Form 5 crystals.
Patent WO2006090413A1 discloses a crystal Form of gefitinib Form 6 and a preparation method thereof, wherein the preparation method comprises the steps of mixing anhydrous gefitinib with water, stirring for 18-20h at ambient temperature, filtering air, and drying to obtain Form 6, wherein the crystal Form is a monohydrate crystal Form, the stability is lower than Form 1, and the similar problem of limited application to Form 5 is also existed.
Patent CN103896863B discloses a new crystal Form 7 of gefitinib and a preparation method thereof, and the pharmacokinetics of the crystal Form in rats are studied, and the results show that the pharmacokinetic parameters of the crystal Form and the crystal Form 1 on the market are not significantly different, but other properties of the crystal Form are not studied.
Patent CN103896861a discloses amorphous gefitinib, form8, and a method for preparing the same, but is not generally selected as a pharmaceutical crystalline Form due to the physicochemical defects of the amorphous material. Patent CN104693127B discloses a gefitinib glycol solvate and a preparation method thereof, but researches show that the content of glycol in the crystal is about 300 times (0.062%) of the pharmacopoeia limit, and the high residual amount of organic solvent makes the crystal form unsuitable as a medicinal crystal form.
Although the prior literature discloses a plurality of gefitinib crystal forms, systematic researches on the crystal forms are still to be perfected, and particularly, the researches on gefitinib eutectic compounds are not reported yet. The new salt form of the pharmaceutical co-crystal refers to the introduction of new co-crystal substances (CCF) through proton transfer, and the self-assembly of the new co-crystal substances with pharmaceutical active ingredients (APT) under the action of hydrogen bonds to form supermolecule crystals with fixed stoichiometric ratio. Due to their potential advantages in terms of dissolution, permeation, moisture absorption, stability, etc., pharmaceutical co-crystals are of increasing interest to researchers in the field of pharmaceutical preparation. Although patent WO2014016848 mentions that gefitinib and parahydroxybenzoic acid can form a eutectic crystal, a corresponding preparation method is not provided, the property of the eutectic crystal is not studied, and the inventors do not successfully obtain the eutectic crystal of gefitinib and parahydroxybenzoic acid by trying a plurality of methods in the research; patent WO2015170345 also mentions co-crystals of gefitinib with benzoic acid, but studies have found that the process is not versatile and that the benzoic acid co-crystals prepared by this patent do not have outstanding properties compared to the existing crystalline forms of gefitinib.
Disclosure of Invention
Aiming at the problems of low solubility, poor stability, poor reproducibility and excessive organic solvent residues in the preparation process of the existing gefitinib crystal form, the invention aims to provide the gefitinib-3-hydroxybenzoic acid eutectic crystal capable of replacing the existing crystal form, which has better chemical stability and higher solubility than the existing crystal form, and the problems of crystal transformation phenomenon and solvent residues of the existing crystal form are effectively avoided through the formation of the eutectic crystal.
The specific technical content of the invention is as follows:
in a first aspect of the invention, there is provided a co-crystal of gefitinib-3-hydroxybenzoic acid. In the co-crystal, the molar ratio of gefitinib to 3-hydroxybenzoic acid is 1:1.
preferably, the gefitinib-3-hydroxybenzoic acid co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 7.06+/-0.2 degrees, 14.08+/-0.2 degrees, 15.92+/-0.2 degrees, 24.66+/-0.2 degrees, 25.06+/-0.2 degrees and 28.33+/-0.2 degrees.
Preferably, the gefitinib-3-hydroxybenzoic acid co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 7.06+/-0.2 degrees, 14.08+/-0.2 degrees, 15.92+/-0.2 degrees, 20.99+/-0.2 degrees, 23.59+/-0.2 degrees, 24.66+/-0.2 degrees, 25.06+/-0.2 degrees, 25.57+/-0.2 degrees, 28.33+/-0.2 degrees and 40.86 +/-0.2 degrees.
Preferably, the gefitinib-3-hydroxybenzoic acid co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern as shown in figure 3.
Preferably, the gefitinib-3-hydroxybenzoic acid co-crystal has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve, and the corresponding temperature range is 187.94-214.85 ℃, particularly preferably 204.96 ℃.
Preferably, the gefitinib-3-hydroxy groupBenzoic acid co-crystals whose crystallographic parameters are: monoclinic system with space group P2 1 C; the unit cell parameters are:α=90.00 °, β= 92.1030 (10) °, γ=90.00°, unit cell volume +.>
In a second aspect of the invention, a preparation method of gefitinib-3-hydroxybenzoic acid co-crystal is provided, which comprises the following specific preparation steps: and (3) placing gefitinib and 3-hydroxybenzoic acid into a mortar, dropwise adding a small amount of organic solvent A, grinding to white powder, adding a proper amount of solvent A again, continuously grinding to obtain a transparent solution, standing at a controlled temperature for crystallization, filtering, and drying in vacuum to obtain gefitinib-3-hydroxybenzoic acid eutectic.
Preferably, the organic solvent A is selected from one or a combination of ethanol, acetone, methanol and isopropanol; further preferably, the organic solvent a is selected from one or a combination of ethanol and methanol.
Preferably, the molar ratio of the gefitinib to the 3-hydroxybenzoic acid is 1.0-1.5: 1, a step of; further preferably, the molar ratio of gefitinib to 3-hydroxybenzoic acid is 1.0-1.2: 1.
preferably, in the preparation method, the time for the first grinding is 30-50 min; the second grinding time is 10-20 min.
Preferably, in the preparation method, the mass-volume ratio of gefitinib to the organic solvent A required by the first grinding is 70-90: 1, mg/ml.
Preferably, in the preparation method, the volume ratio of the organic solvent A required by the second grinding to the organic solvent A required by the first grinding is 2:1.
preferably, in the preparation method, the temperature of Wen Xijing is controlled to be 5-10 ℃.
Preferably, in the preparation method, the crystallization time is 48-72 hours.
Preferably, in the preparation method, the drying temperature is 50-60 ℃ and the drying time is 8-10 hours.
In a third aspect, the invention provides a pharmaceutical composition containing gefitinib-3-hydroxybenzoic acid eutectic and application of the eutectic in preparing medicines for treating diseases such as cancers.
The preparation method of the pharmaceutical composition of the invention can be as follows: the compounds of the present invention are formulated into useful dosage forms by combining them with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques.
The pharmaceutical composition of the invention can be spray, tablet, capsule, powder injection, liquid injection, freeze-dried powder injection and other pharmaceutically available dosage forms.
Confirmation of Crystal Structure
The gefitinib-3-hydroxybenzoic acid co-crystal provided by the invention is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffractometer and the testing conditions related by the invention are as follows: the temperature 293 (2) K was measured using a XtaLAB Synergy X-ray single crystal diffractometer, and the data was collected and Lp corrected using CuKa radiation in an omega scan. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallographic data obtained by testing and analyzing gefitinib-3-hydroxybenzoic acid co-crystals prepared by the invention are (Table 1): the crystallographic parameters are: monoclinic system with space group P2 1 C; the unit cell parameters are: α=90.00 °, β= 92.1030 (10) °, γ=90.00°, unit cell volume +.>The Ji of the inventionThe ORTEP diagram of the co-crystal of non-tinib-3-hydroxybenzoic acid shows (FIG. 1) that one molecule of gefitinib binds one molecule of 3-hydroxybenzoic acid. The hydrogen bond diagram shown in fig. 2 shows that gefitinib and 3-hydroxybenzoic acid are connected through intermolecular hydrogen bonds to form a three-dimensional structure.
TABLE 1 principal crystallographic data of gefitinib-3-hydroxybenzoic acid co-crystals
The X-ray powder diffraction test instrument and test conditions related in the invention: x-ray powder diffractometer: PANalytical Empyrean X-ray powder diffractometer; cu-K alpha; sample stage: a flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; divergence slit: 1/4; anti-scatter slit: 1, a step of; a cable pull slit: 0.04rad; step size: 0.5s; scanning range: 3-50 deg.
According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 3 and Table 2.
TABLE 2 PXRD peaks for gefitinib-3-hydroxybenzoic acid cocrystal
TGA/DSC thermal analysis tester and test conditions in the invention: TGA/DSC thermal analyzer: METTLER TOLEDO TGA/DSC < 3+ >; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; procedure section gas N 2 The method comprises the steps of carrying out a first treatment on the surface of the Gas flow rate: 50mL/min; crucible: 40 μl of aluminum crucible.
The TGA/DSC test result of the gefitinib-3-hydroxybenzoic acid eutectic provided by the invention is shown in figure 4, and a DSC detection spectrum shows that the eutectic has an endothermic peak, the corresponding temperature is 187.94-214.85 ℃, and the peak is 204.96 ℃. According to a TGA detection result, the eutectic crystal has a weight loss step, which shows that the gefitinib-3-hydroxybenzoic acid eutectic crystal is decomposed while being melted, so that the DSC/TGA detection result shows that the gefitinib-3-hydroxybenzoic acid eutectic crystal is successfully prepared, and no organic solvent residue exists in the crystal structure of the gefitinib-3-hydroxybenzoic acid eutectic crystal.
Compared with the prior art, the invention has the technical effects that:
1. the gefitinib-3-hydroxybenzoic acid eutectic provided by the invention has good chemical stability and high solubility.
2. The preparation method provided by the invention has good repeatability and convenient operation, and the solubility of the gefitinib-3 hydroxybenzoic acid eutectic prepared by the method is higher than that of the existing stable crystal, and can effectively inhibit the formation of solvates and the phenomenon of crystal transformation.
3. The gefitinib-3 hydroxybenzoic acid co-crystal prepared by the preparation method has the similar pharmaceutical activity to the Form 1 crystal Form, but effectively avoids the problem that a single pharmaceutical crystal Form contains organic solvent residues, and keeps better medication safety.
Drawings
Fig. 1: ORTEP diagram of gefitinib-3-hydroxybenzoic acid co-crystal.
Fig. 2: hydrogen bonding diagram of gefitinib-3-hydroxybenzoic acid co-crystal.
Fig. 3: x-ray powder diffraction pattern of gefitinib-3-hydroxybenzoic acid co-crystal.
Fig. 4: DSC-TGA profile of gefitinib-3-hydroxybenzoic acid co-crystal.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1
45.0mg of gefitinib and 11.6mg of 3-hydroxybenzoic acid are added into a mortar, 0.5mL of methanol is added dropwise into the mortar, the mixture is fully ground for 35min, 1mL of methanol is added for further grinding for 15min, a transparent solution is obtained, the mixture is kept stand and crystallized for 48 hours at the temperature of 5-10 ℃, the mixture is filtered, and vacuum drying is carried out for 8 hours at the temperature of 55 ℃ to obtain gefitinib-3-hydroxybenzoic acid eutectic with the yield of 91.12 percent, and HPLC:99.94%.
Example 2
Adding 35.0mg of gefitinib and 11.0mg of 3-hydroxybenzoic acid into a mortar, dropwise adding 0.5mL of ethanol into the mortar, fully grinding the mixture for 30min, adding 1mL of ethanol, continuously grinding the mixture for 10min to obtain a transparent solution, standing and crystallizing the transparent solution at a temperature of 5-10 ℃ for 48 h, filtering the transparent solution, and drying the transparent solution in vacuum at 55 ℃ for 10h to obtain gefitinib-3-hydroxybenzoic acid eutectic with a yield of 90.52 percent by HPLC:99.92%.
Example 3
45.0mg of gefitinib and 11.6mg of 3-hydroxybenzoic acid are added into a mortar, 0.5mL of methanol is added dropwise into the mortar, the mixture is fully ground for 50min, 1mL of methanol is added for further grinding for 20min, a transparent solution is obtained, the mixture is kept stand and crystallized for 48 hours at the temperature of 5-10 ℃, the mixture is filtered, and vacuum drying is carried out for 8 hours at the temperature of 55 ℃ to obtain gefitinib-3-hydroxybenzoic acid eutectic with the yield of 90.76 percent by HPLC:99.93%.
Example 4
Adding 35.0mg of gefitinib and 11.0mg of 3-hydroxybenzoic acid into a mortar, dropwise adding 0.5mL of isopropanol into the mortar, fully grinding the mixture for 20min, adding 1mL of isopropanol, continuously grinding the mixture for 15min to obtain a transparent solution, standing and crystallizing the transparent solution at a temperature of 5-10 ℃ for 72 h, filtering the transparent solution, and vacuum-drying the transparent solution at 60 ℃ for 8h to obtain gefitinib-3-hydroxybenzoic acid co-crystal with a yield of 83.99 percent by HPLC:96.15%.
Example 5
Adding 35.0mg of gefitinib and 11.0mg of 3-hydroxybenzoic acid into a mortar, dropwise adding 0.5mL of methanol into the mortar, sufficiently grinding for 35min, adding 1mL of methanol, continuously grinding for 30min to obtain a transparent solution, standing and crystallizing at the temperature of 5-10 ℃ for 72 h, filtering, and vacuum drying at 50 ℃ for 10h to obtain gefitinib-3-hydroxybenzoic acid co-crystal, wherein the yield is 81.66 percent, and HPLC:95.72%.
Example 6
45.0mg of gefitinib and 9.0mg of 3-hydroxybenzoic acid are added into a mortar, 0.5mL of ethanol is added dropwise into the mortar, the mixture is fully ground for 60min, 1mL of ethanol is added, the grinding is continued for 30min, a transparent solution is obtained, the mixture is kept stand and crystallized for 72 h at the temperature of 5-10 ℃, the mixture is filtered, and the mixture is dried in vacuum for 8h at the temperature of 55 ℃ to obtain gefitinib-3-hydroxybenzoic acid co-crystal with the yield of 80.25 percent by HPLC:96.02%.
Comparative example 1
Adding 446.9mg of gefitinib into 10ml of ethanol at the temperature of 25-30 ℃ for dissolution, adding 3-hydroxybenzoic acid (138.1 mg), heating, refluxing and stirring until a clear solution is obtained, continuing refluxing and stirring for 2 hours, cooling the reaction solution to the temperature of 25-30 ℃, continuing stirring overnight, filtering, cooling again, standing and crystallizing, and not precipitating solids; the relevant experimental conditions were adjusted, and no crystals were precipitated.
Comparative example 2
Adding 446.9mg of gefitinib into 10ml of ethanol at the temperature of 25-30 ℃ for dissolution, adding p-hydroxybenzoic acid (138.1 mg), heating, refluxing and stirring until a clear solution is obtained, continuing refluxing and stirring for 2 hours, cooling the reaction solution to the temperature of 25-30 ℃, continuing stirring overnight, filtering, cooling again, standing and crystallizing, and not precipitating solids; the relevant experimental conditions were adjusted, and no crystals were precipitated.
Comparative example 3
100mg of gefitinib and 3-hydroxybenzoic acid (30.9 mg) were pulverized in a mortar, and the pulverized mixture was transferred to a mortar containing acetone-CCl 4 (15 ml, volume ratio 1:1) was heated at 60℃for 30min to dissolve the crystals, then 5ml of a mixed solution of ethanol and water was added to the flask, the filtrate was collected by filtration, and the filtrate was allowed to stand still for 24 hours, and no crystals were precipitated by suction filtration.
Comparative example 4
100mg of gefitinib and 27.35mg of benzoic acid were pulverized in a mortar, after which the pulverized mixture was transferred to a mortar with acetone-CCl 4 (15 ml, volume ratio 1:1) was dissolved by heating at 60℃for 30min, then 5ml of a mixed solution of ethanol and water was added to the flask, and the filtrate was collected by filtration, allowed to stand still for 24 hours, filtered off with suction, and the obtained solid was dried in vacuo to yield 69.1%, HPLC:97.26%.
The crystalline form of gefitinib described in the prior art used in the property inspection experiments was purchased from commercial products or prepared in laboratory according to literature.
Stability test
The specific stability test method is carried out by referring to the guidance method of the fourth section related to stability investigation of the Chinese pharmacopoeia 2015 edition, the purity detection is carried out by using an HPLC method, and the specific test results are shown in the following table.
TABLE 3 stability test results of gefitinib crystalline form under light, high temperature and high humidity conditions
Experiments show that the gefitinib-3-hydroxybenzoic acid eutectic prepared by the invention has similar effects, the purity and appearance of the gefitinib-3-hydroxybenzoic acid eutectic are not obviously changed under the conditions of illumination, high temperature and high humidity, the purity of the existing crystal forms Form 1, form 7, alpha crystal Form and beta crystal Form is greatly reduced under the same experimental conditions, the impurity content of the gefitinib-benzoic acid eutectic prepared by the invention is obviously increased, the purity of the gefitinib-benzoic acid eutectic prepared by the comparative example 4 is lower than that of the gefitinib-3-hydroxybenzoic acid eutectic prepared by the invention, the purity of the gefitinib-3-hydroxybenzoic acid eutectic prepared by the invention is greatly reduced under the conditions of high temperature and high humidity, and the gefitinib-3-hydroxybenzoic acid eutectic prepared by the invention has better stability compared with the existing gefitinib crystal forms or eutectic.
Solubility experiment
The solubility of Form 1, form 7, alpha and beta forms of the examples, comparative examples and prior art disclosures in water and solutions of different pH were determined in experiments. Specifically, 10ml of medium (water, 0.01mol/L HCl solution and phosphate buffer solution with pH=6.8) is respectively measured in a penicillin bottle, excessive sample to be measured is added, the penicillin bottle is sealed and placed in a constant temperature water bath at 25 ℃ for stirring for 1 hour, and the mixture is filtered by a 0.45 mu m filter membrane, and filtrate is taken; the absorbance was measured at 247nm and the solubility was calculated by measuring the absorbance of the standard control.
TABLE 4 solubility of gefitinib crystalline forms in different media
As can be seen from experimental results, compared with the existing crystal forms Form 1, form 7, alpha crystal Form and beta crystal Form, the solubility of the gefitinib-3-hydroxybenzoic acid eutectic prepared by the invention is greatly improved; although the gefitinib-benzoic acid eutectic prepared in comparative example 4 has greatly improved solubility compared with Form 1 crystal Form, the gefitinib-benzoic acid eutectic is lower than the gefitinib-3-hydroxybenzoic acid eutectic, which also shows that the gefitinib-3-hydroxybenzoic acid eutectic provided by the invention obviously improves the solubility of gefitinib.
Sheeting Property experiments
Gefitinib Form 1 was prepared according to prior art CN100404032 example 4; preparing a gefitinib Form 7 crystal Form according to the prior art CN 103896863; preparing gefitinib alpha crystal form according to the prior art CN 103319422; preparing gefitinib beta crystal form according to the prior art CN 106083739; the gefitinib-benzoic acid co-crystal prepared in comparative example 4 had a purity of only 97.26% and also did not show good properties in terms of stability, solubility, etc., so that the sheeting properties thereof were not examined.
According to the preparation method of gefitinib tablets described in the embodiment 2 of the prior art CN1326569C, tablets taking gefitinib-3-hydroxybenzoic acid eutectic crystal, form 1 crystal Form, form 7 crystal Form, alpha crystal Form and beta crystal Form as active ingredients are obtained, and the relevant properties of each crystal Form tablet are examined according to the guidance method of Chinese pharmacopoeia standards. The results are compared in the following table.
TABLE 6 results of gefitinib tablet stability experiments
Note that: the test results for 6 months in the table are accelerated experiments at 40℃under 75% RH
Compared with the tablets prepared by Form 1, form 7, alpha crystal Form and beta crystal Form disclosed by the prior art, the tablet prepared by gefitinib-3-hydroxybenzoic acid eutectic has the advantages of uniform shape, good appearance color, less problems of cracking and the like, and low defective rate; the dissolution rate of the tablet prepared by the eutectic is obviously superior to that of the existing crystal tablet, even if the dissolution rate of the tablet prepared by the eutectic does not change obviously after accelerating for 6 months, the content of relevant substances of the tablet prepared by the eutectic is low, and the tablet prepared by the eutectic does not change greatly after accelerating for 6 months, which indicates that the tablet prepared by the gefitinib-3-hydroxybenzoic acid eutectic has better stability. The experimental result shows that the co-crystal provided by the invention has good preparation forming property, good dissolution property and stability, and is suitable for preparing oral solid preparations.
Claims (8)
1. The gefitinib-3-hydroxybenzoic acid co-crystal is characterized in that the molar ratio of gefitinib to 3-hydroxybenzoic acid in the co-crystal is 1:1, using Cu-ka radiation, the X-ray powder diffraction pattern corresponds to the X-ray powder diffraction pattern shown in fig. 3.
2. The gefitinib-3-hydroxybenzoic acid co-crystal according to claim 1, wherein the gefitinib-3-hydroxybenzoic acid co-crystal has an endothermic peak in a differential scanning calorimetric curve DSC, and the corresponding temperature range is 187.94-214.85 ℃.
3. A process for preparing gefitinib-3-hydroxybenzoic acid co-crystals as defined in any one of claims 1 to 2, characterized in that the specific preparation steps comprise: placing gefitinib and 3-hydroxybenzoic acid into a mortar, dropwise adding a small amount of organic solvent A, grinding to white powder, then adding a proper amount of organic solvent A again, continuously grinding to obtain a transparent solution, standing at a controlled temperature for crystallization, filtering, and vacuum drying to obtain gefitinib-3-hydroxybenzoic acid eutectic; wherein the organic solvent A is selected from one or a combination of ethanol, acetone, methanol and isopropanol.
4. The preparation method of claim 3, wherein the mass-to-volume ratio of gefitinib to the organic solvent A added for the first time is 70-90: 1mg/ml; the volume ratio of the organic solvent A used in the second grinding to the organic solvent A used in the first grinding is 2:1.
5. the preparation method of claim 3, wherein the molar ratio of gefitinib to 3-hydroxybenzoic acid is 1.0-1.5: 1.
6. the method of claim 3, wherein the molar ratio of gefitinib to 3-hydroxybenzoic acid is 1.0-1.2:1.
7. The method of claim 3, wherein the first grinding time is 30-50 min; the second grinding time is 10-20 min.
8. Use of gefitinib-3-hydroxybenzoic acid co-crystals as defined in any one of claims 1-2 for the preparation of a medicament for the treatment of tumors.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910486025.XA CN110128356A (en) | 2019-06-05 | 2019-06-05 | A kind of Gefitinib and 3- hydroxybenzoic acid eutectic |
| CN201910486025X | 2019-06-05 |
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| CN110128356A (en) * | 2019-06-05 | 2019-08-16 | 鲁南制药集团股份有限公司 | A kind of Gefitinib and 3- hydroxybenzoic acid eutectic |
| CN111454221B (en) * | 2020-04-21 | 2023-01-06 | 华南理工大学 | Gefitinib and bumetanide drug cocrystal and preparation method thereof |
| CN113801068B (en) * | 2020-06-15 | 2024-10-11 | 山东新时代药业有限公司 | Organic acid salt of gefitinib |
| CN113929629B (en) * | 2020-06-29 | 2024-12-17 | 鲁南制药集团股份有限公司 | Gefitinib acid addition salts of (a) |
| CN113149946B (en) * | 2021-04-16 | 2022-11-29 | 天津大学 | Dimethylamine michelia lactone-m-hydroxybenzoate, and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103172576A (en) * | 2011-12-21 | 2013-06-26 | 沈阳药科大学 | Malic acid addition salts of Gefitinib, preparation and application |
| WO2014016848A2 (en) * | 2012-07-24 | 2014-01-30 | Laurus Labs Private Limited | Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof |
| WO2015170345A1 (en) * | 2014-05-09 | 2015-11-12 | Council Of Scientific & Industrial Research | Pharmaceutical cocrystals of gefitinib |
| CN110128356A (en) * | 2019-06-05 | 2019-08-16 | 鲁南制药集团股份有限公司 | A kind of Gefitinib and 3- hydroxybenzoic acid eutectic |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103172576A (en) * | 2011-12-21 | 2013-06-26 | 沈阳药科大学 | Malic acid addition salts of Gefitinib, preparation and application |
| WO2014016848A2 (en) * | 2012-07-24 | 2014-01-30 | Laurus Labs Private Limited | Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof |
| WO2015170345A1 (en) * | 2014-05-09 | 2015-11-12 | Council Of Scientific & Industrial Research | Pharmaceutical cocrystals of gefitinib |
| CN110128356A (en) * | 2019-06-05 | 2019-08-16 | 鲁南制药集团股份有限公司 | A kind of Gefitinib and 3- hydroxybenzoic acid eutectic |
Non-Patent Citations (2)
| Title |
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| Combined Virtual/Experimental Multicomponent Solid Forms Screening of Sildenafil: New Salts, Cocrystals, and Hybrid Salt− Cocrystals;Rafael Barbas,等;Cryst. Growth Des.;第18卷;7618-7627 * |
| Isomers, Conformers, and Cocrystal Stoichiometry: Insights from the Crystal Energy Landscapes of Caffeine with the Hydroxybenzoic Acids;Matthew Habgood 等;Crystal Growth & Design;第10卷(第7期);3263–3272 * |
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| CN112047892A (en) | 2020-12-08 |
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