CN112047892A - Gefitinib and 3-hydroxybenzoic acid eutectic - Google Patents
Gefitinib and 3-hydroxybenzoic acid eutectic Download PDFInfo
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- CN112047892A CN112047892A CN202010407084.6A CN202010407084A CN112047892A CN 112047892 A CN112047892 A CN 112047892A CN 202010407084 A CN202010407084 A CN 202010407084A CN 112047892 A CN112047892 A CN 112047892A
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- gefitinib
- hydroxybenzoic acid
- eutectic
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- grinding
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- 230000005496 eutectics Effects 0.000 title claims abstract description 64
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 239000005411 L01XE02 - Gefitinib Substances 0.000 title claims abstract description 52
- 229960002584 gefitinib Drugs 0.000 title claims abstract description 51
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
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- VZGDMQKNWNREIO-UHFFFAOYSA-N carbon tetrachloride Substances ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
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- OQZFWVNMGTZNKT-UHFFFAOYSA-N propan-2-one;tetrachloromethane Chemical compound CC(C)=O.ClC(Cl)(Cl)Cl OQZFWVNMGTZNKT-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a gefitinib and 3-hydroxybenzoic acid eutectic, a preparation method thereof and application thereof in preparing a medicament for treating diseases. The co-crystal of gefitinib and 3-hydroxybenzoic acid has characteristic peaks at 7.06 + -0.2 deg, 14.08 + -0.2 deg, 15.92 + -0.2 deg, 24.66 + -0.2 deg, 25.06 + -0.2 deg, 28.33 + -0.2 deg.of X-ray diffraction spectrum expressed by 2 theta, and has better chemical stability, higher solubility than gefitinib 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 medicinal chemistry, and particularly relates to a gefitinib and 3-hydroxybenzoic acid eutectic, and a preparation method and application thereof.
Background
Gefitinib, which is sold as Iressa and has a 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 Aslicon, is suitable for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) which is not effective or suitable for chemotherapy by platinum antineoplastic agents and docetaxel chemotherapy in the past, is the 1 st small molecular protein tyrosine kinase inhibitor targeted anticancer drug for treating solid tumors, and is officially released to be marketed in China in 2005 with 2-month approval.
At present, many documents report that gefitinib has a polymorphism problem, and different crystal forms of a drug can directly influence the solubility, dissolution rate, target effect and the like of the drug in vivo so as to influence the exertion of drug effect.
Patent WO9633980 discloses for the first time a process for the preparation of gefitinib compounds, but this patent does not specifically disclose whether the compounds prepared are crystalline or amorphous, nor whether the compounds can exist in solvated form.
Patent CN100404032C discloses four crystal forms of gefitinib Form 1 (polymorphic substance), Form 2 (methanol solvate), Form 3(DMSO solvate) and Form 5 (trihydrate) and preparation methods thereof. The patent indicates that after Form 3, Form 2 or Form 5 is washed by a solvent or a solvent mixture, Form 1 polymorphic substances can be obtained through separation, and research finds that Form 1 has good stability and is suitable for solid preparations of gefitinib such as tablets and capsules, but in the actual preparation process, the Form 1 is obtained with poor repeatability, possibly caused by the polymorphic phenomenon of crystals of the Form. Form 2 methanol solvate and Form 3DMSO solvate are both less stable than Form 1, and the content of methanol in the Form 2 crystal Form is about 10 times the pharmacopeia limit (pharmacopeia limit of 0.3%), and the content of DMSO in the Form 3 crystal Form is about 30 times the pharmacopeia limit (pharmacopeia limit of 0.5%), which shows that the Form 2 and Form 3 crystal forms are also easier to prepare, but excessive solvent residue makes them unsuitable for pharmaceutical crystal forms. 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 greatly limits the application of the Form 5 crystal Form.
Patent WO2006090413A1 discloses a gefitinib Form 6 crystal Form and a preparation method thereof, 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, the crystal Form is a monohydrate crystal Form, the stability is lower than Form 1, and the problem of application limitation similar to Form 5 crystal Form also exists.
Patent CN103896863B discloses a new Form 7 Form of gefitinib crystal Form and a preparation method thereof, and researches the pharmacokinetics of the crystal Form in a rat body, and the result shows that the pharmacokinetic parameters of the crystal Form and the Form 1 crystal Form sold on the market are not obviously different, but other properties of the crystal Form are not researched.
Patent CN103896861A discloses amorphous gefitinib, i.e. Form8 Form and preparation method thereof, but generally can not be selected as medicinal crystal Form due to the physicochemical defect of amorphous substance. Patent CN104693127B discloses a gefitinib ethylene glycol solvate and a preparation method thereof, but researches have found that the content of ethylene glycol in the crystal is about 300 times (0.062%) of the pharmacopeia limit, and the crystal form is also not suitable for being used as a medicinal crystal form due to the high residual amount of organic solvent.
Although the existing literature discloses a plurality of gefitinib crystal forms, the systematic research on the crystal forms is still to be perfected, and particularly, the research on gefitinib eutectic compounds is not reported yet. The new salt form of pharmaceutical co-crystal is a supermolecular crystal with fixed stoichiometric ratio formed by introducing new co-crystal substance (CCF) through proton transfer and self-assembling with active pharmaceutical ingredient (APT) under the action of hydrogen bond. Due to potential advantages in terms of dissolution, permeation, moisture absorption, stability, etc., drug co-crystals are of increasing interest to researchers in the field of drug preparation. Although patent WO2014016848 mentions that gefitinib and p-hydroxybenzoic acid can form a eutectic, no corresponding preparation method is given, and the properties of the eutectic are not studied, and the inventors have not succeeded in obtaining the eutectic of gefitinib and p-hydroxybenzoic acid described in the patent by trying a plurality of methods in research; patent WO2015170345 also mentions co-crystals of gefitinib and benzoic acid, but studies have found that the process is not versatile and that the benzoic acid co-crystals prepared in this patent do not have outstanding properties compared to the existing gefitinib crystal forms.
Disclosure of Invention
Aiming at the problems of low solubility, poor stability, poor reproducibility in the preparation process and excessive organic solvent residue of the existing gefitinib crystal form, the invention aims to provide a gefitinib-3-hydroxybenzoic acid eutectic which can replace the existing crystal form, has better chemical stability and higher solubility than the existing crystal form, and effectively avoids the crystal transformation phenomenon and the solvent residue of the existing crystal form through the formation of the eutectic.
The specific technical content of the invention is as follows:
in a first aspect of the invention, provided is a gefitinib-3-hydroxybenzoic acid eutectic. In the co-crystal, the molar ratio of gefitinib to 3-hydroxybenzoic acid is 1: 1.
preferably, the Gefitinib-3-hydroxybenzoic acid eutectic has characteristic peaks at 7.06 + -0.2 deg, 14.08 + -0.2 deg, 15.92 + -0.2 deg, 24.66 + -0.2 deg, 25.06 + -0.2 deg, 28.33 + -0.2 deg by X-ray diffraction spectrum expressed in 2 theta using Cu-Ka radiation.
Preferably, the Gefitinib-3-hydroxybenzoic acid eutectic has characteristic peaks at 7.06 + -0.2 °, 14.08 + -0.2 °, 15.92 + -0.2 °, 20.99 + -0.2 °, 23.59 + -0.2 °, 24.66 + -0.2 °, 25.06 + -0.2 °, 25.57 + -0.2 °, 28.33 + -0.2 ° and 40.86 + -0.2 ° in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.
Preferably, the gefitinib-3-hydroxybenzoic acid cocrystal uses Cu-Ka radiation, and the characteristic peak of the gefitinib-3-hydroxybenzoic acid cocrystal accords with an X-ray powder diffraction pattern shown in figure 3.
Preferably, the gefitinib-3-hydroxybenzoic acid eutectic has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve, and the corresponding temperature range is 187.94-214.85 ℃, and particularly preferably 204.96 ℃.
Preferably, the crystal parameters of the gefitinib-3-hydroxybenzoic acid eutectic are as follows: monoclinic system, space group P21C; the unit cell parameters are:
α is 90.00 °, β is 92.1030(10 °), γ is 90.00 °, unit cell volume
In a second aspect of the present invention, there is provided a method for preparing gefitinib-3-hydroxybenzoic acid eutectic, comprising the specific steps of: putting gefitinib and 3-hydroxybenzoic acid into a mortar, dropwise adding a small amount of organic solvent A, grinding to obtain white powder, then 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 the 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 of ethanol, methanol or a combination thereof.
Preferably, the molar ratio of the gefitinib to the 3-hydroxybenzoic acid is 1.0-1.5: 1; 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 time of the second grinding is 10-20 min.
Preferably, in the preparation method, the mass-to-volume ratio of gefitinib to the organic solvent A required for the first grinding is 70-90: 1, mg/ml.
Preferably, in the preparation method, the volume ratio of the organic solvent a required for the second grinding to the organic solvent a required for the first grinding is 2: 1.
preferably, in the preparation method, the temperature-controlled crystallization temperature is 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 of the invention, the invention provides a pharmaceutical composition containing the gefitinib-3-hydroxybenzoic acid eutectic and application of the eutectic in preparing a medicament for treating diseases such as cancer.
The preparation method of the pharmaceutical composition of the invention can be as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare useful dosage forms.
The pharmaceutical composition can be spray, tablets, capsules, powder injections, liquid injections, freeze-dried powder injections and other pharmaceutically available formulations.
Confirmation of the Crystal Structure
The gefitinib-3-hydroxybenzoic acid eutectic provided by the invention is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffraction instrument and the test conditions related by the invention are as follows: chemistry xtlab Synergy X-ray single crystal diffractometer, test temperature 293(2) K, use CuKa radiation, collect data in omega scan mode and perform Lp correction. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The crystallographic data obtained by testing and analyzing the gefitinib-3-hydroxybenzoic acid eutectic prepared by the invention are (table 1): the crystallography of ginsengThe number is: monoclinic system, space group P21C; the unit cell parameters are:
α is 90.00 °, β is 92.1030(10 °), γ is 90.00 °, unit cell volume
The ORTEP plot of the gefitinib-3-hydroxybenzoic acid cocrystal of the present invention shows (fig. 1) that one molecule of gefitinib binds one molecule of 3-hydroxybenzoic acid. The hydrogen bond diagram shown in fig. 2 indicates that gefitinib and 3-hydroxybenzoic acid are connected by intermolecular hydrogen bonds to form a three-dimensional structure.
TABLE 1 Primary crystallographic data for Gefitinib-3-hydroxybenzoic acid cocrystals
The X-ray powder diffraction test instrument and the test conditions involved in the invention are as follows: x-ray powder diffractometer: PANALYTIC EMPyrean X-ray powder diffractometer; Cu-K alpha; a sample stage: a flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40 mA; divergent slit: 1/4, respectively; anti-scattering slit: 1; rope pulling of a slit: 0.04 rad; step length: 0.5 s; scanning range: 3 to 50 degrees.
According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in FIG. 3 and Table 2.
TABLE 2 PXRD peaks of Gefitinib-3-hydroxybenzoic acid cocrystals
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram: METTLER TOLEDO TGA/DSC3 +; dynamic temperature segment: 30-300 ℃; heating rate: 10 ℃/min; segment gas N2(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.
The TGA/DSC test result of the gefitinib-3-hydroxybenzoic acid eutectic is shown in figure 4, and the DSC test chart shows that the eutectic has an endothermic peak with the corresponding temperature of 187.94-214.85 ℃ and the peak value of 204.96 ℃. According to the TGA detection result, a weight loss step exists in the eutectic, which indicates that the gefitinib-3-hydroxybenzoic acid eutectic is decomposed while melting, so that the DSC/TGA detection result indicates that the gefitinib-3-hydroxybenzoic acid eutectic is successfully prepared, and no organic solvent residue exists in the crystal structure.
Compared with the prior art, the invention has the following technical effects:
1. the gefitinib-3-hydroxybenzoic acid eutectic provided by the invention has better chemical stability and higher solubility.
2. The preparation method provided by the invention has good reproducibility and convenient operation, the solubility of the gefitinib-3 hydroxybenzoic acid eutectic prepared by the method is higher than that of the existing stable crystal, and the formation and crystal transformation phenomena of a solvate can be effectively inhibited.
3. The gefitinib-3 hydroxybenzoic acid eutectic obtained by the preparation method has the pharmaceutical activity similar to Form 1 crystal Form, but effectively avoids the problem that a single drug 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: and (3) a hydrogen bond diagram of the gefitinib-3-hydroxybenzoic acid eutectic.
FIG. 3: an X-ray powder diffraction pattern of the gefitinib-3-hydroxybenzoic acid eutectic.
FIG. 4: DSC-TGA picture of gefitinib-3-hydroxybenzoic acid eutectic.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
Adding 45.0mg of gefitinib and 11.6mg of 3-hydroxybenzoic acid into a mortar, dropwise adding 0.5mL of methanol into the mortar, fully grinding for 35min, adding 1mL of methanol, continuously grinding for 15min to obtain a transparent solution, controlling the temperature to be 5-10 ℃, standing and crystallizing for 48 h, filtering, and drying in vacuum for 8h at 55 ℃ to obtain gefitinib-3-hydroxybenzoic acid eutectic, wherein the yield is 91.12%, and HPLC: 99.94 percent.
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 for 30min, adding 1mL of ethanol, continuously grinding for 10min to obtain a transparent solution, standing and crystallizing for 48 h at the temperature of 5-10 ℃, filtering, and drying in vacuum for 10h at the temperature of 55 ℃ to obtain gefitinib-3-hydroxybenzoic acid eutectic, wherein the yield is 90.52%, and the HPLC: 99.92 percent.
Example 3
Adding 45.0mg of gefitinib and 11.6mg of 3-hydroxybenzoic acid into a mortar, dropwise adding 0.5mL of methanol into the mortar, fully grinding for 50min, adding 1mL of methanol, continuously grinding for 20min to obtain a transparent solution, standing and crystallizing for 48 h at the temperature of 5-10 ℃, filtering, and drying in vacuum for 8h at the temperature of 55 ℃ to obtain gefitinib-3-hydroxybenzoic acid eutectic, wherein the yield is 90.76%, and HPLC: 99.93 percent.
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 for 20min, adding 1mL of isopropanol, continuously grinding for 15min to obtain a transparent solution, standing and crystallizing for 72 h at the temperature of 5-10 ℃, filtering, and drying in vacuum for 8h at the temperature of 60 ℃ to obtain gefitinib-3-hydroxybenzoic acid eutectic, wherein the yield is 83.99%, and the HPLC: 96.15 percent.
Example 5
Adding 35.0mg of gefitinib and 11.0mg of 3-hydroxybenzoic acid into a mortar, dropwise adding 0.5mL of methanol alcohol into the mortar, fully grinding for 35min, adding 1mL of methanol, continuously grinding for 30min to obtain a transparent solution, standing and crystallizing for 72 h at the temperature of 5-10 ℃, filtering, and drying in vacuum for 10h at the temperature of 50 ℃ to obtain gefitinib-3-hydroxybenzoic acid eutectic, wherein the yield is 81.66%, and the HPLC: 95.72 percent.
Example 6
Adding 45.0mg of gefitinib and 9.0mg of 3-hydroxybenzoic acid into a mortar, dropwise adding 0.5mL of ethanol into the mortar, fully grinding for 60min, adding 1mL of ethanol, continuously grinding for 30min to obtain a transparent solution, standing and crystallizing for 72 h at the temperature of 5-10 ℃, filtering, and drying in vacuum for 8h at the temperature of 55 ℃ to obtain gefitinib-3-hydroxybenzoic acid eutectic, wherein the yield is 80.25%, and HPLC: 96.02 percent.
Comparative example 1
Adding 446.9mg of gefitinib into 10ml of ethanol for dissolving at 25-30 ℃, then adding 3-hydroxybenzoic acid (138.1mg), heating, refluxing and stirring until a clear solution is obtained, continuing to reflux and stir for 2 hours, cooling the reaction liquid to 25-30 ℃, then continuing to stir overnight, filtering, re-cooling, standing and crystallizing until no solid is precipitated; no crystal was precipitated even by adjusting the relevant experimental conditions.
Comparative example 2
Adding 446.9mg of gefitinib into 10ml of ethanol for dissolving at 25-30 ℃, then adding p-hydroxybenzoic acid (138.1mg), heating, refluxing and stirring until a clear solution is obtained, continuing to reflux and stir for 2 hours, cooling the reaction liquid to 25-30 ℃, then continuing to stir overnight, filtering, and cooling again to stand for crystallization until no solid is precipitated; no crystal was precipitated even by adjusting the relevant experimental conditions.
Comparative example 3
100mg of gefitinib and 3-hydroxybenzoic acid (30.9mg) were put into a mortar for pulverization, and the pulverized mixture was transferred to a container containing acetone-CCl4Heating at 60 deg.C for 30min to dissolve in a flask (15ml, volume ratio 1:1), adding 5ml of mixed solution of ethanol and water into the flask, filtering, collecting filtrate, standing for crystallizing for 24 hr, and vacuum filtering to remove crystalsAnd (4) precipitating.
Comparative example 4
100mg of gefitinib and 27.35mg of benzoic acid were pulverized in a mortar, and the pulverized mixture was transferred to a container containing acetone-CCl4(15ml, volume ratio 1:1) in a flask, heating at 60 ℃ for 30min to dissolve, then adding 5ml of a mixed solution of ethanol and water into the flask, filtering to collect the filtrate, standing the filtrate for crystallization for 24 hours, suction-filtering, and vacuum-drying the obtained solid with a yield of 69.1%, HPLC: 97.26 percent.
The prior art-documented crystalline forms of gefitinib used in the property study experiments were purchased from commercially available products or prepared in the laboratory according to the literature.
Stability test
The specific stability test method refers to a guidance method related to stability investigation in the fourth part of the Chinese pharmacopoeia 2015 edition, the purity detection is performed by an HPLC method, and 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 approximate effect, the purity and the 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 existing crystal forms 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, and the purity of the gefitinib-3-hydroxybenzoic acid eutectic is greatly reduced in the high temperature and high humidity environment, so that the gefitinib-3-hydroxybenzoic acid eutectic prepared by the invention has better stability compared with the existing gefitinib crystal Form or eutectic.
Solubility test
The solubility of Form 1, Form 7, alpha crystal Form and beta crystal Form disclosed in the examples, comparative examples and prior art in water and solutions of different pH values was determined in the experiments. Respectively measuring 10ml of media (water, 0.01mol/L HCl solution and phosphate buffer solution with pH of 6.8) into a penicillin bottle, adding excessive samples to be detected, sealing the penicillin bottle, placing the penicillin bottle in a constant-temperature water bath at 25 ℃, stirring for 1 hour, filtering through a 0.45-micrometer filter membrane, and taking filtrate; the absorbance at 247nm was measured, and the solubility was calculated by measuring the absorbance of the standard control.
Table 4 solubility of gefitinib crystalline forms in different media
The experimental result shows that the solubility of the gefitinib-3-hydroxybenzoic acid eutectic prepared by the invention is greatly improved compared with the solubility of the existing crystal forms Form 1, Form 7, alpha crystal Form and beta crystal Form; although the solubility of the gefitinib-benzoic acid eutectic prepared in comparative example 4 is greatly improved compared with Form 1 crystal Form, the gefitinib-benzoic acid eutectic is also lower than the gefitinib-3-hydroxybenzoic acid eutectic, which also shows that the solubility of gefitinib is remarkably improved by the gefitinib-3-hydroxybenzoic acid eutectic provided by the invention.
Test for sheet Property
Preparing gefitinib Form 1 crystal Form according to embodiment 4 of CN100404032 in the prior art; 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 eutectic prepared in comparative example 4 has a purity of only 97.26%, and also does not exhibit good properties in terms of stability, solubility, etc., and thus its tableting properties are not examined.
Tablets respectively 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 according to the preparation method of gefitinib tablets recorded in embodiment 2 of CN1326569C in the prior art, and the related properties of each crystal Form tablet are inspected according to the guidance method of Chinese pharmacopoeia standards. The results are compared in the following table.
TABLE 6 Gefitinib tablet stability test results
Note: the results of the 6-month test in the table are accelerated tests at 40 ℃ and 75% RH
Therefore, 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 the gefitinib-3-hydroxybenzoic acid eutectic has the advantages of uniform shape, good appearance and 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 form tablet, and the dissolution rate of the tablet prepared by the eutectic is not obviously changed even after the tablet is accelerated for 6 months, and the related substance content of the tablet prepared by the eutectic is lower and is not greatly changed after the tablet is accelerated for 6 months, so that the tablet prepared by the eutectic of gefitinib-3-hydroxybenzoic acid has better stability. The experimental results show that the eutectic provided by the invention has good preparation forming performance, good dissolution and stability, and is suitable for preparing oral solid preparations.
Claims (10)
1. The gefitinib-3-hydroxybenzoic acid eutectic is characterized in that the molar ratio of gefitinib to 3-hydroxybenzoic acid in the eutectic is 1: 1.
2. the gefitinib-3-hydroxybenzoic acid co-crystal of claim 1, wherein an X-ray diffraction pattern expressed in 2 Θ using Cu-ka radiation has characteristic peaks at 7.06 ± 0.2 °, 14.08 ± 0.2 °, 15.92 ± 0.2 °, 24.66 ± 0.2 °, 25.06 ± 0.2 °, 28.33 ± 0.2 °.
3. The gefitinib-3-hydroxybenzoic acid eutectic of claim 1, wherein an X-ray diffraction pattern expressed in 2 Θ using Cu-ka radiation has characteristic peaks at 7.06 ± 0.2 °, 14.08 ± 0.2 °, 15.92 ± 0.2 °, 20.99 ± 0.2 °, 23.59 ± 0.2 °, 24.66 ± 0.2 °, 25.06 ± 0.2 °, 25.57 ± 0.2 °, 28.33 ± 0.2 °, 40.86 ± 0.2 °.
4. Gefitinib-3-hydroxybenzoic acid co-crystal of claim 1, wherein, using Cu-ka radiation, the characteristic peaks follow the X-ray powder diffraction pattern shown in figure 3.
5. The gefitinib-3-hydroxybenzoic acid eutectic of claim 1, having an endothermic peak in Differential Scanning Calorimetry (DSC) curve corresponding to a temperature range of 187.94-214.85 ℃.
6. A method for preparing the gefitinib 3-hydroxybenzoic acid co-crystal of claims 1-6, comprising the specific steps of: putting gefitinib and 3-hydroxybenzoic acid into a mortar, dropwise adding a small amount of organic solvent A, grinding to obtain white powder, then 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 the gefitinib-3-hydroxybenzoic acid eutectic.
7. The preparation method according to claim 6, wherein the organic solvent A is selected from one or a combination of ethanol, acetone, methanol and isopropanol; wherein the mass-volume ratio of the gefitinib to the organic solvent A added for the first time is 70-90: 1, mg/ml; the volume ratio of the organic solvent A used for the second grinding to the solvent A used for the first grinding is 2: 1.
8. the preparation method according to claim 6, wherein the molar ratio of gefitinib to 3-hydroxybenzoic acid is 1.0-1.5: 1, preferably 1.0 to 1.2: 1.
9. the method according to claim 6, wherein the first grinding time is 30 to 50 min; the time of the second grinding is 10-20 min.
10. Use of gefitinib-3-hydroxybenzoic acid co-crystal of claims 1-5 for the preparation of a medicament for the treatment of disease, preferably for the preparation of a medicament for the treatment of tumor.
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| CN111454221B (en) * | 2020-04-21 | 2023-01-06 | 华南理工大学 | Gefitinib and bumetanide drug cocrystal and preparation method thereof |
| CN113754596A (en) * | 2020-06-01 | 2021-12-07 | 鲁南制药集团股份有限公司 | Gefitinib co-crystal |
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| CN113149946A (en) * | 2021-04-16 | 2021-07-23 | 天津大学 | Michellac dimethylamine lactone-m-hydroxybenzoate and preparation method and application thereof |
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