CN112047893B - Gefitinib and salicylic acid co-crystal - Google Patents
Gefitinib and salicylic acid co-crystal Download PDFInfo
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- CN112047893B CN112047893B CN202010407103.5A CN202010407103A CN112047893B CN 112047893 B CN112047893 B CN 112047893B CN 202010407103 A CN202010407103 A CN 202010407103A CN 112047893 B CN112047893 B CN 112047893B
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- 239000013078 crystal Substances 0.000 title claims abstract description 108
- 229960004889 salicylic acid Drugs 0.000 title claims abstract description 74
- 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 62
- 239000005411 L01XE02 - Gefitinib Substances 0.000 title claims abstract description 59
- 229960002584 gefitinib Drugs 0.000 title claims abstract description 58
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 title claims abstract description 54
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 230000005496 eutectics Effects 0.000 claims abstract description 38
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 238000000227 grinding Methods 0.000 claims abstract description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000004570 mortar (masonry) Substances 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 6
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- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 229910017488 Cu K Inorganic materials 0.000 description 5
- 229910017541 Cu-K Inorganic materials 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
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- 239000007789 gas Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 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
- 230000001376 precipitating effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 150000004684 trihydrates Chemical class 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 150000004924 Gefitinib derivatives Chemical class 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
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- 230000002175 menstrual effect Effects 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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 co-crystal of gefitinib and salicylic acid, a preparation method thereof and application thereof in preparing medicines for treating diseases. The molar ratio of gefitinib to salicylic acid in the co-crystal is 1:2, the X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 5.90+/-0.2 degrees, 6.59+/-0.2 degrees, 13.20+/-0.2 degrees, 13.96+/-0.2 degrees, 16.50+/-0.2 degrees and 20.01+/-0.2 degrees; the eutectic crystal has better chemical stability, higher solubility and better bioavailability; the co-crystal of gefitinib and salicylic acid can be obtained by a grinding method, and the method is simple and convenient to operate, stable in yield and high in repeatability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a gefitinib and salicylic 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 Form1 (polymorph), form 2 (methanol solvate), form 3 (DMSO solvate), form 5 (trihydrate) and methods of making the same. The patent teaches that Form1 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 Form1 has good stability and is suitable for solid formulations of gefitinib such as tablets and capsules, but in the actual preparation process, the Form1 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 Form1, 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 Form1, 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 Form1, 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 Form1 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 has disclosed numerous crystalline forms of gefitinib, systematic studies on the crystalline forms of gefitinib remain to be perfected, and particularly, comprehensive studies on gefitinib eutectic compounds have not been 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-salicylic acid eutectic crystal capable of replacing the existing crystal form, which has good chemical stability and high solubility, and the problems of the crystal transformation phenomenon and the 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 and salicylic acid, wherein the co-crystal has a molar ratio of gefitinib to salicylic acid of 1:2.
Preferably, the gefitinib-salicylic acid co-crystal uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 5.90+/-0.2 degrees, 6.59+/-0.2 degrees, 13.20+/-0.2 degrees, 13.96+/-0.2 degrees, 16.50+/-0.2 degrees and 20.01+/-0.2 degrees.
Preferably, the gefitinib-salicylic acid co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 5.90+/-0.2 degrees, 6.59+/-0.2 degrees, 8.22+/-0.2 degrees, 10.35+/-0.2 degrees, 10.97+/-0.2 degrees, 11.83+/-0.2 degrees, 13.20+/-0.2 degrees, 13.96+/-0.2 degrees, 16.50+/-0.2 degrees, 17.24+/-0.2 degrees, 20.01+/-0.2 degrees and 22.24+/-0.2 degrees and 25.0+/-0.2 degrees.
Preferably, the gefitinib-salicylic acid co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 5.90+/-0.2 degrees, 6.59+/-0.2 degrees, 8.22+/-0.2 degrees, 10.35+/-0.2 degrees, 10.97+/-0.2 degrees, 11.83+/-0.2 degrees, 13.20+/-0.2 degrees, 13.96+/-0.2 degrees, 16.18+/-0.2 degrees, 16.50+/-0.2 degrees, 17.24+/-0.2 degrees, 17.80+/-0.2 degrees, 18.33+/-0.2 degrees, 20.01+/-0.2 degrees, 20.80+/-0.2 degrees, 22.24+/-0.2 degrees, 22.93+/-0.2 degrees, 25.04+/-0.2 degrees and 28.14+/-0.2 degrees.
Preferably, the gefitinib-salicylic acid co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 3.
Preferably, the gefitinib-salicylic acid co-crystal has an endothermic peak in a differential scanning calorimetric curve DSC, and the corresponding temperature range is 196.44-215.43 ℃ and the peak value is 201.62 ℃.
Preferably, the gefitinib-salicylic acid co-crystal has the following crystallographic parameters: monoclinic system with space group P2 1 2 1 2 1 The method comprises the steps of carrying out a first treatment on the surface of the The unit cell parameters are:α=90.00 °, β=90.00 °, γ=90.00 °, unit cell volume +.>
In a second aspect of the invention, a preparation method of gefitinib-salicylic acid co-crystal is provided, and the specific preparation steps comprise: and (3) placing gefitinib and salicylic 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 vacuum drying to obtain gefitinib-salicylic 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 salicylic acid is 1:1.8-2.5; further preferably, the molar ratio of gefitinib to salicylic acid is 1:1.8-2.1.
Preferably, the time of the first grinding is 30-50 min, and the time of the second grinding is 10-20 min.
Preferably, the mass-volume ratio of gefitinib to the organic solvent A required by the first grinding is 50-80:1, mg/ml.
Preferably, the volume ratio of the organic solvent A required by the second grinding to the organic solvent A required by the first grinding is 1:1.
Preferably, the temperature of the control Wen Xijing is 0-10 ℃, preferably 0-5 ℃.
Preferably, the crystallization time is 48-72 hours.
Preferably, 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-salicylic acid co-crystal and application of the co-crystal in preparing medicines for treating diseases.
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 comprises spray, tablet, capsule, powder injection, liquid injection, freeze-dried powder injection and other pharmaceutically usable dosage forms.
Confirmation of Crystal Structure
The gefitinib-salicylic acid eutectic 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 data was collected by omega scanning using CuKa radiation and corrected for Lp. 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-salicylic acid co-crystals prepared by the invention are (table 1): the crystallographic parameters are: monoclinic system with space group P2 1 2 1 2 1 The method comprises the steps of carrying out a first treatment on the surface of the The unit cell parameters are: α=90.00 °, β=90.00 °, γ=90.00 °, unit cell volume +.>ORTEP diagram of gefitinib-salicylic acid co-crystal of the invention shows (FIG. 1), two moleculesGefitinib incorporates four molecules of salicylic acid. The hydrogen bond diagram (figure 2) of gefitinib-salicylic acid co-crystal of the invention shows that gefitinib and salicylic acid are connected into a three-dimensional structure through intermolecular hydrogen bonds.
TABLE 1 principal crystallographic data of gefitinib-salicylic 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-salicylic acid co-crystals
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-salicylic acid eutectic prepared by the method is shown in figure 4, and the DSC detection spectrogram shows that the eutectic has an endothermic peak, the corresponding temperature range is 196.44-215.43 ℃, and the peak value is 201.62 ℃. According to a TGA detection result, the eutectic crystal has a weight loss step, which shows that the gefitinib-salicylic acid eutectic crystal is decomposed while being melted, so that the DSC/TGA detection result shows that the prepared crystal form is the gefitinib-salicylic acid eutectic crystal, and no organic solvent residue exists in the crystal structure of the crystal form.
Compared with the prior art, the invention has the technical effects that:
1. the gefitinib-salicylic acid eutectic provided by the invention has better chemical stability and higher solubility.
2. The preparation method provided by the invention has good repeatability and convenient operation, and the solubility of the eutectic prepared by the method is higher than that of the existing crystal form, and can effectively inhibit the formation of solvates and the phenomenon of crystal transformation.
3. The gefitinib-salicylic acid co-crystal prepared by the preparation method has the pharmaceutical activity similar to that of Form1 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-salicylic acid co-crystal.
Fig. 2: hydrogen bonding diagram of gefitinib-salicylic acid co-crystal.
Fig. 3: x-ray powder diffraction pattern of gefitinib-salicylic acid co-crystal.
Fig. 4: DSC-TGA profile of gefitinib-salicylic acid co-crystals.
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
60.0mg of gefitinib and 38.9mg of salicylic acid are added into a mortar, 1mL of methanol is added dropwise into the mortar, the mixture is sufficiently ground for 35min, 1mL of methanol is added for further grinding for 15min, a transparent solution is obtained, standing and crystallization are carried out for 48 h at the temperature of 0-5 ℃, filtering is carried out, vacuum drying is carried out for 8h at the temperature of 55 ℃, gefitinib-salicylic acid co-crystal is obtained, the yield is 90.32%, HPLC:99.93%.
Example 2
50.0mg of gefitinib and 32.4mg of salicylic acid are added into a mortar, 1mL of ethanol is added dropwise into the mortar, the mixture is fully ground for 30min, 1mL of ethanol is added, the mixture is continuously ground for 10min, a transparent solution is obtained, the mixture is kept stand and crystallized for 48 h at the temperature of 0-5 ℃, the mixture is filtered, and the mixture is dried in vacuum for 8h at the temperature of 55 ℃ to obtain gefitinib-salicylic acid co-crystals, the yield is 90.06 percent, and HPLC:99.92%.
Example 3
Adding 80.0mg of gefitinib and 51.9mg of salicylic acid into a mortar, dropwise adding 1mL 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 0-5 ℃, filtering, and vacuum drying for 8h at the temperature of 55 ℃ to obtain gefitinib-salicylic acid co-crystal, wherein the yield is 90.14 percent, and HPLC:99.92%.
Example 4
60.0mg of gefitinib and 38.9mg of salicylic acid are added into a mortar, 1mL of isopropanol is added dropwise into the mortar, the mixture is sufficiently ground for 20min, 1mL of isopropanol is added, the grinding is continued for 15min, a transparent solution is obtained, the mixture is kept stand and crystallized for 48 h at the temperature of 0-5 ℃, the mixture is filtered, and the mixture is dried in vacuum for 10h at the temperature of 60 ℃ to obtain gefitinib-salicylic acid eutectic with the yield of 81.25 percent, and HPLC:97.96%.
Example 5
60.0mg of gefitinib and 38.9mg of salicylic acid are added into a mortar, 1mL of methanol is added dropwise into the mortar, the mixture is sufficiently ground for 35min, 1mL of methanol is added for further grinding for 30min, a transparent solution is obtained, standing and crystallization are carried out for 48 h at the temperature of 0-5 ℃, filtering is carried out, vacuum drying is carried out for 10h at the temperature of 50 ℃ to obtain gefitinib-salicylic acid co-crystal, the yield is 85.16 percent, and HPLC:98.27%.
Example 6
90.0mg of gefitinib and 58.4mg of salicylic acid are added into a mortar, 1mL of acetone is added dropwise into the mortar, the mixture is fully ground for 60min, 1mL of acetone is added for further grinding for 30min, a transparent solution is obtained, standing and crystallization are carried out for 72 h at the temperature of 0-5 ℃, filtering is carried out, vacuum drying is carried out for 8h at the temperature of 55 ℃, gefitinib-salicylic acid co-crystal is obtained, the yield is 80.52 percent, and HPLC:97.36%.
Comparative example 1
Adding 446.9mg of gefitinib into 10ml of ethanol at the temperature of 25-30 ℃ for dissolution, adding 138.1mg of salicylic acid, 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 still 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 138.1mg of p-hydroxybenzoic acid, 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 30.9mg of salicylic acid were added to a mortar and pulverized, after which the pulverized mixture was transferred to a mortar containing 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, and no crystals were precipitated by suction filtration.
Comparative example 4
100mg of gefitinib and 27.35mg of benzoic acid were crushed in a mortar, and the crushed mixture was transferred to a mortar containing 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 is purchased from commercial products or prepared in laboratory according to literature
Stability test
Specific stability test methods are carried out by referring to the guidance method of stability investigation specified in the fourth section of the Chinese pharmacopoeia 2015 edition, 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-salicylic acid eutectic prepared by the invention has similar effects, the purity and appearance of the gefitinib-salicylic acid eutectic are not obviously changed under the conditions of illumination, high temperature and high humidity, the purity of the existing crystal forms Form1, form 7, alpha crystal Form and beta crystal Form is greatly reduced under the same experimental conditions, the impurity content of the gefitinib-salicylic 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 salicylic acid eutectic prepared by the invention, the purity of the gefitinib-salicylic acid eutectic is also greatly reduced under the conditions of high temperature and high humidity, and the prepared eutectic has better stability compared with the crystal forms or the eutectic disclosed by the prior art.
Solubility experiment
The solubility of the forms 1, form 7, alpha and beta forms of the examples, comparative examples and prior art disclosures in water and solutions of different pH values were determined in experiments. The specific test method comprises the following steps: respectively weighing 10ml of medium (water, 0.01mol/L HCl solution and phosphate buffer solution with pH=6.8) into a penicillin bottle, adding excessive sample to be tested, sealing the penicillin bottle, placing the penicillin bottle in a constant temperature water bath at 25 ℃ for stirring for 1 hour, filtering the penicillin bottle by a 0.45 mu m filter membrane, and taking filtrate; the absorbance of the resulting filtrate was measured at a wavelength of 249nm, and the solubility was calculated by testing 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 Form1, form 7, alpha crystal Form and beta crystal Form, the solubility of the gefitinib-salicylic acid eutectic prepared by the invention is greatly improved; although the solubility of the gefitinib-benzoic acid eutectic prepared in the comparative example 4 is greatly improved relative to Form1, the solubility of the gefitinib-salicylic acid eutectic is still far lower than that of the gefitinib-salicylic acid eutectic, and the co-crystal structure formed by gefitinib and salicylic acid also shows that the solubility of the gefitinib is remarkably improved, and the physicochemical property of the gefitinib-salicylic acid eutectic is improved.
Sheeting Property experiments
Gefitinib Form1 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 method for preparing gefitinib tablets described in the embodiment 2 of the prior art CN1326569C, 1000 tablets taking gefitinib-salicylic acid eutectic crystal, form1 crystal Form, form 7 crystal Form, alpha crystal Form or beta crystal Form as active ingredients are respectively prepared, and the relevant properties of each crystal Form tablet are examined according to the Chinese pharmacopoeia standard method.
TABLE 6 results of gefitinib tablet stability experiments
Note that: accelerated experiments at 40℃and 75% RH for 6 months of the Table
Compared with the tablets prepared from Form1, form 7, alpha crystal Form and beta crystal Form disclosed in the prior art, the tablet prepared from gefitinib-salicylic acid co-crystal has the advantages of uniform shape, good appearance and luster, 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 proves that the tablet prepared by the gefitinib-salicylic 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 (7)
1. The gefitinib-salicylic acid co-crystal is characterized in that the molar ratio of gefitinib to salicylic acid in the co-crystal is 1:2, using Cu-ka radiation, the X-ray powder diffraction pattern corresponds to the X-ray powder diffraction pattern shown in fig. 3.
2. Gefitinib-salicylic acid co-crystal according to claim 1, characterized in that it has an endothermic peak in a differential scanning calorimetric curve DSC, corresponding to a temperature range of 196.44-215.43 ℃.
3. A process for preparing gefitinib-salicylic acid co-crystals according to any one of claims 1-2, characterized in that the specific preparation steps comprise: placing gefitinib and salicylic 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-salicylic acid eutectic; wherein the organic solvent A is one or more selected from 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 50-80: 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 1:1.
5. the preparation method of claim 3, wherein the molar ratio of gefitinib to salicylic acid is 1:1.8-2.5; the first grinding time is 30-50 min, and the second grinding time is 10-20 min.
6. The preparation method of claim 3, wherein the molar ratio of gefitinib to salicylic acid is 1:1.8-2.1.
7. Use of gefitinib-salicylic acid co-crystals according to any one of claims 1-2 for the treatment of antitumor drugs.
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| 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 |
| CN110156700A (en) * | 2019-06-05 | 2019-08-23 | 鲁南制药集团股份有限公司 | Gefitinib and salicylic acid eutectic |
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| 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 |
| CN110156700A (en) * | 2019-06-05 | 2019-08-23 | 鲁南制药集团股份有限公司 | Gefitinib and salicylic acid eutectic |
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