CN113929630B - Gefitinib drug co-crystal - Google Patents

Gefitinib drug co-crystal Download PDF

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CN113929630B
CN113929630B CN202010668988.4A CN202010668988A CN113929630B CN 113929630 B CN113929630 B CN 113929630B CN 202010668988 A CN202010668988 A CN 202010668988A CN 113929630 B CN113929630 B CN 113929630B
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gefitinib
molar ratio
crystal
methanol
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CN113929630A (en
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翟立海
张朝花
许秀艳
路来菊
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Shandong New Time Pharmaceutical Co Ltd
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    • 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
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    • 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
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and relates to a gefitinib pharmaceutical co-crystal and a preparation method thereof, wherein the invention specifically provides a gefitinib-malonic acid co-crystal with a molar ratio of 1:2, gefitinib and succinic acid in a molar ratio of 4:1, gefitinib: emodin: the co-crystal formed by combining methanol according to the molar ratio of 1:2:1 has higher solubility and good solubility, is beneficial to improving bioavailability, and has important value for optimizing and developing gefitinib preparations.

Description

Gefitinib drug co-crystal
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to gefitinib pharmaceutical co-crystals and a preparation method 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 a 1 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 WO9633980A1 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 can exist in solvated form.
Patent CN100404032C discloses four crystal forms of gefitinib Form1 (polymorph), form 2 (methanol solvate), form3 (DMSO solvate), form 5 (trihydrate) and a preparation method thereof, and the patent indicates that Form1 polymorph can be obtained after washing Form3, form 2 or Form 5 with a solvent or a solvent mixture and separating, and researches find that Form1 has good stability and is suitable for solid preparations of gefitinib such as tablets and capsules, but in the actual preparation process, the obtaining of Form1 has poor reproducibility. 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 Form3 forms is about 30 times the pharmacopoeial limit (0.5% pharmacopoeial limit), it is seen that forms of Form 2 and Form3 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 18-20 hours at the ambient temperature, filtering air, and drying to obtain Form 6, wherein the crystal Form is a monohydrate crystal Form, the stability is lower than that of Form 1, and the similar problem of limited application to Form 5 also exists.
Patent CN103896863B discloses a new crystal Form 7 Form of gefitinib and a preparation method thereof, and the pharmacokinetics of the crystal Form in rats is studied, and the result shows that the pharmacokinetic parameters of the crystal Form and the commercially available Form 1 crystal Form are not significantly different, but other properties of the crystal Form are not studied.
Patent application CN103896861a discloses amorphous gefitinib, form8, and a method for preparing the same, but is generally not 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 find 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 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 have tried various methods in the research to successfully obtain the eutectic crystal of gefitinib and parahydroxybenzoic acid.
Patent WO2015170345 mentions co-crystals of gefitinib and malonic acid, but researches find that the preparation method is poor in repeatability, and the co-crystals reported by the patent are poor in solubility characteristics compared with the existing gefitinib crystal forms.
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 (API) under the action of hydrogen bonds to form supermolecular 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.
Disclosure of Invention
In view of the deficiencies of the prior art, the present invention provides gefitinib drug co-crystals and methods of preparing these co-crystals, as well as compositions comprising a co-crystal.
In a first aspect of the invention, there is provided a gefitinib pharmaceutical co-crystal consisting of gefitinib and a co-crystal former selected from malonic acid, succinic acid, emodin.
For ease of reference, the different co-crystals described herein are consistently represented in this application as gefitinib to malonic acid in a molar ratio of 1:2, gefitinib and succinic acid in a molar ratio of 4:1, gefitinib is combined with emodin and methanol according to a mol ratio of 1:2:1.
Gefitinib and malonic acid in a molar ratio of 1:2, co-crystal of 2
In one embodiment, the invention relates to co-crystals formed by combining gefitinib and malonic acid, in particular gefitinib and malonic acid in a molar ratio of 1:2, herein referred to as gefitinib to malonic acid in a molar ratio of 1:2, and a co-crystal formed by the same. Based on the physical characteristics, gefitinib and malonic acid are mixed in a molar ratio of 1:2 is a crystalline form.
Gefitinib and malonic acid in a molar ratio of 1:2 may be characterized as having one or more of the following physical characteristics:
(a) An X-ray diffraction peak at 2θ including 6.26±0.2°,7.59±0.2°,7.83±0.2°,11.57±0.2°,19.05±0.2°,25.64±0.2°, or an X-ray diffraction peak at 2θ including 6.26±0.2°,7.59±0.2°,11.57±0.2°,19.05±0.2°,25.64±0.2°, or an X-ray diffraction peak at 2θ including 6.26±0.2°,7.83±0.2°,11.57±0.2°,19.05±0.2°,25.64±0.2° (using cu—kα radiation, an X-ray diffraction spectrum expressed by 2θ); preferably, the diffraction peak is selected from five or more diffraction peaks consisting of diffraction peaks at 6.26±0.2°,7.59±0.2°,7.83±0.2°,11.57±0.2°,14.18±0.2°,16.15±0.2°,19.05±0.2°,19.99±0.2°,21.48±0.2°,24.22±0.2°,25.64±0.2°,26.74±0.2°,27.04±0.2°, or five or more diffraction peaks consisting of diffraction peaks at 6.26±0.2°,7.59±0.2°,7.83±0.2°,11.57±0.2°,14.18±0.2°,16.15±0.2°,19.05±0.2°,19.99±0.2°,21.48±0.2°,24.22±0.2°,25.64±0.2°,27.04±0.2°, or five or more diffraction peaks consisting of diffraction peaks at 6.26±0.2°,7.59±0.2°,7.83±0.2°,11.57±0.2°,14.18±0.2°,16.15±0.2°,19.05±0.2°,19.99±0.2°,21.48±0.2°,24.22±0.2°,25.64±0.2°,26.74±0.2°; further preferably, there is an X-ray powder diffraction pattern as shown in figure 1;
(b) The crystallographic parameters are: triclinic system, the space group is P-1; the unit cell parameters are: α= 64.4281 (18) °, β= 77.124 (3) °, γ= 79.788 (2) °, unit cell volume/> A unit cell structure of (2);
(c) Has an endothermic peak with a temperature range of 187.25-200.68 ℃ and a differential scanning calorimetric spectrum with a peak value of 189.62 ℃.
Gefitinib and succinic acid in a molar ratio of 4:1, co-crystal of 1
In one embodiment, the invention relates to a co-crystal formed by combining gefitinib and succinic acid, in particular to a co-crystal formed by combining gefitinib and succinic acid in a molar ratio of 4:1, herein referred to as gefitinib and succinic acid in a molar ratio of 4: 1. Based on the physical characteristics, gefitinib and succinic acid are mixed according to a molar ratio of 4:1 is a crystal form.
Gefitinib and succinic acid in a molar ratio of 4:1 may be characterized as having one or more of the following physical characteristics:
(a) Having an X-ray diffraction peak at 2θ including 5.85±0.2°,6.46±0.2°,9.99±0.2°,13.07±0.2°,18.39±0.2° (using cu—kα radiation, X-ray diffraction spectrum expressed in 2θ), preferably, five or more diffraction peaks selected from the group consisting of diffraction peaks at 5.85±0.2°,6.46±0.2°,7.85±0.2°,9.99±0.2°,13.07±0.2°,18.39±0.2°,19.32±0.2°,21.72±0.2°,24.82±0.2°,26.59±0.2°, further preferably, having an X-ray powder diffraction spectrum as shown in fig. 2;
(b) The crystallographic parameters are: triclinic system, the space group is P-1; the unit cell parameters are: α= 91.5500 (10) °, β= 109.8010 (10) °, γ= 95.9810 (10) °, unit cell volume/> A unit cell structure of (2);
(c) Has an endothermic peak with a temperature range of 191.50-213.36 ℃ and a differential scanning calorimetric spectrum with a peak value of 194.21 ℃.
Co-crystal formed by combining gefitinib, emodin and methanol according to mol ratio of 1:2:1
In one embodiment, the present invention relates to co-crystals of gefitinib in combination with emodin and methanol, referred to herein as co-crystals of gefitinib in combination with emodin and methanol in a molar ratio of 1:2:1. Based on the physical characteristics, co-crystals formed by combining gefitinib, emodin and methanol according to a molar ratio of 1:2:1 are one crystal form.
Co-crystals of gefitinib in combination with emodin and methanol in a molar ratio of 1:2:1 may be characterized as having one or more of the following physical characteristics:
(a) Having an X-ray diffraction peak (using Cu-ka radiation, X-ray diffraction spectrum expressed in 2θ) at 2θ including 4.83±0.2°,6.10±0.2°,7.05±0.2°,8.33±0.2°,8.86±0.2°,9.33±0.2°,9.70±0.2°,17.81±0.2°, preferably, including five or more diffraction peaks selected from the group consisting of diffraction peaks at 4.83±0.2°,6.10±0.2°,7.05±0.2°,8.33±0.2°,8.86±0.2°,9.33±0.2°,9.70±0.2°,10.91±0.2°,13.18±0.2°,14.16±0.2°,14.76±0.2°,16.74±0.2°,17.81±0.2°,19.60±0.2°,23.12±0.2°,24.66±0.2°,25.10±0.2°,25.58±0.2°,26.25±0.2°, or including five or more diffraction peaks selected from the group consisting of diffraction peaks at 4.83±0.2°,6.10±0.2°,7.05±0.2°,8.33±0.2°,8.86±0.2°,9.33±0.2°,9.70±0.2°,10.91±0.2°,13.18±0.2°,14.16±0.2°,14.76±0.2°,16.74±0.2°,17.81±0.2°,19.60±0.2°,23.12±0.2°,24.66±0.2°,25.10±0.2°,25.58±0.2°,26.79±0.2°, or including five or more diffraction peaks selected from the group consisting of diffraction peaks at 4.83±0.2°,6.10±0.2°,7.05±0.2°,8.33±0.2°,8.86±0.2°,9.33±0.2°,9.70±0.2°,10.91±0.2°,13.18±0.2°,14.16±0.2°,14.76±0.2°,16.74±0.2°,17.81±0.2°,19.60±0.2°,23.12±0.2°,24.66±0.2°,25.10±0.2°,25.58±0.2°,26.25±0.2°,26.79±0.2°, further preferably, having an X-ray powder diffraction pattern as shown in fig. 3;
(b) The crystallographic parameters are: monoclinic system, the space group is P2 1/c; the unit cell parameters are: α=90°, β= 96.3038 (6) °, γ=90°, unit cell volume/> A unit cell structure of (2);
(c) Has two groups of differential scanning calorimetric maps with the temperature ranges of 145.52-172.11 ℃ of endothermic peaks and 184.09-202.94 ℃ of endothermic peaks respectively.
Preparation and characterization of gefitinib drug co-crystal
Gefitinib can be synthesized using a variety of methods or is commercially available. A representative method for synthesizing gefitinib is shown in patent CN1882569B.
Methods that can be used to prepare gefitinib drug co-crystals are described in examples 1-9, wherein examples 1-3 describe gefitinib to malonic acid in a molar ratio of 1:2, examples 4-6 describe gefitinib and succinic acid in a molar ratio of 4:1, examples 7-9 describe the preparation of co-crystals of gefitinib in combination with emodin and methanol in a molar ratio of 1:2:1.
Various experiments were performed to physically characterize gefitinib drug co-crystals, including X-ray powder diffraction (XRPD), differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA). Methods for assaying the solubility of gefitinib drug co-crystals are described in examples 10-11.
Gefitinib and malonic acid in a molar ratio of 1:2, co-crystal of 2
Gefitinib and malonic acid in a molar ratio of 1:2 can be prepared by crystallization from a variety of solvents used in the polymorph screening process and under a variety of crystallization conditions (e.g., fast and slow evaporation, cooling of saturated solutions, milling, solvent and anti-solvent addition). Examples 1-3 summarize one method of preparing gefitinib to malonic acid in a molar ratio of 1:2, and a method of forming a eutectic. For example, gefitinib and malonic acid are put into a mortar, added with an organic solvent A and ground into white powder, then added with the organic solvent A and ground into solution, kept stand for Wen Xijing, filtered and dried in vacuum to obtain the product.
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 one of ethanol and methanol or a combination thereof.
Preferably, the mass volume ratio of gefitinib to the organic solvent A required by the first grinding is 50-80: 1, wherein the mass is in mg and the volume is in ml.
Preferably, the molar ratio of gefitinib to malonic acid is 1:1.95-2.5.
Further preferably, the molar ratio of gefitinib to malonic acid is 1:2.0-2.2.
Preferably, the time of the first grinding is 20-50 min.
Preferably, the volume ratio of the organic solvent A required by the first grinding to the organic solvent A required by the second grinding is 1:3 to 10.
Preferably, the temperature of Wen Xijing is controlled to be 0-10 ℃.
Further preferably, the temperature of Wen Xijing is controlled to be 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.
Gefitinib to malonic acid was characterized by XRPD, TGA, DSC in a molar ratio of 1:2, and a co-crystal formed by the same.
Fig. 1 shows gefitinib to malonic acid in a molar ratio of 1:2 (cukα,). XRPD pattern confirmed gefitinib to malonic acid in a molar ratio of 1:2 is a crystal. The main X-ray diffraction expressed as 2 theta and its relative intensities are summarized in table 1.
Table 1 gefitinib and malonic acid in a molar ratio of 1:2 (CuK alpha)
The above set of XRPD peak positions, or a subset thereof, can be used to identify gefitinib to malonic acid in a molar ratio of 1:2, and a co-crystal formed by the same.
Fig. 4 is gefitinib to malonic acid in a molar ratio of 1:2, the TGA analysis shows that the molar ratio of gefitinib to malonic acid is 1 from 148.91 to 212.69 ℃): 2 shows a larger weight loss, indicating that gefitinib and malonic acid are mixed in a molar ratio of 1:2, and a DSC detection spectrogram shows that the eutectic has an endothermic peak, the temperature range is 187.25-200.68 ℃, and the peak is 189.62 ℃.
Gefitinib and succinic acid in a molar ratio of 4:1, co-crystal of 1
Gefitinib and succinic acid in a molar ratio of 4:1 can be prepared by crystallization from a variety of solvents used in the polymorph screening process and under a variety of crystallization conditions (e.g., fast and slow evaporation, cooling of saturated solutions, solvent and anti-solvent addition). Examples 4-6 summarize one method of preparing gefitinib and succinic acid in a molar ratio of 4:1, and a method for producing a co-crystal of the same. For example, gefitinib and succinic acid are dissolved in a mixed solvent of methanol and an organic solvent B, and the mixture is subjected to ultrasonic heating until the solid is completely dissolved, standing for crystallization, filtering and drying to obtain the gefitinib-succinic acid.
Preferably, the organic solvent B is selected from one or more of acetone, ethanol, isopropanol, acetonitrile and water.
Preferably, the volume fraction of the methanol in the mixed solvent is 11% -100%.
Preferably, the molar ratio of the gefitinib to the succinic acid is 3.5-4.2:1.
Further preferably, the molar ratio of the gefitinib to the succinic acid is 3.9-4.1:1.
Preferably, the heating temperature is 40-60 ℃.
Preferably, the mass-volume ratio of the gefitinib to the mixed solvent is 8-20:1, wherein the mass is in mg and the volume is in mL.
Further preferably, the mass-volume ratio of the gefitinib to the mixed solvent is 10-15:1; wherein the mass is in mg and the volume is in mL.
Preferably, the crystallization time is 24 to 72 hours.
Preferably, the crystallization temperature is 15-40 ℃.
Preferably, the drying temperature is 26-55 ℃ and the drying time is 8-24 hours.
The following further details the gefitinib and succinic acid of the present invention in a molar ratio of 4:1, a preparation method of a co-crystal formed by the following steps:
dissolving gefitinib and succinic acid in a molar ratio of 3.9-4.1:1 in a mixed solvent of methanol and an organic solvent B, starting ultrasonic treatment to heat the solution to 40-60 ℃, filtering after the gefitinib and the succinic acid are dissolved, standing the filtrate for crystallization, filtering to obtain crystals, and drying for 8-24 hours to obtain the product.
Preferably, the organic solvent B is selected from one or more of water, ethanol, acetone and acetonitrile.
Fig. 2 shows gefitinib and succinic acid in a molar ratio of 4:1 (cukα,). XRPD pattern confirmed gefitinib to succinic acid in a molar ratio of 4:1 is a crystal. The main X-ray diffraction expressed as 2 theta and its relative intensities are summarized in table 2.
Table 2. Gefitinib and succinic acid in a molar ratio of 4:1 (CuK alpha)
The above set of XRPD peak positions, or a subset thereof, can be used to identify gefitinib to succinic acid in a molar ratio of 4: 1.
Fig. 5 is gefitinib to succinic acid in a molar ratio of 4:1, and the DSC analysis shows that at the temperature ranging from 185.2 ℃ to 300.97 ℃, the co-crystal formed by gefitinib and succinic acid in the molar ratio of 4:1 shows a larger weight loss, and the co-crystal formed by gefitinib and succinic acid in the molar ratio of 4:1 is decomposed while being melted, and the DSC detection spectrogram shows that the co-crystal has an endothermic peak, wherein the temperature range is 191.50 ℃ to 213.36 ℃ and the peak value is 194.21 ℃.
Co-crystal formed by combining gefitinib, emodin and methanol according to mol ratio of 1:2:1
Co-crystals of gefitinib in combination with emodin and methanol in a molar ratio of 1:2:1 can be prepared by a variety of solvents used in the polymorph screening process and crystallizing under various crystallization conditions (e.g., fast and slow evaporation, cooling of saturated solutions, solvent and anti-solvent addition). Examples 7-9 summarize a process for preparing co-crystals of gefitinib in combination with emodin and methanol in a molar ratio of 1:2:1. For example: adding gefitinib and emodin into methanol, heating for reaction, filtering, standing filtrate for crystallization, filtering, and vacuum drying.
Preferably, the molar ratio of gefitinib to emodin is 1:0.9 to 1.5.
Further preferably, the molar ratio of gefitinib to emodin is 1:1.
The mass-volume ratio of gefitinib to methanol in the system is 5-10:1, wherein the mass is calculated in mg and the volume is calculated in ml.
The heating temperature is 45-60 ℃.
The heating reaction time is 3-5 hours.
The temperature of standing crystallization is room temperature.
Preferably, the standing crystallization mode is solvent evaporation crystallization.
Figure 3 shows a characteristic XRPD spectrum of co-crystals of gefitinib combined with emodin and methanol in a molar ratio of 1:2:1 (cuka,). XRPD patterns confirmed that co-crystals of gefitinib combined with emodin and methanol in a molar ratio of 1:2:1 were crystalline. The main X-ray diffraction expressed as 2θ and its relative intensities are summarized in table 3.
TABLE 3 major XRD peaks of co-crystals formed by gefitinib combined with emodin and methanol in a molar ratio of 1:2:1
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The above set of XRPD peak positions, or a subset thereof, can be used to identify co-crystals of gefitinib in combination with emodin and methanol in a molar ratio of 1:2:1.
FIG. 6 is a DSC/TGA plot of co-crystals of gefitinib combined with emodin and methanol at a molar ratio of 1:2:1, with two sets of endothermic peaks at temperatures ranging from 145.52 to 172.11 ℃and 184.09 to 202.94 ℃respectively, with peaks at 157.99 ℃and 190.11 ℃respectively.
In a third aspect, the invention provides a pharmaceutical composition comprising the gefitinib pharmaceutical co-crystal of the invention.
The preparation method of the pharmaceutical composition of the invention can be as follows: the gefitinib pharmaceutical co-crystals 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 and other pharmaceutically usable dosage forms.
In a fourth aspect of the invention, there is provided the use of gefitinib pharmaceutical co-crystals as active ingredient for the preparation of a medicament for the treatment of locally advanced or metastatic non-small cell lung cancer which is ineffective or unsuitable for chemotherapy.
Confirmation of gefitinib drug co-crystal structure:
the gefitinib drug 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 or 102.63 (10) 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.
Testing and analyzing gefitinib and malonic acid prepared by the invention according to the molar ratio of 1: the crystallographic data obtained for the co-crystal constituted by 2 are given in table 4, the crystallographic parameters of which are: triclinic system, the space group is P-1; the unit cell parameters are: α= 64.4281 (18) °, β= 77.124 (3) °, γ= 79.788 (2) °, unit cell volume/> The eutectic ORTEP diagram of gefitinib and malonic acid combination in the invention shows that one molecule of gefitinib is combined with two molecules of malonic acid, as shown in figure 7, and the molar ratio of gefitinib to malonic acid in the invention is 1: a stacked view of the eutectic of 2 is shown in fig. 10.
Table 4 gefitinib and malonic acid in a molar ratio of 1:2 primary crystallographic data of co-crystal of composition
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Testing and analyzing gefitinib and succinic acid prepared by the invention according to the molar ratio of 4: the crystallographic data obtained for the co-crystal constituted by 1 are given in table 5, the crystallographic parameters of which are: triclinic system, the space group is P-1; the unit cell parameters are: α= 91.5500 (10) °, β= 109.8010 (10) °, γ= 95.9810 (10) °, unit cell volume/> The eutectic ORTEP diagram of gefitinib and succinic acid combination in the invention shows that four molecules of gefitinib are combined with one molecule of succinic acid, as shown in figure 8, and the molar ratio of gefitinib to succinic acid in the invention is 4: a stacked view of the eutectic of 1 is shown in fig. 11.
Table 5 molar ratio of gefitinib to succinic acid 4: primary crystallographic data of 1-constituted eutectic
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The crystallographic data obtained by testing and analyzing the co-crystal formed by combining gefitinib, emodin and methanol according to the mol ratio of 1:2:1 are shown in Table 6, and the crystallographic parameters are as follows: monoclinic system, the space group is P2 1/c; the unit cell parameters are: α=90°, β= 96.3038 (6) °, γ=90°, unit cell volume/> The eutectic ORTEP diagram of gefitinib combined with emodin and methanol in the invention shows that one molecule of gefitinib is combined with two molecules of emodin and one molecule of methanol, as shown in figure 9.
TABLE 6 principal crystallographic data for co-crystals of gefitinib combined with emodin and methanol in a molar ratio of 1:2:1
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The X-ray powder diffraction test instrument and test conditions related in the invention: x-ray powder diffractometer: PANALYTICAL EMPYREAN; 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.
Compared with the currently reported gefitinib crystal form, the gefitinib pharmaceutical co-crystal prepared by the method has the following advantages:
(1) High solubility. Gefitinib and malonic acid in a molar ratio of 1:2, and the solubility of the co-crystal formed by the composition 2 in water, hydrochloric acid with the pH value of 1.2 and phosphate buffer with the pH value of 6.8 is high, and the molar ratio of gefitinib to succinic acid is 4:1, the solubility of the co-crystal constituted by 1 in hydrochloric acid solution at ph=1.2 is as high as 27.41mg/ml.
(2) The dissolution characteristic is good. Gefitinib and malonic acid in a molar ratio of 1:2, gefitinib and succinic acid in a molar ratio of 4:1, the dissolution concentration is high, the dissolution rate is stable, and the preparation is suitable for being prepared in hydrochloric acid solution with pH=3.
Drawings
Fig. 1: gefitinib and malonic acid in a molar ratio of 1:2, an X-ray powder diffraction pattern of the co-crystal formed by 2;
fig. 2: gefitinib and succinic acid in a molar ratio of 4:1, an X-ray powder diffraction pattern of the co-crystal formed by 1;
fig. 3: x-ray powder diffraction pattern of co-crystal formed by combining gefitinib, emodin and methanol according to a molar ratio of 1:2:1;
fig. 4: gefitinib and malonic acid in a molar ratio of 1:2, a DSC/TGA profile of the co-crystal formed;
Fig. 5: gefitinib and succinic acid in a molar ratio of 4:1, a DSC/TGA profile of the co-crystal of 1;
fig. 6: a DSC/TGA diagram of a co-crystal formed by combining gefitinib, emodin and methanol according to a molar ratio of 1:2:1;
Fig. 7: gefitinib and malonic acid in a molar ratio of 1:2, an ORTEP diagram of the co-crystal formed by 2;
fig. 8: gefitinib and succinic acid in a molar ratio of 4:1, an ORTEP diagram of the co-crystal formed by 1;
Fig. 9: ORTEP diagram of co-crystal formed by combining gefitinib, emodin and methanol according to a mol ratio of 1:2:1;
fig. 10: gefitinib and malonic acid in a molar ratio of 1:2, stacking the eutectic formed by the two layers;
fig. 11: gefitinib and succinic acid in a molar ratio of 4:1, a stacking diagram of the co-crystal formed by 1;
Fig. 12: and a stacking diagram of co-crystals formed by combining gefitinib, emodin and methanol according to a molar ratio of 1:2:1.
Detailed Description
The invention is further illustrated by the following description of specific embodiments with the understanding that: the examples of the present invention are merely illustrative of the present invention and are not intended to be limiting. Therefore, simple modifications to the invention, which are within the scope of the claimed invention, are possible with the method of the invention.
1. Gefitinib and malonic acid in a molar ratio of 1:2, the preparation method of the co-crystal formed by the following steps:
example 1
60.0Mg of gefitinib and 27.9mg of malonic acid are put into a mortar, 1mL of methanol is added dropwise into the mortar, the mixture is sufficiently ground for 35min, 5mL of methanol is added into the mixture for continuous grinding for 15min, a clear solution is obtained, the temperature is controlled to be 0-5 ℃, standing and crystallization are carried out for 48 hours, filtration is carried out, vacuum drying is carried out at 50.5 ℃ for 8 hours, and the gefitinib and malonic acid are obtained according to the molar ratio of 1:2, the yield is 94.32%, and the HPLC purity is 99.96%.
Example 2
50.0Mg of gefitinib and 23.9mg of malonic acid are put into a mortar, 1mL of ethanol is added dropwise into the mortar, the mixture is sufficiently ground for 30min, 3mL of ethanol is added into the mixture to be continuously ground for 10min, a clear solution is obtained, the temperature is controlled to be 5-10 ℃, standing and crystallization are carried out for 52 h, filtration is carried out, vacuum drying is carried out at 55 ℃ for 10h, and the gefitinib and malonic acid are obtained according to the molar ratio of 1:2, the yield is 95.76%, and the HPLC purity is 99.97%.
Example 3
Putting 80.0mg of gefitinib and 41.0mg of malonic acid into a mortar, dropwise adding 1mL of methanol into the mortar, fully grinding the mixture for 50min, adding 10mL of ethanol, continuously grinding the mixture for 20min to obtain a clear solution, controlling the temperature to be 0-5 ℃, standing and crystallizing the clear solution for 72 h, filtering the clear solution, and drying the clear solution in vacuum at 60 ℃ for 9h to obtain gefitinib and malonic acid in a molar ratio of 1:2, the yield is 94.14% and the HPLC purity is 99.95%.
2. Gefitinib and succinic acid in a molar ratio of 4:1, a preparation method of a co-crystal formed by the following steps:
Example 4
178.8Mg of gefitinib and 11.8mg of succinic acid are dissolved in 15mL of mixed solvent (10 mL of methanol+2 mL of purified water+3 mL of acetone), ultrasonic heating is carried out to 50 ℃, the solid is dissolved, filtration is carried out, the filtrate is kept stand and crystallized for 40-45 hours under the environment of 15-20 ℃, filtration is carried out, and drying is carried out for 10 hours at 26-30 ℃ to obtain gefitinib and succinic acid according to the molar ratio of 4: 1. The yield was 94.48% and the HPLC purity was 99.96%.
Example 5
178.8Mg of gefitinib and 11.5mg of succinic acid are dissolved in 18mL of mixed solvent (10 mL of methanol+4 mL of purified water+4 mL of ethanol), ultrasonic heating is carried out to 40 ℃, the solid is dissolved, filtration is carried out, the filtrate is kept stand and crystallized for 45-50 hours under the environment of 20-25 ℃, filtration is carried out, and drying is carried out for 15 hours at 30-35 ℃ to obtain gefitinib and succinic acid according to the molar ratio of 4: 1. The yield was 94.12% and the HPLC purity was 99.93%.
Example 6
178.8Mg of gefitinib and 12.1mg of succinic acid are dissolved in 12mL of mixed solvent (6 mL of methanol+6 mL of purified water), ultrasonic heating is carried out to 60 ℃, solid is dissolved, filtration is carried out, filtrate is kept stand and crystallized for 50-55 hours under the environment of 25-30 ℃, filtration is carried out, drying is carried out for 8 hours at 35-40 ℃, and gefitinib and succinic acid are obtained according to the molar ratio of 4: 1. Yield 93.75% and HPLC purity 99.90%.
3. Preparation method of co-crystal formed by combining gefitinib, emodin and methanol according to mol ratio of 1:2:1
Example 7
Adding 44.6mg of gefitinib and 27.0mg of emodin into a single-neck round-bottom flask, adding 6.0mL of methanol, heating to 50 ℃, reacting for 4 hours, filtering, placing into a small glass bottle, sealing by a sealing film, puncturing a plurality of holes, volatilizing, crystallizing, filtering, drying under reduced pressure to obtain co-crystals formed by combining gefitinib, emodin and methanol according to a molar ratio of 1:2:1, and obtaining the HPLC purity: 99.98%.
Example 8
Adding 44.6mg of gefitinib and 24.3mg of emodin into a single-neck round-bottom flask, adding 5.0mL of methanol, heating to 60 ℃, reacting for 3 hours, filtering, placing into a small glass bottle, sealing by a sealing film, puncturing a plurality of holes, volatilizing, crystallizing, filtering, drying under reduced pressure to obtain co-crystals formed by combining gefitinib, emodin and methanol according to a molar ratio of 1:2:1, and obtaining the HPLC purity: 99.96%.
Example 9
Adding 44.6mg of gefitinib and 40.5mg of emodin into a single-neck round-bottom flask, adding 9.0mL of methanol, heating to 45 ℃, reacting for 5 hours, filtering, placing into a small glass bottle, sealing by a sealing film, puncturing a plurality of holes, volatilizing, crystallizing, filtering, drying under reduced pressure to obtain co-crystals formed by combining gefitinib, emodin and methanol according to a molar ratio of 1:2:1, and obtaining the HPLC purity: 99.94%.
Example 10: solubility test
Referring to the method of pharmacopoeia, in order to save materials, the dosage is reduced in the same proportion, hydrochloric acid solution with the pH value of 1.2, phosphate buffer solution with the pH value of 6.8 and water are prepared, and a proper amount of gefitinib and malonic acid are respectively taken according to the molar ratio of 1:2, gefitinib and succinic acid in a molar ratio of 4:1, gefitinib, emodin and methanol are combined according to a molar ratio of 1:2:1, water, a hydrochloric acid solution with pH value of 1.2 and a phosphate buffer solution with pH value of 6.8 are sequentially placed into a test tube with a plug, a sample is placed into a water bath constant temperature oscillator, balanced for 24 hours under the condition of 200r/min at 37 ℃, sampling is carried out at a preset time, a 0.45 mu m microporous filter membrane is used for filtering, a subsequent filtrate is taken, the water is diluted to a linear range, an aqueous solution is taken as a blank solution, and absorbance is measured at a wavelength of 254nm until the absorbance is not changed any more. The experimental results were measured in terms of the equilibrium solubility of gefitinib. The test results are shown in Table 7.
TABLE 7 solubility of gefitinib drug co-crystals
The result shows that the molar ratio of gefitinib to malonic acid prepared by the invention is 1:2, the solubility of the co-crystal formed by the method in water, a hydrochloric acid solution with the pH value of 1.2 and a phosphate buffer with the pH value of 6.8 is high; gefitinib and succinic acid in a molar ratio of 4:1 up to 27.41mg/ml in hydrochloric acid solution at ph=1.2; the co-crystal formed by combining gefitinib, emodin and methanol according to the mol ratio of 1:2:1 has higher solubility in water and phosphate buffer with pH=6.8.
Example 11: characteristic dissolution Rate test
Gefitinib to malonic acid was studied in a molar ratio of 1 in HCl solution at ph=3 using a USP certified Electrolab TDL-08 tablet dissolution tester at 37 ℃ and 50 rpm/min: 2, gefitinib and succinic acid in a molar ratio of 4:1, gefitinib, emodin and methanol are combined according to a molar ratio of 1:2:1. Aliquots (1 ml) were removed at specific time intervals and replenished with an equal amount of fresh pH solution to maintain a constant volume. These aliquots were analyzed by a UV spectrophotometer (UV-1601PC,Shimadzu Scientific Instrument) at a wavelength of 254nm and compared to a standard calibration curve. The results are shown in Table 8.
TABLE 8 characteristic dissolution Rate test results
All gefitinib drug co-crystals of the same kind prepared by the invention have the same dissolution characteristics.
The result shows that the molar ratio of gefitinib to malonic acid prepared by the invention is 1:2, gefitinib and succinic acid in a molar ratio of 4:1 in a hydrochloric acid solution with pH=3, and the dissolution rate is stable, and the preparation is suitable for preparation.

Claims (5)

1. A gefitinib drug co-crystal is characterized in that the co-crystal is formed by combining gefitinib, emodin and methanol according to a molar ratio of 1:2:1, and characteristic peaks are formed at positions of 4.83+/-0.2 degrees, 6.10+/-0.2 degrees, 7.05+/-0.2 degrees, 8.33+/-0.2 degrees, 8.86+/-0.2 degrees, 9.33+/-0.2 degrees, 9.70+/-0.2 degrees and 17.81+/-0.2 degrees by using an X-ray diffraction spectrum expressed by 2 theta radiation.
2. Gefitinib pharmaceutical co-crystal according to claim 1, characterized in that the characteristic peaks conform to the X-ray powder diffraction pattern as shown in fig. 3 using Cu-ka radiation.
3. A process for the preparation of a gefitinib pharmaceutical co-crystal according to any one of claims 1-2, comprising the specific steps of: adding gefitinib and emodin into methanol, heating for reaction, filtering, standing filtrate for crystallization, filtering, and vacuum drying.
4. A pharmaceutical composition comprising the gefitinib pharmaceutical co-crystal of any one of claims 1-2 and comprising a pharmaceutically acceptable additional adjuvant component.
5. Use of gefitinib drug co-crystals according to any one of claims 1-2 as active ingredient for the preparation of a medicament for the treatment of locally advanced or metastatic non-small cell lung cancer which is not effective or suitable for chemotherapy.
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