CN114957206B - Imatinib eutectic crystal and preparation method thereof - Google Patents

Abstract

The invention discloses an imatinib eutectic crystal and a preparation method thereof, wherein the eutectic crystal is formed by imatinib and a citric acid ligand or a combination ligand of fumaric acid and n-butyl alcohol, the molar ratio of the imatinib to the ligand or the combination ligand is 1:1, and the molar ratio of the fumaric acid to the n-butyl alcohol in the combination ligand is 1:1. The eutectic has excellent solubility and stability on the basis of retaining the biological activity of the imatinib, improves the pharmacokinetic property of the imatinib in organisms, improves the bioavailability of the medicine, can reduce the dosage of the medicine, improves the safety of the medicine, ensures that the medicine has more excellent clinical application effect, and has simple and convenient preparation method and easy operation, thereby being suitable for industrial scale preparation.

Description

Imatinib co-crystal and preparation method thereof

Technical field

The present invention relates to an imatinib co-crystal and a preparation method thereof, in particular to an imatinib co-crystal with excellent solubility and stability and a preparation method thereof.

Background technique

The therapeutic efficacy of oral medications depends strictly on their bioavailability. The ability of a drug to penetrate the gastrointestinal membrane is related to its solubility and dissolution in the gastrointestinal tract, and this property is a key parameter in controlling bioavailability. Based on this attribute, the Biopharmaceutics Classification System (BCS) was constructed, in which drugs with poor oral bioavailability are usually classified into Class II (low solubility-high permeability) and Class III (high solubility-low permeability). ) or Class IV (low solubility-low permeability). Unfortunately, about 40% of marketed drugs have poor water solubility, of which 30% belong to Class II and 10% of Class IV in the BCS classification. In addition, among the candidate drugs that are still being explored, Class II and Class IV The percentages increased significantly to about 70% and 20%.

Imatinib (IM) is a classic anti-tumor drug developed by Novartis. IM is a specific inhibitor of platelet-derived growth factor receptors PDGFRα, PDGFRβ, protein tyrosine kinase Bcr-Abl and c-Kit receptor. It exerts cytotoxic activity by binding to the ATP-binding fragment of the kinase domain, thereby preventing the subsequent phosphorylation process of downstream proteins. Imatinib is widely used in the treatment of chronic myeloid leukemia (CML), gastrointestinal interstitial Gastrointestinal stromal tumors (GIST) and many other diseases.

Imatinib is almost insoluble in water and weakly alkaline media, and its low solubility becomes a major obstacle in the drug research process. The drug prescription currently on the market contains imatinib mesylate salt (IM-ME) developed by Novartis, with the trade name In the preparation process, methanesulfonic acid is used to form a salt with the drug to improve the physical and chemical properties of imatinib. Although the solubility of imatinib mesylate in water increases, its structure is not stable in weakly alkaline media. Experimenters found about 25% of the parent drug in the patient's excrement. The reason may be that the salt form is unstable in the intestinal environment and precipitates in the form of the parent drug before it is fully absorbed, and is subsequently excreted from the body. Another thing to note is that the dose of imatinib mesylate used clinically is very high, 400 mg per day in the chronic phase, and the dose suddenly rises to 600-800 mg per day in the accelerated or acute phase. Long-term high doses may cause Lead to various adverse reactions, such as neutropenia, thrombocytopenia, anemia, nausea, vomiting and other symptoms.

Contents of the invention

Purpose of the invention: In view of the problems of poor solubility and instability in the body of existing imatinib drugs, the present invention aims to provide an imatinib with excellent solubility and stability, improved bioavailability and drug safety. Ni eutectic and its preparation method.

Technical solution: As the first aspect of the present invention, the imatinib co-crystal of the present invention is formed by imatinib and any of the following ligand systems:

(1)Citric acid ligand;

or (2) the combined ligand of fumaric acid and n-butanol;

Among them, the molar ratio of imatinib and citric acid ligand is 1:1; the molar ratio of imatinib, fumaric acid and n-butanol is 1:1:1.

The selected active pharmaceutical ingredient (API) is imatinib (IM), whose structure is shown in formula I; the ligand (CCF) is fumaric acid (FA) and citric acid (CA), whose structures are shown in formulas II and III respectively. As shown, two new structure drug cocrystals were prepared.

Cocrystal is essentially a supramolecular self-assembly system, which is the result of the balance of thermodynamics, dynamics, and molecular interactions. In the process of molecular self-assembly, intermolecular interactions and spatial effects affect the formation of supramolecular networks, which in turn directly affect the composition of crystals. Within the eutectic structure, different intermolecular interactions mainly include hydrogen bonds, π-π stacking, van der Waals forces, and halogen bonds. The bond energy of hydrogen bonding is 4-120kJ/mol, which is much larger than other weak interactions and is directional, so hydrogen bonding is the most important force in the formation of eutectic.

As a case of co-crystal, when the co-crystal is a citric acid-imatinib co-crystal, the co-crystal is a monoclinic system, the space group is centrosymmetric P2 ₁ /c, and the unit cell parameters are : α=90°, β=102.295(2)°, γ=90°, and each unit cell contains four groups of structural units.

The co-crystal specifically consists of an imatinib molecule and a citric acid molecule connected together through hydrogen bonds to form the basic structural unit of the imatinib drug co-crystal IM-CA. Within each group of structural units, imatinib and citric acid are connected to each other through two sets of hydrogen bonds. These two sets of hydrogen bonds are respectively located between the hydrogen connected to N4 in the imine structure of imatinib molecule and O3 on citric acid, and between the hydrogen connected to N3 and O4 of citric acid in the pyrimidine structure of imatinib molecule.

Specifically, the crystallographic data of imatinib drug co-crystal IM-CA are as follows:

More specifically, expressed as a diffraction angle 2θ±0.2°, the eutectic is at 8.430°, 10.097°, 10.913°, 12.416°, 13.633°, 15.030°, 15.750°, 16.236°, 17.409°, 18.015°, 18.884° , 20.015°, 20.731°, 21.440°, 21.880°, 22.770°, 23.349°, 24.916°, 25.471°, 27.480°, 28.517°, 29.700° has at least one diffraction characteristic peak; it has characteristic melting at 200.7±0.2℃ peak.

As another case of a co-crystal, when the co-crystal is a fumaric acid-imatinib-n-butanol co-crystal, the co-crystal is an orthorhombic crystal system, and the space group is non-centrosymmetric Pna2 ₁ , The unit cell parameters are: α=90°, β=90°, γ=90°, and each unit cell contains four groups of structural units.

The co-crystal specifically consists of an imatinib molecule, a fumaric acid molecule and an n-butanol molecule connected together through hydrogen bonds and other weak interactions to form the basic structure of the imatinib drug co-crystal IM-FA-nBu. unit. n-butanol is close to one end of the piperazine ring of the imatinib molecule, and fumaric acid is close to one end of the pyridine and pyrimidine rings of imatinib.

Specifically, the crystallographic data of the imatinib drug co-crystal IM-FA-nBu are as follows:

More specifically, expressed as a diffraction angle 2θ±0.2°, the eutectic is at 7.282°, 8.568°, 9.690°, 10.992°, 12.175°, 14.593°, 16.088°, 16.678°, 17.196°, 18.034°, 19.333° , there is at least one diffraction characteristic peak at 20.644° and 21.071°; it has characteristic melting peaks at 144.2±0.2℃ and 206.3±0.2℃.

As a second aspect of the present invention, the above-mentioned imatinib co-crystal can be prepared by grinding method or solvent evaporation method.

As one of the preparation methods, the solvent evaporation method includes the following steps:

(1) Dissolve imatinib and citric acid or fumaric acid in a good solvent without heavy atoms at a molar ratio of 30 to 60°C, where the dosage ratio of solute to solvent is 2 to 15 mg/mL;

(2) After filtration, evaporate and crystallize.

Specifically, when the ligand is citric acid, the good solvent in step (1) is methanol, ethanol or isopropyl alcohol; the volatilization crystallization temperature in step (2) is 19-23°C.

When the ligands are fumaric acid and n-butanol, the good solvent in step (1) is n-butanol, methanol-n-butanol, ethanol-n-butanol or isopropanol-n-butanol, wherein, methanol, The volume ratio of ethanol or isopropyl alcohol to n-butanol is 2:1 to 4:1; the volatilization and crystallization temperature in step (2) is 27 to 34°C. Wherein, when the good solvent is methanol-n-butanol, ethanol-n-butanol or isopropanol-n-butanol, imatinib and fumaric acid are first dissolved in methanol, ethanol or isopropyl alcohol, and then added n-butanol; or first dissolve fumaric acid with methanol-n-butanol, ethanol-n-butanol or isopropanol-n-butanol, and then add imatinib.

Volatile crystallization can be carried out in a container. The opening of the container needs to be sealed to isolate external water vapor. If necessary, a water removal agent can be added to the container.

As another preparation method, the grinding method is:

Add imatinib and citric acid or fumaric acid in a molar ratio to a good solvent that does not contain heavy atoms to assist in grinding. The good solvents suitable for the two co-crystals are the same as above. The amount of solvent added during grinding is appropriate to wet the powder. There is no need to slurry the raw materials, and reaction progress can be monitored by X-ray powder diffraction. This grinding method can be used for large-scale production.

Specifically, when the co-crystal is a citric acid-imatinib co-crystal, the raw material is prepared by moistening it with methanol, ethanol or isopropanol for grinding; the co-crystal is fumaric acid-imatinib-n-butyl When alcohol eutectic is used, the raw materials are prepared by moistening n-butanol, methanol-n-butanol, ethanol-n-butanol or isopropanol-n-butanol for grinding. Among them, the ratio of methanol, ethanol or isopropanol to n-butanol is The volume ratio is 2:1~4:1.

The above imatinib co-crystal and a pharmaceutically acceptable carrier can be further prepared to obtain a pharmaceutical composition.

Specifically, the imatinib cocrystal can be prepared by adding pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions or injections. The preparations can be added with flavors, sweeteners, liquids, etc. /Solid fillers, diluents and other commonly used pharmaceutical excipients.

The above-mentioned imatinib co-crystal or pharmaceutical composition containing imatinib co-crystal retains the biological activity of imatinib and can be used as a drug for treating tumor diseases.

Beneficial effects: Compared with the existing technology, the present invention has the following significant advantages:

(1) On the basis of retaining the molecular structure and pharmacological effects of imatinib, the solubility and dissolution rate of this imatinib co-crystal are significantly higher than those of imatinib and imatinib mesylate, and even higher Two orders of magnitude higher, and the drug molecules are more stable and do not produce drug precipitation, which can improve the bioavailability and medication safety of the drug;

(2) The preparation method is simple and easy to operate, and is suitable for industrial-scale preparation.

Description of drawings

Figure 1 is a vector diagram of the structural elements of imatinib co-crystal IM-CA;

Figure 2 is a schematic diagram of the imatinib cocrystal IM-CA unit cell, Figure 2a: a view in the direction a, Figure 2b: a view in the b direction, Figure 2c: view in the c direction;

Figure 3 is the powder X-ray diffraction (PXRD) pattern of imatinib co-crystal IM-CA;

Figure 4 is a differential scanning calorimetry (DSC) diagram of imatinib co-crystal IM-CA;

Figure 5 is a vector diagram of the structural elements of the imatinib cocrystal IM-FA-nBu;

Figure 6 is a schematic diagram of the imatinib cocrystal IM-FA-nBu unit cell, Figure 6a: a view in the direction a, Figure 6b: view in the b direction, Figure 6c: view in the c direction;

Figure 7 is the powder X-ray diffraction (PXRD) pattern of imatinib co-crystal IM-FA-nBu;

Figure 8 is a differential scanning calorimetry (DSC) picture and a thermogravimetric analysis (TG) picture of the imatinib cocrystal IM-FA-nBu;

Figure 9 is the peak area-molar concentration curve of imatinib IM;

Figure 10 shows imatinib IM, imatinib mesylate IM-ME, imatinib co-crystal IM-CA, imatinib gallate IM-GA, and imatinib fumarate IM-FA. , Schematic diagram of the solubility curve of imatinib co-crystal IM-FA-nBu simulating intestinal environment, Figure 10a: 0~200min, Figure 10b: 0~1440min;

Figure 11a is a PXRD pattern of the precipitation of imatinib cocrystal IM-FA-nBu coformer;

Figure 11b is the PXRD pattern of the precipitated imatinib fumarate IM-FA coformer.

Figure 11c is a PXRD pattern of the precipitation of imatinib mesylate IM-ME coformer.

Detailed ways

The technical solution of the present invention will be further described below with reference to examples.

The instruments for detecting the structure and performance of drug eutectic in the present invention are as follows:

Eutectic structure data are obtained in graphite with monochromatic Cu Kα radiation Collected on a Bruker D8Venture single crystal diffractometer. The structure was resolved by the direct method and ^F2 was refined by the full matrix least squares method using the SHELX-2014/7 program. All non-hydrogen atoms are anisotropically refined.

Powder X-ray diffraction analysis (PXRD): Bruker D8Advance X-ray diffractometer from Bruker AXS Company of Germany was used, and the ray source was Cu/Kα The scanning range is 3 to 60° (2θ), the scanning step is 0.02°, the rate is 4°/min, and the power supply is set to 40kV, 40mA.

Differential scanning calorimetry analysis (DSC): The NETZSCH DSC204 differential thermal analyzer of the German NETZSCH company is used. The sample mass is about 3 mg. The temperature is raised in a nitrogen atmosphere. The test temperature range is r.t～280°C. Among them, the fumaric acid sample Raise the temperature to 350°C with a heating rate of 10°C/min.

Example 1

Weigh IM (0.25mmol) and CA (0.25mmol) with a stoichiometric ratio of 1:1, add 50 mL of ethanol solvent, stir and reflux at 60°C for 1 hour, filter with a 0.22 μm filter, transfer to a crystallization bottle and place in a constant temperature bath In a bell jar, it slowly evaporates and crystallizes at 21°C. After about 30 hours, light yellow needle-like crystals IM-CA were obtained.

Example 2

Weigh IM (0.25mmol) and FA (0.25mmol) with a stoichiometric ratio of 1:1, first add FA to 50mL of a mixed solvent of n-butanol and ethanol (v/v=1:2), and dissolve it with ultrasound. Add IM and stir to reflux at 60°C for 1 hour. After filtering with a 0.22 μm filter, transfer it to a crystallization bottle placed in a bell jar in a constant temperature bath and slowly evaporate and crystallize at 32°C. After about 30h, light yellow needle-shaped crystals IM-FA-nBu were obtained.

The crystal structure of the imatinib co-crystal IM-CA prepared above was detected. The detection results are shown in Figures 1 to 4.

From the analyzed vector diagram, it was found that no proton transfer occurred between citric acid and imatinib, proving that it is a eutectic rather than a salt. There are four groups of structural units in each unit cell of imatinib-citric acid, and within each group of structural units, imatinib and citric acid are connected to each other through two sets of hydrogen bonds. These two sets of hydrogen bonds are respectively located between the hydrogen connected to N4 in the imine structure of imatinib molecule and O3 on citric acid, and between the hydrogen connected to N3 and O4 of citric acid in the pyrimidine structure of imatinib molecule. This crystal is a monoclinic crystal, and its space group is centrosymmetric P2 ₁ /c.

As can be seen from Figure 3, the PXRD pattern of the ground product is consistent with the pattern simulated by the structure analyzed by single crystal diffraction, indicating that the method of grinding and synthesizing drug cocrystal CA-IM described in the present invention is feasible.

Example 3

Weigh IM (0.25mmol) and CA (0.25mmol) with a stoichiometric ratio of 1:1 and place them in a mortar.

Grinding adopts the method of adding liquid to assist grinding. For liquid-added assisted grinding, use a micro-syringe to add ethanol during grinding. The amount of solvent added each time is appropriate to moisten the raw materials. After grinding for 0.5 h, the drug cocrystal IM-CA with a crystallinity of more than 60% can be obtained.

Example 4

Weigh IM (0.25mmol) and FA (0.25mmol) with a stoichiometric ratio of 1:1 and place them in a mortar.

Grinding adopts the method of adding liquid to assist grinding. For liquid-added assisted grinding, use a micro-syringe to add n-butanol during grinding. The amount added each time is appropriate to wet the raw materials. After grinding for 0.5 h, the drug cocrystal FA-IM-nBu with a crystallinity of more than 60% can be obtained.

The crystal structure of the imatinib co-crystal IM-CA prepared above was detected. The detection results are shown in Figures 5 to 8.

From the analyzed vector diagram, it was found that no proton transfer occurred between fumaric acid, n-butanol and imatinib, proving that they are co-crystals rather than salts. The IM-FA-nBu eutectic belongs to the orthorhombic crystal system, the space group is non-centrosymmetric Pna2 ₁ , and there are four groups of structural primitives in each unit cell. Each structural unit contains one imatinib molecule, one fumaric acid molecule and one n-butanol solvent molecule. n-butanol is close to one end of the piperazine ring of the imatinib molecule, and fumaric acid is close to one end of the pyridine and pyrimidine rings of imatinib. In each unit cell, two imatinib molecules are L-shaped and arranged side by side in the c direction, with a section containing a pyridine ring and a pyrimidine ring arranged relatively staggered, and two n-butanols are located close to each other. One end of the piperazine ring of the imatinib molecule, and two fumaric acids are located near one end of the pyridine ring and the pyrimidine ring of imatinib. The other two sets of structural primitives are stacked in the c direction with the same orientation, maintaining a certain angle with the first two groups of structural primitives to form an S-shaped chain structure along the c direction. The unit cells then stack up, forming a fine 3D crystal structure.

As can be seen from Figure 7, the IM-FA-nBu spectrum of the ground product is consistent with the pattern simulated by the structure analyzed by single crystal diffraction, indicating that the method of grinding and synthesizing drug co-crystal IM-FA-nBu described in the present invention is feasible.

As can be seen from Figure 8, the melting point of IM-FA-nBu is 144.2°C, followed by a small amount of material decomposition and some crystallization. The new crystal form melts at 206.3°C and then begins to desolvate. It can be found that the second slope interval in the TGA curve is approximately 12%, which exactly corresponds to the mass percentage of n-butanol in a repeating unit. So the product structure obtained from n-butanol should contain a solvent molecule.

Example 5: Solubility test simulating intestinal environment

1. Test materials

Methanol (Shanghai Xingke High Purity Solvent Co., Ltd., chromatographically pure); Acetonitrile (Anhui Tiandi High Purity Solvent Co., Ltd., chromatographically pure); Potassium dihydrogen phosphate (Shanghai Aladdin Biochemical Technology Co., Ltd., 99%); Sodium chloride (Nanjing Chemical Reagent Co., Ltd., analytical grade).

UltiMate3000 high performance liquid chromatography (Thermo Fisher Scientific), VMD-3100 variable wavelength detector, Agilent Eclipse XDB-C18 column (5 μm, 4.6 × 250 mm).

2. Test method

(1) Standard curve drawing

Precisely weigh 10.9 mg of IM standard material and dissolve it in 100 mL of methanol to make a mother solution. Precisely measure 1, 2, 3, 4, 5, 6, 7, 8, and 9 mL of the mother solution respectively, transfer them to a 10 mL volumetric flask, and quantify to the mark with methanol to obtain a series of standard solutions with concentration gradients. Filter a series of standard solutions with a 0.22 μm syringe filter and filter them into injection bottles for testing.

High-performance liquid chromatography was used to measure the concentration of imatinib in the solution. The detection wavelength was 267 nm; the column temperature was set to 25°C; the flow rate was set to 1.0 mL·min ^-1 ; the injection volume was 10 μL; the mobile phase A was methanol, and the mobile phase A was methanol. Phase B is acetonitrile. Add 2.7346g potassium dihydrogen phosphate and 2mL ammonia water to 1000mL pure water to obtain mobile phase C. Mobile phase A: mobile phase B: mobile phase C = 30:40:30.

(2) Study on the dissolution behavior of eutectic

A 50mM phosphate buffer solution at pH 6.8 and 37°C was used to simulate the physiological conditions of the intestine. For the raw material IM, the commercially available active forms of the drug imatinib mesylate (IM-ME), IM-GA (methanol), IM -CA-acetone conducts powder dissolution experiments. A phosphate buffer with pH 6.8 was prepared according to the standards of the Chinese Pharmacopoeia. The preparation method is to take 250mL of 0.2mol/L potassium dihydrogen phosphate solution, add 118mL of 0.2mol/L sodium hydroxide solution, dilute to 1000mL with purified water, and shake well.

Precisely weigh 2.000g of the uniformly ground sample, add it to 100mL of pH 6.8 phosphate buffer, stir at a speed of 500rpm/min under constant temperature conditions of 37.0℃ (±0.5℃), and stir at 1, 2, 3, and Take samples at the time points of 4, 5, 10, 15, 20, 25, 30, 60, 90, 180, 660, 1020, and 1440 minutes. After filtering with a 0.22 μm nylon filter, dilute it to a concentration of 1% and add it to the sampling bottle. To be tested. During the experiment, a sufficient amount of solids was introduced into the slurry to maintain a supersaturated solution. After each sampling, the solution volume is not added. If the curve does not reach equilibrium after 1440 minutes, continue stirring the solution until the concentration is stable.

High performance liquid chromatography was used to measure the concentration of imatinib in the solution. The liquid phase method was consistent with the standard solution test method. Two samples were taken from each sample and each sample was measured twice.

3. Test results

(1) Standard curve drawing

Figure 9 shows the relationship between the peak area and molar concentration of imatinib solution. The peak area (A) of imatinib solution has a good linear relationship with molar concentration within 0.02~0.20 μM (A=386.2772c-3.1021, R ² =0.998).

(2) Study on dissolution behavior

The time concentration dissolution curves of IM, IM-ME, IM-CA, IM-GA, IM-FA and IM-FA (1-Butanol) in the first 180 min are shown in Figure 10.

As can be seen from Figure 10, the solubility of IM in phosphate buffer is very low, about 0.02mM, and it is almost insoluble in the buffer. IM-ME currently on the market dissolves rapidly after being added to the buffer system and reaches the highest concentration in about 15 minutes, and maintains a high concentration of more than 25mM within 30 minutes. But then the concentration of IM dropped sharply, reaching the lowest value around 1.5h, and finally stabilized at the concentration level of 10mM after 3h. When IM-ME is initially dissolved, it is obvious that it can be completely dissolved, but gradually precipitates.

This finding may explain why some experimenters found about 25% of the parent drug in the patient's excrement. For the patient, imatinib only maintained a high concentration in the body for a short period of time, resulting in the drug not being fully absorbed. After precipitating in the intestine, it can no longer be absorbed by the intestine and is thus excreted by the patient, reducing the therapeutic effect of the drug on the patient. Increasing the dose will not necessarily lead to better effects, but may increase the side effects of the drug.

IM-CA dissolves quickly after adding phosphate buffer, and reaches the highest concentration at about 35mM in about 25 minutes. Then the concentration of IM decreases slightly, reaching the lowest level of 14mM in about 3h, and then begins to rise again, finally stabilizing at about 25mM. High concentration levels above. During the dissolution process, no precipitation was seen throughout the process. Perhaps because the dissociated ions of IM-CA are more stable, IM is more stable in the solution and can maintain a higher concentration level for a long time. This feature is conducive to the absorption of the drug in the patient's body and can prolong the drug's stay in the patient's body. Absorption time.

The solubility of IM-GA after phosphate buffer is smaller than that of other co-formers. It reaches the highest concentration of 3mM in about 25 minutes and then remains stable at 2-3mM. However, its solubility is still more than 100 times higher than that of IM API.

The dissolution situation of IM-FA-nBu is different from that of IM-FA. Both IM-FA-nBu and IM-FA reached concentration peaks within 30 minutes, with a concentration of about 22mM. Then the concentration of IM-FA-nBu began to rise, rising to a peak of about 25mM in about 3h, and then dropped to about 5mM and remained stable; The concentration of IM-FA dropped to a low point at about 3 hours, and then began to rise. It rose to a peak of about 25mM at about 11 hours. After reaching the peak, it gradually dropped to 5mM, a level close to IM-FA-nBu.

The reason why IM-FA-nBu reaches the concentration peak before IM-FA may be that there is a solvent molecule in the IM-FA-nBu crystal lattice, and the crystal has a greater tendency to desolvate, so the crystal lattice collapses quickly to release the drug activity. molecular. The subsequent rapid decrease in concentration may also be due to the entry of solvent molecules into the buffer, which has a certain impact on the polarity of the buffer, causing it to precipitate prematurely.

Compared with the IM API, the solubility of several co-active forms of substances is more than two orders of magnitude greater and more stable. Compared with IM-ME, except IM-GA, the dissolution state of several other substances before 10 h is better. IM-CA has superior dissolution characteristics and stability than IM-ME throughout the process.

After the dissolution experiment, except for IM-CA, all other co-action forms precipitated, so PXRD analysis was performed on the precipitates to understand their status. The results are shown in Figure 11.

From the PXRD patterns of the precipitates produced after powder dissolution experiments of different coformers, it can be found that the precipitation of each coformer is different from the prototype drug crystal form. Compared with the raw material drug IM, the precipitate has been converted into another crystal form. It can be speculated that the crystallization of IM after taking it may also be one of the reasons affecting its absorption. The PXRD patterns of the precipitation of the three coformants are similar, but the PXRD patterns of the original substances are different, so the possibility of precipitation of the original crystals is ruled out, but new substances generated after dissolution and precipitation.

Claims (6)

1. An imatinib co-crystal, characterized in that the co-crystal is formed from imatinib and a citric acid ligand; wherein, the mole ratio of the imatinib to the citric acid ligand is 1:1;

the eutectic is monoclinic system, and the space group is centrosymmetric P2 ₁ And/c, the unit cell parameters are as follows:α＝90°，β＝102.295(2)°，γ＝90°。

2. the imatinib co-crystal according to claim 1, characterized in that it has at least one diffraction characteristic peak at 8.430 °,10.097 °,10.913 °,12.416 °,13.633 °,15.030 °,15.750 °,16.236 °,17.409 °,18.015 °,18.884 °,20.015 °,20.731 °,21.440 °,21.880 °,22.770 °,23.349 °,24.916 °,25.471 °,27.480 °,28.517 °,29.700 ° expressed as diffraction angle 2Θ ± 0.2 °.

3. The imatinib co-crystal according to claim 1, characterized in that the co-crystal has a characteristic melting peak at 200.7 ± 0.2 ℃.

4. A method for preparing the imatinib co-crystal according to any one of claims 1 to 3, characterized in that the preparation method is a grinding method or a solvent evaporation method;

the solvent volatilization method comprises the following steps:

(1) Dissolving imatinib and citric acid in a good solvent without heavy atoms according to a molar ratio at 30-60 ℃, wherein the good solvent is methanol, ethanol or isopropanol, and the dosage ratio of solute to solvent is 2-15 mg/mL;

(2) After filtration, volatilizing and crystallizing at 19-23 ℃;

the grinding method is to grind raw materials prepared by wetting methanol, ethanol or isopropanol.

5. A pharmaceutical composition comprising the co-crystal of imatinib according to any one of claims 1-3 and a pharmaceutically acceptable carrier.

6. Use of the co-crystal of imatinib according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment of chronic granulocytic leukemia, gastrointestinal stromal tumor.