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

Imatinib eutectic crystal and preparation method thereof Download PDF

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CN114957206B
CN114957206B CN202210372405.2A CN202210372405A CN114957206B CN 114957206 B CN114957206 B CN 114957206B CN 202210372405 A CN202210372405 A CN 202210372405A CN 114957206 B CN114957206 B CN 114957206B
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imatinib
crystal
eutectic
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徐开俊
丁鹏飞
隋菁
司承运
张天秀
昌洋
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China Pharmaceutical University
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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 eutectic crystal and preparation method thereof
Technical Field
The invention relates to an imatinib eutectic crystal and a preparation method thereof, in particular to an imatinib eutectic crystal with excellent solubility and stability and a preparation method thereof.
Background
The therapeutic effect of an oral drug is strictly dependent on its bioavailability. The ability of a drug to permeate the membrane of the gastrointestinal tract is related to its solubility and dissolution in the gastrointestinal tract, and this property is a key parameter in controlling bioavailability. Based on this property biopharmaceutical classification systems (Biopharmaceutics Classification System, BCS) were constructed, wherein drugs with poor oral bioavailability were generally classified as class II (low solubility-high permeability), class III (high solubility-low permeability) or class IV (low solubility-low permeability). Unfortunately, about 40% of the marketed drugs have poor water solubility, with 30% of the drugs belonging to class II and 10% of the drugs belonging to class IV in the BCS classification, and, in addition, the percentages of class II and class IV still increase significantly to about 70% and 20% among the candidate drugs being investigated.
Imatinib (IM) is a classical antitumor drug developed by Novartis (Novartis). IM is a specific inhibitor of platelet-derived growth factor receptors PDGFR alpha, PDGFR beta, protein tyrosine kinase Bcr-Abl and c-Kit receptors. It exerts cytotoxic activity by binding to ATP-binding fragments of the kinase domain, thereby preventing subsequent phosphorylation of downstream proteins, imatinib is widely used in the treatment of chronic myeloid leukemia (chronic myeloid leukemia, CML), gastrointestinal stromal tumor (gastrointestinal stromal tumors, GIST), and many other diseases.
Imatinib is almost insoluble in water and weakly alkaline media, and its low solubility is a major obstacle to the drug research process. The pharmaceutical formulation currently on the market contains imatinib mesylate (IM-ME) developed by North America under the trade nameThe physical and chemical properties of the imatinib are improved by salifying methanesulfonic acid with the medicine in the preparation process. Although imatinib mesylate has increased solubility in water, its structure is not stable in weakly alkaline media. The experimenter found about 25% of the parent drug in the patient's faeces, probably because the salt form was unstable in the intestinal environment, precipitated as the parent drug when not fully absorbed, and subsequently expelled from the body. In addition, it is important to note that imatinib mesylate is used in a high clinical dosage, 400mg daily in the chronic phase, and the dosage in the acceleration phase or the acute phase is suddenly increased to 600-800mg daily, and long-term high dosage may cause various adverse reactions such as neutropenia, thrombocytopenia, anemia, nausea, vomiting and the like.
Disclosure of Invention
The invention aims to: aiming at the problems of poor solubility, unstable in vivo and the like of the existing imatinib drug, the invention aims to provide an imatinib eutectic crystal with excellent solubility and stability and improved bioavailability and drug safety and a preparation method thereof.
The technical scheme is as follows: as a first aspect to which the invention relates, the co-crystal of imatinib of the invention is formed from imatinib and any one of the following ligand systems:
(1) A citric acid ligand;
or (2) fumaric acid and n-butanol;
wherein, the mole ratio of the imatinib to the citric acid ligand is 1:1; the molar ratio of the imatinib, the fumaric acid and the n-butanol is 1:1:1.
The selected Active Pharmaceutical Ingredient (API) is Imatinib (IM), and the structure is shown as formula I; the ligand (CCF) is Fumaric Acid (FA) and Citric Acid (CA) with structures shown in formulas II and III respectively, and the pharmaceutical co-crystals with two novel structures are prepared.
Eutectic is essentially a supermolecule self-assembly system, which is the result of thermodynamic, kinetic, molecular equilibrium. In the molecular self-assembly process, intermolecular interactions and spatial effects affect the formation of a supramolecular network, which in turn directly affects the formation of crystals. In the eutectic structure, different intermolecular interactions mainly include hydrogen bonds, pi-pi stacking effects, van der Waals forces, halogen bonds and the like. The bond energy of hydrogen bonds is between 4 and 120kJ/mol, much greater than other weak interactions, and directional, so hydrogen bonds are the most important forces in eutectic formation.
As a case of the co-crystal, when the co-crystal is citric acid-imatinib co-crystal, the co-crystal 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°, four sets of structural elements being contained in each unit cell.
The eutectic is specifically formed by connecting an imatinib molecule and a citric acid molecule together through hydrogen bonds to form a basic structural unit of the imatinib pharmaceutical eutectic IM-CA. Wherein within each set of structural motifs, imatinib and citric acid are linked to each other by two sets of hydrogen bonds. The two groups of hydrogen bonds are respectively positioned between the hydrogen connected with N4 in the imatinib molecular imine structure and O3 on citric acid and between the hydrogen connected with N3 and O4 on citric acid in the imatinib molecular pyrimidine structure.
Specifically, the crystallography data for imatinib pharmaceutical co-crystal IM-CA are as follows:
more specifically, expressed in terms of diffraction angles 2θ±0.2°, the co-crystal 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 °; has a characteristic melting peak at 200.7 + -0.2deg.C.
As another case of the co-crystal, when the co-crystal is fumaric acid-imatinib-n-butanol co-crystal, the co-crystal is orthorhombic, and the space group is non-centrosymmetric Pna2 1 The unit cell parameters are: α=90°, β=90°, γ=90°, four sets of structural elements contained in each unit cell.
The eutectic is specifically formed by connecting an imatinib molecule, a fumaric acid molecule and an n-butanol molecule together through hydrogen bonds and other weak interactions, so as to form a basic structural unit of the imatinib pharmaceutical eutectic IM-FA-nBu. N-butanol is near one end of the piperazine ring of the imatinib molecule, and fumaric acid is near one end of the pyridine ring and pyrimidine ring of the imatinib.
Specifically, the crystallographic data of the imatinib pharmaceutical co-crystal IM-FA-nBu are as follows:
more specifically, expressed in terms of diffraction angle 2θ±0.2°, the co-crystal has at least one diffraction characteristic peak at 7.282 °,8.568 °,9.690 °,10.992 °,12.175 °,14.593 °,16.088 °,16.678 °,17.196 °,18.034 °,19.333 °,20.644 °,21.071 °; has characteristic melting peak at 144.2+ -0.2deg.C and 206.3+ -0.2deg.C.
As a second aspect of the present invention, the above-mentioned imatinib cocrystal may be prepared by a milling method or a solvent evaporation method.
As one of the preparation methods, the solvent evaporation method comprises the steps of:
(1) Dissolving imatinib and citric acid or fumaric acid in a good solvent without heavy atoms according to a molar ratio at 30-60 ℃, wherein the dosage ratio of solute to solvent is 2-15 mg/mL;
(2) After filtration, the crystals were evaporated.
Specifically, when the ligand is citric acid, the good solvent in the step (1) is methanol, ethanol or isopropanol; the volatilizing and crystallizing temperature in the step (2) is 19-23 ℃.
When the ligand is fumaric acid and n-butanol, the good solvent in the step (1) is n-butanol, methanol-n-butanol, ethanol-n-butanol or isopropanol-n-butanol, wherein the volume ratio of methanol, ethanol or isopropanol to n-butanol is 2:1-4:1; the volatilizing and crystallizing temperature in the step (2) is 27-34 ℃. When the good solvent is methanol-n-butanol, ethanol-n-butanol or isopropanol-n-butanol, dissolving imatinib and fumaric acid by using methanol, ethanol or isopropanol, and then adding n-butanol; or dissolving fumaric acid with methanol-n-butanol, ethanol-n-butanol or isopropanol-n-butanol, and then adding imatinib.
The volatilizing crystallization can be carried out in a container, the opening of the container needs to be sealed to isolate external water vapor, and a water scavenger can be additionally arranged in the container when necessary.
As another preparation method thereof, the grinding method is as follows:
adding imatinib and citric acid or fumaric acid into a good solvent without heavy atoms according to a molar ratio for auxiliary grinding, wherein the good solvents suitable for the two eutectic situations are the same, the amount of the added solvent is suitable for wetting powder during grinding, raw materials do not need to be pulped, and the reaction progress can be monitored by X-ray powder diffraction. Such grinding methods can be used for large-scale production.
Specifically, when the eutectic is citric acid-imatinib eutectic, raw materials are prepared by wetting with methanol, ethanol or isopropanol and are ground; when the eutectic crystal is fumaric acid-imatinib-n-butanol eutectic crystal, n-butanol, methanol-n-butanol, ethanol-n-butanol or isopropanol-n-butanol are used for wetting preparation raw materials for grinding, wherein the volume ratio of methanol, ethanol or isopropanol to n-butanol is 2:1-4:1.
The imatinib eutectic crystal and a pharmaceutically acceptable carrier can be further prepared into a pharmaceutical composition.
Specifically, the imatinib eutectic crystal can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, syrup, suspending agents or injection, and the preparations can be added with common medicinal auxiliary materials such as perfume, sweetener, liquid/solid filler, diluent and the like.
The imatinib cocrystal or the pharmaceutical composition containing the imatinib cocrystal retains the biological activity of the imatinib and can be used as a medicament for treating tumor diseases.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) On the basis of retaining the molecular structure and pharmacological action of the imatinib, the solubility and the dissolution rate of the imatinib eutectic are obviously higher than those of the imatinib and the imatinib mesylate, even higher by two orders of magnitude, and the drug molecules are more stable and do not generate drug precipitation, so that the bioavailability and the drug safety of the drug can be improved;
(2) The preparation method is simple and convenient, is easy to operate, and is suitable for industrial scale preparation.
Drawings
FIG. 1 is a vector diagram of an imatinib eutectic IM-CA structure primitive;
fig. 2 is a schematic diagram of the imatinib eutectic IM-CA unit cell, fig. 2a: a-direction view, fig. 2b: b-direction view, fig. 2c: c, a direction view;
FIG. 3 is a powder X-ray diffraction (PXRD) pattern of imatinib co-crystal IM-CA;
FIG. 4 is a Differential Scanning Calorimetric (DSC) diagram of imatinib co-crystal IM-CA;
FIG. 5 is a vector diagram of an imatinib eutectic IM-FA-nBu structural element;
FIG. 6 is a schematic diagram of an imatinib eutectic IM-FA-nBu unit cell, FIG. 6a: a direction view, fig. 6b: b-direction view, fig. 6c: c, a direction view;
FIG. 7 is a powder X-ray diffraction (PXRD) pattern of imatinib co-crystal IM-FA-nBu;
FIG. 8 is a differential scanning calorimeter analysis (DSC) and thermogravimetric analysis (TG) plot of imatinib co-crystal IM-FA-nBu;
FIG. 9 is a plot of peak area versus molar concentration for imatinib IM;
fig. 10 is a schematic diagram showing solubility curves of imatinib IM, imatinib mesylate IM-ME, imatinib co-crystal IM-CA, imatinib gallate IM-GA, imatinib fumarate IM-FA, imatinib co-crystal IM-FA-nBu simulated intestinal environments, fig. 10a: 0-200 min, fig. 10b: 0-1440 min;
FIG. 11a is a PXRD diagram of imatinib eutectic IM-FA-nBu co-former precipitate;
FIG. 11b is a PXRD pattern of imatinib fumarate IM-FA co-former precipitate
FIG. 11c is a PXRD pattern of imatinib mesylate IM-ME coform precipitate.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
The instrument for detecting the eutectic structure and the performance of the medicine in the invention is as follows:
eutectic structure data is in the presence of graphite monochromatic Cu K alpha radiationCollected on a Bruker D8Venture single crystal diffractometer. Resolving the structure by direct method and pairing F by full matrix least squares method using SHELX-2014/7 program 2 And (5) refining. All non-hydrogen atoms were refined anisotropically.
Powder X-ray diffraction analysis (PXRD): a Bruker D8 advanced X-ray diffractometer of Bruker AXS company of Germany is adopted, and a ray source is Cu/K alphaThe scanning range is 3-60 degrees (2 theta), the scanning step length is 0.02 degrees, the speed is 4 degrees/min, the power supply is set to 40kV, and 40mA.
Differential scanning calorimetry analysis (DSC): and heating the sample by using a NETZSCH DSC204 type differential thermal analyzer of NETZSCH company in Germany under the nitrogen atmosphere, wherein the temperature is r.t-280 ℃, and the temperature of the fumaric acid sample is raised to 350 ℃ at a heating rate of 10 ℃/min.
Example 1
IM (0.25 mmol) and CA (0.25 mmol) in a stoichiometric ratio of 1:1 were weighed, 50mL of ethanol solvent was added, stirred and refluxed at 60℃for 1h, filtered with a 0.22 μm filter membrane, and then transferred into a crystallization flask placed in a bell jar in a constant temperature bath, and slowly evaporated and crystallized at 21 ℃. Pale yellow needle crystals IM-CA were obtained after about 30 h.
Example 2
IM (0.25 mmol) and FA (0.25 mmol) in a stoichiometric ratio of 1:1 are weighed, FA is added into 50mL of a mixed solvent of n-butanol and ethanol (v/v=1:2) firstly, then IM is added into the mixed solvent for stirring and refluxing at 60 ℃ for 1h after ultrasonic dissolution, a filter membrane with the thickness of 0.22 μm is used for filtration, and the mixture is transferred into a crystallization bottle and placed into a bell jar in a constant temperature tank, and slowly volatilized and crystallized at 32 ℃. Pale yellow needle crystals IM-FA-nBu were obtained after about 30 h.
And detecting the crystal structure of the imatinib eutectic IM-CA, wherein the detection results are shown in figures 1-4.
From the resolved vector diagram, no proton transfer occurs between citric acid and imatinib, which proves to be a eutectic rather than a salt. There are four sets of structural motifs within each unit cell of imatinib-citric acid, wherein imatinib and citric acid are interconnected within each set of structural motifs by two sets of hydrogen bonds. The two groups of hydrogen bonds are respectively positioned between the hydrogen connected with N4 in the imatinib molecular imine structure and O3 on citric acid and between the hydrogen connected with N3 and O4 on citric acid in the imatinib molecular pyrimidine structure. The crystal is monoclinic, its space group is central symmetrical P2 1 /c。
As can be seen from fig. 3, the PXRD pattern of the milled product is consistent with that simulated by the structure of single crystal diffraction analysis, demonstrating that the manner in which the milled synthetic pharmaceutical co-crystals CA-IM described in this invention is viable.
Example 3
IM (0.25 mmol) and CA (0.25 mmol) in a stoichiometric ratio of 1:1 were weighed and placed in a mortar.
The grinding adopts a liquid adding auxiliary grinding mode. Liquid adding auxiliary grinding, adding ethanol by a micro-injector during grinding, wherein the amount of solvent added each time is proper to wet the raw materials. Grinding for 0.5h to obtain the pharmaceutical eutectic IM-CA with the crystallinity of more than 60 percent.
Example 4
IM (0.25 mmol) and FA (0.25 mmol) in a stoichiometric ratio of 1:1 were weighed and placed in a mortar.
The grinding adopts a liquid adding auxiliary grinding mode. Liquid adding auxiliary grinding, adding n-butanol with microinjector, and wetting raw materials. Grinding for 0.5h to obtain the pharmaceutical eutectic FA-IM-nBu with the crystallinity of more than 60 percent.
The crystal structure of the imatinib eutectic IM-CA prepared by the method is detected, and the detection results are shown in figures 5-8.
From the resolved vector diagram, no proton transfer occurs between fumaric acid, n-butanol and imatinib, which proves to be a eutectic rather than a salt. The IM-FA-nBu eutectic belongs to an orthorhombic system, and the space group is Pna2 with non-central symmetry 1 Four sets of structural elements are provided in each unit cell. Each structural element contains one imatinib molecule, one fumaric acid molecule and one n-butanol solvent molecule. N-butanol is near one end of the piperazine ring of the imatinib molecule, and fumaric acid is near one end of the pyridine ring and pyrimidine ring of the imatinib. In each unit cell, two imatinib molecules are arranged in parallel and opposite in the same direction in the direction of c in an L shape, wherein one section containing pyridine rings and pyrimidine rings is arranged in a relatively staggered manner, wherein two n-butanol are respectively positioned at one end close to piperazine rings of the imatinib molecules, and two fumaric acid are respectively positioned at one end close to the imatinib pyridine rings and pyrimidine rings. The other two groups of structural elements are stacked in the c-direction in the same orientation, and form an s-shaped chain structure along the c-direction at an angle with the first two groups of structural elements. The unit cells then accumulate to form a fine 3D crystal structure.
As can be seen from FIG. 7, the IM-FA-nBu spectrum of the milled product was consistent with the structure simulated by single crystal diffraction analysis, demonstrating that the manner in which the milled synthetic pharmaceutical co-crystals IM-FA-nBu described in the present invention is feasible.
As can be seen from FIG. 8, the IM-FA-nBu melting point is 144.2℃with subsequent small material decomposition and partial seeding. The new form melted at 206.3 ℃ and then started to desolvate, and the second slope interval in the TGA profile was found to be about 12% which corresponds exactly to the mass percentage of n-butanol in one repeat unit. The product structure obtained from n-butanol should contain a solvent molecule.
Example 5: solubility test simulating intestinal environment
1. Test materials
Methanol (high purity solvent, inc., starfish, chromatogrAN_SNhy); acetonitrile (high purity solvent limited, anhui heaven, chromatography); monopotassium phosphate (Shanghai Ala Biochemical technologies Co., ltd., 99%); sodium chloride (Nanjing Chemicals Co., ltd., analytical grade).
UltiMate3000 high performance liquid chromatograph (Simer Feichi technologies Co.), VMD-3100 variable wavelength detector, agilent Eclipse XDB-C18 column (5 μm, 4.6X1250 mm).
2. Test method
(1) Standard curve drawing
10.9mg of IM standard substance was precisely weighed and dissolved in 100mL of methanol to prepare a mother solution. 1, 2, 3, 4, 5, 6, 7, 8 and 9mL of mother solution are respectively measured precisely, transferred into a 10mL volumetric flask, and are quantified to scale by methanol, so as to obtain a series of standard solutions with concentration gradients. A series of standard solutions are filtered by a 0.22 mu m injection filter and are filtered into a sample injection bottle for detection.
Measuring the concentration of imatinib in the solution by adopting a high performance liquid chromatography, wherein the detection wavelength is 267nm; setting the column temperature to 25 ℃; the flow rate was set to 1.0mL min -1 The method comprises the steps of carrying out a first treatment on the surface of the The sample injection amount is 10 mu L; mobile phase a was methanol, mobile phase B was acetonitrile, and 2.7346g of potassium dihydrogen phosphate and 2mL of aqueous ammonia were added to 1000mL of pure water to obtain mobile phase C. Mobile phase a mobile phase B mobile phase c=30:40:30.
(2) Eutectic dissolution behavior study
The physiological conditions of the intestinal tract were simulated with 50mM phosphate buffer solution at pH 6.8 and 37℃and powder dissolution experiments were performed on the drug substance IM, commercially available pharmaceutically active forms imatinib mesylate (IM-ME), IM-GA (methanol), IM-CA-acetone. Phosphate buffer with pH of 6.8 was prepared according to the standards of Chinese pharmacopoeia. The preparation method comprises the steps of taking 250mL of 0.2mol/L potassium dihydrogen phosphate solution, adding 118mL of 0.2mol/L sodium hydroxide solution, diluting to 1000mL with purified water, and shaking uniformly.
Precisely weighing 2.000g of uniformly ground sample, adding into 100mL of phosphate buffer solution with pH of 6.8, stirring at a constant temperature of 37.0 ℃ (+/-0.5 ℃) at a speed of 500rpm/min, sampling at time points of 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 60, 90, 180, 660, 1020 and 1440min respectively, filtering by a nylon filter with a size of 0.22 mu m, diluting to 1% concentration, and adding into a sample bottle to be tested. During the experiment, the amount of solids in the slurry was introduced sufficiently to maintain a supersaturated solution. After each sampling, the volume of solution was not replenished. If the curve does not reach equilibrium after 1440min, stirring the solution is continued until the concentration stabilizes.
And (3) measuring the concentration of the imatinib in the solution by adopting a high performance liquid chromatography, wherein the liquid phase method is consistent with a standard solution testing method. Two samples were taken for each sample and the measurements were repeated twice for each sample.
3. Test results
(1) Standard curve drawing
FIG. 9 is a graph showing the relationship between the peak area and the molar concentration of an imatinib solution, wherein the peak area (A) of the imatinib solution has a good linear relationship with the molar concentration within 0.02 to 0.20. Mu.M (A= 386.2772c-3.1021, R 2 ＝0.998)。
(2) Dissolution behavior study
The time concentration dissolution curves of IM, IM-ME, IM-CA, IM-GA, IM-FA and IM-FA (1-Butanol) at the first 180min are shown in FIG. 10.
As can be seen from FIG. 10, the solubility of IM in phosphate buffer was very low, about 0.02mM, and almost insoluble in the buffer. IM-ME sold in the market at present is added into a buffer system, and then is dissolved rapidly, and reaches the highest concentration within about 15min, and the high concentration of more than 25mM is maintained within 30 min. But then the IM concentration drops sharply to a minimum value of around 1.5h and eventually stabilizes at a concentration level of 10mM after 3 h. At the time of initial dissolution of the IM-ME, it was found that the whole of the solution was found, but a precipitate was gradually precipitated.
This finding may explain why about 25% of the parent drug is found in the excreta of the patient, and for the patient, imatinib is only maintained at a high concentration in the body for a short period of time, so that the drug is precipitated in the intestinal tract without being sufficiently absorbed and cannot be absorbed by the intestinal tract any more, and is discharged from the body by the patient, thereby reducing the therapeutic effect of the drug on the patient. Increasing the dose does not necessarily have a better effect, but rather may increase the side effects of the drug.
The IM-CA added phosphate buffer dissolved rapidly and reached the highest concentration around 25min, about 35mM, followed by a slight decrease in IM concentration, about 3h down to the lowest 14mM, after which an increase was initiated and eventually stabilized at a high concentration level above about 25 mM. In the dissolution process, no precipitation is found in the whole process. The ion after dissociation of IM-CA is more stable, so that IM is more stable in the solution, and a higher concentration level can be maintained for a long time.
The solubility of IM-GA in phosphate buffer was smaller than that of other coforms, and it was stable at 2-3 mM after reaching the maximum concentration of 3mM in about 25 min. However, compared with the IM bulk drug, the solubility of the pharmaceutical drug is still increased by more than 100 times.
The IM-FA-nBu dissolution is different from that of IM-FA. The IM-FA-nBu reaches a peak concentration of about 22mM within 30min, then the concentration of the IM-FA-nBu starts to rise to about 25mM at the peak of about 3h, then drops to about 5mM and remains stable; the IM-FA concentration decreased to a low point at about 3h, then began to rise to about 11h, to about 25mM at the peak, and gradually decreased to a level of 5mM near the IM-FA-nBu after reaching the peak.
The reason why IM-FA-nBu reaches the concentration peak before IM-FA probably is that there is a solvent molecule in the IM-FA-nBu lattice, the tendency of the crystal to desolvate is relatively large, so that the collapse of the lattice is relatively rapid to release pharmaceutically active molecules. The subsequent rapid decrease in concentration may also be due to the fact that the entry of solvent molecules into the buffer has a certain effect on the polarity of the buffer, causing its premature precipitation.
Compared with the IM bulk drug, the solubility of substances in several coactive forms is more than two orders of magnitude, and the substances are more stable. Compared with IM-ME, the dissolution state of several substances except for IM-GA is more excellent before 10 hours. IM-CA is more fully characterized by superior dissolution characteristics and stability than IM-ME.
After dissolution experiments, all but IM-CA had precipitated, and PXRD analysis was performed on the precipitate to see its status. The results are shown in FIG. 11.
The PXRD pattern of the precipitate produced after powder dissolution experiments from different coformulants can be found that the precipitate of each coform is already different compared to the proto-drug form. And compared with the crude drug IM, the precipitate has been converted into another crystal form, it can be hypothesized that the crystal transformation of IM after administration may also be one of the reasons for affecting the absorption thereof. The PXRD patterns of the three kinds of co-formed matter precipitate are similar, but the PXRD patterns of the three kinds of co-formed matter precipitate are different from those of the original matter, so that the possibility of the original crystal precipitation is eliminated, and new matter generated after dissolution and precipitation is generated.

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.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1264375A (en) * 1997-07-18 2000-08-23 诺瓦提斯公司 Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use
CN103864752A (en) * 2010-05-19 2014-06-18 江苏豪森药业股份有限公司 Crystal form of imatinib mesylate and preparation method thereof
CN106518844A (en) * 2015-04-14 2017-03-22 江苏豪森药业集团有限公司 An imatinib mesylate crystal form suitable for officinal uses and a preparing method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1264375A (en) * 1997-07-18 2000-08-23 诺瓦提斯公司 Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use
CN103864752A (en) * 2010-05-19 2014-06-18 江苏豪森药业股份有限公司 Crystal form of imatinib mesylate and preparation method thereof
CN106518844A (en) * 2015-04-14 2017-03-22 江苏豪森药业集团有限公司 An imatinib mesylate crystal form suitable for officinal uses and a preparing method thereof

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