CN114685455A - AZD9291 crystalline solid - Google Patents

AZD9291 crystalline solid Download PDF

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CN114685455A
CN114685455A CN202011629177.XA CN202011629177A CN114685455A CN 114685455 A CN114685455 A CN 114685455A CN 202011629177 A CN202011629177 A CN 202011629177A CN 114685455 A CN114685455 A CN 114685455A
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oxitinib
degrees
crystalline solid
adipic acid
ethanol
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张贵民
翟立海
梁茂征
张明明
黄超
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Lunan Pharmaceutical Group Corp
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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Abstract

The invention relates to the technical field of crystal form drug molecules, in particular to the technical field of preparation of AZD9291 crystals serving as cancer treatment drugs. The invention provides a novel AZD9291 crystalline solid, which specifically comprises the following components: an oxitinib-adipic acid crystal, wherein an X-ray diffraction spectrum expressed by 2 theta at least has characteristic peaks at 6.60 +/-0.2, 15.65 +/-0.2, 19.73 +/-0.2, 19.80 +/-0.2, 20.41 +/-0.2, 21.01 +/-0.2, 21.32 +/-0.2, 24.86 +/-0.2 and 26.18 +/-0.2; the Oxcetin-3, 5-dihydroxy benzoic acid ethanol water solvate has an X-ray diffraction spectrum expressed by 2 theta and has characteristic peaks at least at 6.00 +/-0.2 degrees, 8.52 +/-0.2 degrees, 11.85 +/-0.2 degrees, 16.45 +/-0.2 degrees, 19.75 +/-0.2 degrees, 23.66 +/-0.2 degrees. The crystal form of AZD9291 provided by the invention has improved physical and chemical properties such as solubility, stability and the like.

Description

AZD9291 crystalline solid
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to the technical field of preparation of AZD9291 crystals serving as cancer treatment drugs.
Background
AZD9291 has the chinese name oxitinib (Osimertinib), chemical name: n- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide, english name: n- (2- { [2- (dimethyllamino) ethyl ] (methyl) amino } -4-methoxy-5- { [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino } phenyl) acrylamide. The structural formula is as follows:
Figure BDA0002879742070000011
if the lung cancer patient has EGFR or ALK gene mutation, the targeted drug can obtain better survival benefit. However, the efficacy of these drugs is generally short-lived, and resistance occurs in months 9-11, which arises because cancer cells can evade the therapeutic activity of EGFR or ALK inhibitors by mutating and changing the growth pattern.
ADZ9291, developed by AstraZeneca (AstraZeneca), is a third generation oral, irreversible selective EGFR mutation inhibitor useful for activating and resistant mutant EGFR, i.e., 50% of acquired resistance to EGFR treatment for advanced non-small cell lung cancer patients is caused by the T790M mutation, and ADZ9291 can nullify this challenging mutation. ADZ9291 has better treatment effect on NSCLC patients with existing resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and T790M mutation.
Patent CN103702990A discloses a compound structure. Polymorphic forms of this compound and its mesylate salt are also disclosed in this patent. Patent CN104961731A discloses oxitinib phosphate; patent CN106432231A discloses oxitinib pharmaceutically acceptable salts sulfate, p-toluenesulfonate, tartrate, acetate and citrate; patent CN107915725A patent discloses novel pharmaceutically acceptable salts of maleic acid, fumaric acid, gluconic acid, malonic acid, succinic acid and lactic acid.
The former company used the mesylate salt of oxitinib for clinical studies. However, methanesulfonic acid is highly toxic and, in selective cases, unsuitable for pharmaceutical use. And the methanesulfonate has problems of high hygroscopicity and deliquescence due to high humidity. Therefore, it is necessary to develop other salts with high bioavailability, low toxicity and suitability for pharmaceutical use. Although the existing literature discloses a plurality of oxitinib crystal forms, the systematic research on the oxitinib crystal forms is still to be perfected, and particularly, the comprehensive research on the oxitinib eutectic compound is not reported yet. Many other salts have been reported, but their pharmaceutical properties are still under study.
The invention provides a simple and easy-to-operate method for preparing a high-purity oxitinib crystal form, and provides a better basis for the application of oxitinib in the aspect of drug therapy, so that the medicinal value of oxitinib is exerted more efficiently.
Disclosure of Invention
In view of the deficiencies in the physicochemical properties of the crystalline form of oxitinib disclosed in the prior art, it is an object of the present invention to provide a novel crystalline form of oxitinib, which is improved and improved in the physicochemical properties of solubility, stability, etc.
On one hand, the invention provides a novel AZD9291 crystalline solid, in particular an oxitinib-adipic acid crystal and oxitinib-3, 5-dihydroxy benzoic acid ethanol water solvate.
Preferably, the oxitinib-adipic acid crystal has an X-ray diffraction spectrum expressed by 2 theta using Cu-Ka radiation and has characteristic peaks at least at 6.60 +/-0.2 degrees, 15.65 +/-0.2 degrees, 19.73 +/-0.2 degrees, 19.80 +/-0.2 degrees, 20.41 +/-0.2 degrees, 21.01 +/-0.2 degrees, 21.32 +/-0.2 degrees, 24.86 +/-0.2 degrees and 26.18 +/-0.2 degrees.
Preferably, the oxitinib-adipic acid crystal has an X-ray diffraction spectrum expressed by 2 theta using Cu-Ka radiation, which has characteristic peaks at least at 6.60 +/-0.2 degrees, 8.64 +/-0.2 degrees, 10.15 +/-0.2 degrees, 10.65 +/-0.2 degrees, 11.29 +/-0.2 degrees, 13.60 +/-0.2 degrees, 14.13 +/-0.2 degrees, 15.65 +/-0.2 degrees, 19.02 +/-0.2 degrees, 19.73 +/-0.2 degrees, 19.80 +/-0.2 degrees, 20.41 +/-0.2 degrees, 21.01 +/-0.2 degrees, 21.32 +/-0.2 degrees, 22.55 +/-0.2 degrees, 23.64 +/-0.2 degrees, 23.98 +/-0.2 degrees, 24.86 +/-0.2 degrees, 26.18 +/-0.2 degrees, 28.37 +/-0.2 degrees.
Preferably, the oxitinib-adipic acid crystal uses Cu-Ka radiation, and the characteristic peak has an X-ray powder diffraction pattern or data shown in figure 1 or table 2.
Further preferably, in a preferred embodiment of the present invention, the first endothermic peak of the oxitinib-adipic acid crystal detected by Differential Scanning Calorimetry (DSC) starts at 137.02 ℃ and the peak appears at 145.33 ℃, as shown in fig. 2.
Preferably, the oxicetinic acid-3, 5-dihydroxy benzoic acid ethanol water solvate has an X-ray diffraction spectrum expressed by 2 theta and using Cu-Ka radiation, and has characteristic peaks at least at 6.00 +/-0.2 degrees, 8.52 +/-0.2 degrees, 11.85 +/-0.2 degrees, 16.45 +/-0.2 degrees, 19.75 +/-0.2 degrees and 23.66 +/-0.2 degrees.
Preferably, the oxicetinic acid-3, 5-dihydroxy benzoic acid ethanol water solvate has an X-ray diffraction spectrum expressed by 2 theta by using Cu-Ka radiation, and has characteristic peaks at least at 6.00 +/-0.2 degrees, 8.52 +/-0.2 degrees, 11.85 +/-0.2 degrees, 12.32 +/-0.2 degrees, 13.14 +/-0.2 degrees, 13.45 +/-0.2 degrees, 13.78 +/-0.2 degrees, 16.45 +/-0.2 degrees, 17.18 +/-0.2 degrees, 18.40 +/-0.2 degrees, 19.75 +/-0.2 degrees, 20.42 +/-0.2 degrees, 22.12 +/-0.2 degrees and 23.66 +/-0.2 degrees.
Preferably, the oxicetinic-3, 5-dihydroxybenzoic acid ethanol water solvate has characteristic peaks at least at 6.00 +/-0.2 degrees, 8.52 +/-0.2 degrees, 11.85 +/-0.2 degrees, 12.32 +/-0.2 degrees, 13.14 +/-0.2 degrees, 13.45 +/-0.2 degrees, 13.78 +/-0.2 degrees, 15.30 +/-0.2 degrees, 16.45 +/-0.2 degrees, 17.18 +/-0.2 degrees, 18.40 +/-0.2 degrees, 19.75 +/-0.2 degrees, 20.42 +/-0.2 degrees, 21.75 +/-0.2 degrees, 22.12 +/-0.2 degrees, 22.95 +/-0.2 degrees, 23.66 +/-0.2 degrees, 24.08 +/-0.2 degrees, 24.65 +/-0.2 degrees, 25.64 +/-0.2 degrees, 26.51 +/-0.2 degrees by using Cu-Kalpha radiation and an X-ray diffraction spectrum expressed by 2 theta.
Preferably, the oxicetinic acid-3, 5-dihydroxy benzoic acid ethanol water solvate has characteristic peaks with X-ray powder diffraction patterns or data shown in figure 5 or table 3 by using Cu-Ka radiation.
Preferably, in a preferred embodiment of the present invention, the ethanol hydrosolvent of oxitinib-3, 5-dihydroxybenzoic acid is characterized by a differential scanning thermal analysis (DSC) with a first endothermic peak at 63.71 ℃, a second endothermic peak at 153.04 ℃, and a third endothermic peak at 213.63 ℃, as shown in fig. 6.
In a second aspect of the invention, there is provided a process for the preparation of the AZD929 crystalline solid described. The oxitinib-adipic acid crystal can be prepared by the following method:
dissolving the oxitinib and adipic acid in an organic solvent A, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain the oxitinib-adipic acid crystal.
Preferably, the organic solvent A is selected from one or a mixed solvent of at least two of acetone, methanol, ethanol and acetonitrile; one or two of acetone and ethanol are preferred.
Preferably, the feeding molar ratio of the oxitinib to the adipic acid is 1: 0.8-1.5; preferably 1: 0.9-1.1.
Preferably, the mass volume ratio of the oxitinib to the organic solvent A in the system is 5-40: 1, wherein mass is in mg and volume is in ml; preferably 15-20: 1, wherein the mass is in mg and the volume is in ml.
Preferably, the temperature for dissolving and heating is 40-60 ℃; the temperature for cooling and crystallizing is 0-30 ℃; preferably 5-20 ℃; the crystallization time is 24-36 hours.
The oxitinib-3, 5-dihydroxy benzoic acid ethanol hydrosolvent can be prepared by the following method: dissolving oxitinib and 3, 5-dihydroxybenzoic acid in a mixed solvent, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain the oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate crystal.
Preferably, the mixed solvent is a mixture of ethanol and purified water.
Preferably, in the mixed solvent, the purified water accounts for 15-30% of the volume of the mixed solvent; preferably 20%.
Preferably, the molar ratio of the oxitinib to the 3, 5-dihydroxybenzoic acid is 1: 0.8-1.5; the preferable molar ratio is 1:0.9 to 1.1.
Preferably, the mass-volume ratio of the oxitinib to the mixed solvent is 5-25: 1, wherein mass is in mg and volume is in ml; preferably 8-15: 1, wherein the mass is in mg and the volume is in ml.
Preferably, the temperature for dissolving and heating is 40-60 ℃; the temperature for cooling and crystallizing is 0-30 ℃, and preferably 0-15 ℃; the crystallization time is more than 24 hours.
In a further aspect, the invention provides a pharmaceutical composition comprising as active ingredient the crystalline solid AZD9291 according to the invention, together with other pharmaceutically acceptable ingredients; it is further preferred that the composition contains, in addition to the aforementioned components, other active ingredients that can be used in combination.
Preferably, the other components include other active ingredients, excipients, fillers, etc. that may be used in combination.
Preferably, the pharmaceutical composition can be prepared into spray, tablets, capsules, powder injections, liquid injections and the like by using standard and conventional technologies.
And (3) structure confirmation:
oxitinib adipic acid crystal
X-ray crystal data were collected on a jtaab Synergy model instrument, japan, testing temperature 293(2) K, irradiating with CuKa, collecting data in an omega scan fashion and Lp correction. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The crystallographic data obtained by testing and analyzing the Oxitinib-adipic acid crystal prepared by the invention (detailed in Table 1) are that the crystallographic parameters are as follows: monoclinic system, chiral space group P2C(ii) a The unit cell parameters are:
Figure BDA0002879742070000042
Figure BDA0002879742070000043
α is 94.956(2) °, β is 106.305(2) °, γ is 103.030(2) °, unit cell volume
Figure BDA0002879742070000044
The molecular formula is: c34H43N7O6The molecular weight is: 645.75. the structural analysis chart of the oxitinib-adipic acid crystal of the invention shows that the crystal has no solvent, and is shown in figure 4. The hydrogen bond stacking diagram of the oxitinib-adipic acid crystal of the invention is specifically shown in fig. 3.
TABLE 1 principal crystallographic data for Oxitinib-adipic acid crystals
Figure BDA0002879742070000041
Figure BDA0002879742070000051
The invention relates to an X-ray powder diffraction test instrument and test conditions in an Oxitinib-adipic acid crystal test, which are as follows: PANALYTIC EMPyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction path: PLXCEL, voltage 45KV, current 40mA, divergence slit 1/4 degrees, anti-divergence slit 1 degree, cable-stayed slit 0.04rad degree, counting time of each step 0.5s, and scanning range 3-50 degrees.
According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in figure 1 and table 2.
TABLE 2 main PXRD peaks of Oxitinib-adipic acid crystals
Figure BDA0002879742070000052
Figure BDA0002879742070000061
All the oxitinib-adipic acid crystal samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns.
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3 +; movable partState temperature section: 30-300 ℃; heating rate: 10 ℃/min; segment gas N2(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.
The Differential Scanning Calorimetry (DSC) result of the Oxcetin-adipic acid crystal prepared by the method is shown in figure 2, and only one endothermic peak in the Differential Scanning Calorimetry (DSC) is 145.33 ℃, which is the melting point of the Oxcetin-adipic acid crystal; the thermogravimetric analysis (TGA) of the crystal has only one weight loss step, which indicates that the oxitinib-adipic acid crystal has no solvent and has stable structure. The oxitinib-adipic acid crystals present a DSC/TGA profile as shown in figure 2.
Oxitinib-3, 5-dihydroxybenzoic acid ethanol hydrosolvent
X-ray crystal data were collected on a jtaab Synergy model instrument, japan, testing temperature 293(2) K, irradiating with CuKa, collecting data in an omega scan fashion and Lp correction. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The crystallographic data obtained by testing and analyzing the oxicetin-3, 5-dihydroxy benzoic acid ethanol water solvate prepared by the invention is (table 3), wherein the crystallographic parameters are as follows: monoclinic system, chiral space group P21C(ii) a The unit cell parameters are:
Figure BDA0002879742070000062
Figure BDA0002879742070000063
α is 90.00 °, β is 115.9728(11 °), γ is 90.00 °, unit cell volume
Figure BDA0002879742070000064
The molecular formula is: c37H47N7O8The molecular weight is: 717.81. the structure analysis chart of the oxicetinic-3, 5-dihydroxy benzoic acid ethanol hydrosolvent of the invention shows that one molecule of ethanol and one molecule of water exist in the crystal, and the structure analysis chart is specifically shown in figure 8. The invention relates to anThe hydrogen bond diagram stacking diagram of the ethanol hydrosolvent of cetin-3, 5-dihydroxybenzoic acid is shown in FIG. 7.
TABLE 3 Main crystallographic data of oxicetini-3, 5-dihydroxybenzoic acid ethanol solvate
Figure BDA0002879742070000071
The invention relates to an X-ray powder diffraction test instrument and test conditions in an oxicetini-3, 5-dihydroxy benzoic acid ethanol hydrosolvent test, which are as follows: PANALYTIC EMPyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction path: PIXCEL, voltage 45KV, current 40mA, divergence slit 1/4 degrees, anti-divergence slit 1 degree, cable-stayed slit 0.04rad degree, counting time of each step 0.5s, and scanning range 3-50 degrees.
According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in detail in FIG. 5 and Table 4.
TABLE 4 principal PXRD peaks of oxicetini-3, 5-dihydroxybenzoic acid ethanol hydrosolvent
Figure BDA0002879742070000072
Figure BDA0002879742070000081
All samples of oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate prepared in the examples have the same crystallographic parameters and X-ray powder diffraction pattern.
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3 +; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; segment gas N2(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.
The results of a Differential Scanning Calorimetry (DSC) curve of the oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate prepared by the method are shown in figure 6, wherein the starting point of one endothermic peak of three endothermic peaks in the Differential Scanning Calorimetry (DSC) curve is 63.71 ℃, the starting point of the second endothermic peak is 153.04 ℃, and the starting point of the third endothermic peak is 213.63 ℃, which respectively correspond to the melting point of the hydrosolvent absorption peak, the ethanol absorption peak and the oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate; the thermogravimetric analysis (TGA) only has three weight loss steps, which shows that the oxitinib-3, 5-dihydroxy-benzoic acid ethanol water solvate has two different solvents and has stable structure. The oxitinib-3, 5-dihydroxybenzoic acid ethanol hydrosolvent has a DSC/TGA spectrum as shown in figure 6.
Compared with the prior art, the method for preparing the oxitinib-adipic acid crystal and the oxitinib-3, 5-dihydroxy-benzoic acid ethanol water solvate is simple and convenient to operate, the prepared crystal is high in purity, the AZD9291 crystalline solid oxitinib-adipic acid crystal and the oxitinib-3, 5-dihydroxy-benzoic acid ethanol water solvate provided by the invention have better chemical stability and better solubility, and a better crystal form is provided for exerting the effect of oxitinib in treating cancers.
Drawings
Figure 1X-ray powder diffraction pattern of oxitinib-adipic acid.
FIG. 2 is a Differential Scanning Calorimetry (DSC) curve of Oxitinib-adipic acid.
FIG. 3 is a diagram showing the stacking of Oxcininib-adipic acid.
Figure 4 ORTEP of axitinib-adipic acid.
FIG. 5 is an X-ray powder diffraction pattern of oxitinib-3, 5-dihydroxybenzoic acid ethanol hydrosolvent.
FIG. 6 is a Differential Scanning Calorimetry (DSC) chart of an ethanol hydrosolvent of oxitinib-3, 5-dihydroxybenzoic acid.
FIG. 7 shows a schematic diagram of a stack of ethanol hydrosolvent of oxitinib-3, 5-dihydroxybenzoic acid.
FIG. 8 is an ORTEP diagram of an ethanol hydrosolvent of oxitinib-3, 5-dihydroxybenzoic acid.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1 Oxitinib adipic acid Crystal
Adding 1.7g of oxitinib and 0.5g of adipic acid into 110ml of ethanol, heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 0.5 hour, slowly cooling to 5-10 ℃, standing at a controlled temperature for crystallization for 30 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain the oxitinib-adipic acid eutectic, wherein the yield is 92.68%, and the purity is 99.95%.
Example 2 Oxitinib adipic acid Crystal
Adding 1.7g of oxitinib and 0.45g of adipic acid into 85ml of ethanol, heating to 50 ℃, stirring for dissolving, carrying out reflux reaction for 0.5 hour, slowly cooling to 5-10 ℃, standing at a controlled temperature for crystallization for 36 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain the oxitinib-adipic acid eutectic, wherein the yield is 91.56%, and the purity is 99.95%.
Example 3 Oxitinib adipic acid Crystal
Adding 1.7g of oxitinib and 0.55g of adipic acid into 170ml of ethanol, heating to 40 ℃, stirring for dissolving, carrying out reflux reaction for 0.5 hour, slowly cooling to 5-10 ℃, standing at a controlled temperature for crystallization for 30 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 50 ℃ for 12 hours to obtain the oxitinib-adipic acid eutectic, wherein the yield is 92.28%, and the purity is 99.94%.
Example 4 Oxitinib adipic acid Crystal
Adding 1.7g of oxitinib and 0.5g of adipic acid into 110ml of acetone, heating to 40 ℃, stirring for dissolving, carrying out reflux reaction for 0.5 hour, slowly cooling to 5-10 ℃, standing at a controlled temperature for crystallization for 24 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain the oxitinib-adipic acid eutectic, wherein the yield is 91.26%, and the purity is 99.94%.
Example 5 Oxisitinib-3, 5-Dihydroxybenzoic acid ethanol hydrosolvent
Adding 666.8mg of oxitinib and 205.7mg of 3, 5-dihydroxybenzoic acid into a mixed solution of 54ml of ethanol and 13ml of purified water, heating to 50 ℃, stirring for dissolving, carrying out reflux reaction for 1 hour, slowly cooling to 5 ℃, standing at a controlled temperature for crystallization for 30 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 60 ℃ for 8 hours to obtain the oxitinib-3, 5-dihydroxybenzoic acid ethanol solvate, wherein the yield is 90.56% and the purity is 99.96%.
Example 6 Oxisitinib-3, 5-Dihydroxybenzoic acid ethanol hydrosolvent
Adding 666.8mg of oxitinib and 226.27mg of 3, 5-dihydroxybenzoic acid into a mixed solution of 66ml of ethanol and 16ml of purified water, heating to 40 ℃, stirring for dissolving, carrying out reflux reaction for 1 hour, slowly cooling to 10 ℃, standing at a controlled temperature for crystallization for 36 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 60 ℃ for 10 hours to obtain an oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate, wherein the yield is 89.78% and the purity is 99.95%.
Example 7 Oxisitinib-3, 5-Dihydroxybenzoic acid ethanol hydrosolvent
Adding 666.8mg of oxitinib and 185.1mg of 3, 5-dihydroxybenzoic acid into 38 ml of ethanol and 7ml of purified water, heating to 60 ℃, stirring for dissolving, performing reflux reaction for 1 hour, slowly cooling to 0 ℃, standing at a controlled temperature for crystallization for 24 hours, filtering, washing a filter cake with ethanol, and performing vacuum drying at 60 ℃ for 10 hours to obtain the oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate, wherein the yield is 89.86% and the purity is 99.96%.
Example 8 Oxisitinib-3, 5-Dihydroxybenzoic acid ethanol hydrosolvent
Adding 666.8mg of oxitinib and 205.7mg of 3, 5-dihydroxybenzoic acid into 57ml of ethanol and 10ml of purified water, heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 1 hour, slowly cooling to 15 ℃, standing at a controlled temperature for crystallization for 48 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 60 ℃ for 12 hours to obtain the oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate, wherein the yield is 87.56% and the purity is 99.94%.
Stability test
The specific stability test method is carried out according to the guidance method of stability investigation in the fourth part of the Chinese pharmacopoeia 2015 edition, the purity detection is carried out by an HPLC method, and the specific detection results are shown in Table 5.
TABLE 5 stability test results under light, high temperature and high humidity conditions
Figure BDA0002879742070000101
Figure BDA0002879742070000111
The results in the table show that the novel AZD9291 crystalline solid oxitinib-adipic acid crystal and the oxitinib-3, 5-dihydroxy-benzoic acid ethanol water solvate prepared by the method have good stability without significant change in purity under strong light, high temperature or high humidity environments.
Solubility test
The conventional method comprises the following steps: respectively measuring 10ml of medium (water, 0.1mol/LHCl solution and phosphate buffer solution with pH of 6.8) into a penicillin bottle, adding excessive samples to be detected, sealing the penicillin bottle, placing the penicillin bottle in a constant-temperature water bath at 25 ℃, stirring for 1 hour, filtering through a 0.45-micron filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 210nm, and the solubility was calculated by measuring the absorbance of a standard control.
TABLE 6 solubility in different media (mg/ml)
Figure BDA0002879742070000112
The results in the table show that the solubility of the oxitinib-adipic acid crystal and the oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate prepared by the method is improved compared with that of the conventional crystal form, the oxitinib-adipic acid crystal has relatively high solubility, and the oxitinib-adipic acid crystal shows relatively good solubility in water or acidic environment, so that a new crystal form is provided for solving the problem of solubility of oxitinib.

Claims (10)

  1. The AZD9291 crystalline solid is characterized by specifically comprising an oxitinib-adipic acid crystal and an oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate.
  2. 2. The crystalline solid according to claim 1, wherein the oxitinib-adipic acid crystal has an X-ray diffraction pattern, expressed in 2 Θ using Cu-ka radiation, having characteristic peaks at least at 6.60 ± 0.2 °, 15.65 ± 0.2 °, 19.73 ± 0.2 °, 19.80 ± 0.2 °, 20.41 ± 0.2 °, 21.01 ± 0.2 °, 21.32 ± 0.2 °, 24.86 ± 0.2 °, 26.18 ± 0.2 °.
  3. 3. The crystalline solid of claim 1, wherein the oxitinib-adipic acid crystal has an X-ray diffraction pattern, expressed in 2 Θ using Cu-ka radiation, characterized by peaks at least at 6.60 ± 0.2 °, 8.64 ± 0.2 °, 10.15 ± 0.2 °, 10.65 ± 0.2 °, 11.29 ± 0.2 °, 13.60 ± 0.2 °, 14.13 ± 0.2 °, 15.65 ± 0.2 °, 19.02 ± 0.2 °, 19.73 ± 0.2 °, 19.80 ± 0.2 °, 20.41 ± 0.2 °, 21.01 ± 0.2 °, 21.32 ± 0.2 °, 22.55 ± 0.2 °, 23.64 ± 0.2 °, 23.98 ± 0.2 °, 24.86 ± 0.2 °, 26.18 ± 0.2 °, 28.37 ± 0.2 °.
  4. 4. The crystalline solid of claim 1, wherein the oxitinib-adipic acid crystals, using Cu-ka radiation, have characteristic peaks having an X-ray powder diffraction pattern or data as shown in figure 1 or table 2.
  5. 5. The crystalline solid of claim 1, wherein the oxitinib-3, 5-dihydroxybenzoic acid ethanol aqueous solvate has an X-ray diffraction pattern expressed in terms of 2 Θ using Cu-ka radiation having characteristic peaks at least at 6.00 ± 0.2 °, 8.52 ± 0.2 °, 11.85 ± 0.2 °, 16.45 ± 0.2 °, 19.75 ± 0.2 °, 23.66 ± 0.2 °.
  6. 6. The crystalline solid of claim 1, wherein the oxitinib-3, 5-dihydroxybenzoic acid ethanol aqueous solvate has an X-ray diffraction pattern, expressed in 2 Θ, using Cu-ka radiation having characteristic peaks at least at 6.00 ± 0.2 °, 8.52 ± 0.2 °, 11.85 ± 0.2 °, 12.32 ± 0.2 °, 13.14 ± 0.2 ° 13.45 ± 0.2 °, 13.78 ± 0.2 °, 16.45 ± 0.2 °, 17.18 ± 0.2 °, 18.40 ± 0.2 °, 19.75 ± 0.2 °, 20.42 ± 0.2 °, 22.12 ± 0.2 °, 23.66 ± 0.2 °.
  7. 7. The crystalline solid of claim 1, wherein the oxitinib-3, 5-dihydroxybenzoic acid ethanol aqueous solvate, using Cu-ka radiation, has characteristic peaks with an X-ray powder diffraction pattern or data as shown in figure 5 or table 4.
  8. 8. A process for preparing a crystalline solid according to any one of claims 2 to 4, wherein the crystalline oxitinib-adipic acid is prepared by:
    dissolving oxitinib and adipic acid in an organic solvent A, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain oxitinib-adipic acid crystals; wherein the organic solvent A is selected from one or a mixed solvent of at least two of acetone, methanol, ethanol and acetonitrile.
  9. 9. A process for preparing a crystalline solid according to any one of claims 5 to 7, wherein the oxitinib-3, 5-dihydroxybenzoic acid ethanolic water solvate is prepared by: dissolving oxitinib and 3, 5-dihydroxybenzoic acid in a mixed solvent, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain oxitinib-3, 5-dihydroxybenzoic acid ethanol water solvate; wherein the mixed solvent is a mixture of ethanol and purified water.
  10. 10. A pharmaceutical composition comprising the crystalline solid according to any one of claims 1 to 7 as an active ingredient, together with other pharmaceutically acceptable ingredients.
CN202011629177.XA 2020-12-31 2020-12-31 AZD9291 crystalline solid Pending CN114685455A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023098848A1 (en) * 2021-12-03 2023-06-08 湖南湘源美东医药科技有限公司 Osimertinib co-crystal, preparation method, and application as drug or in pharmaceutical formulation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023098848A1 (en) * 2021-12-03 2023-06-08 湖南湘源美东医药科技有限公司 Osimertinib co-crystal, preparation method, and application as drug or in pharmaceutical formulation

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