Quinazoline derivative salt crystal form, preparation method and application
View Patent ↗A quinazoline derivative (represented by the formula (I)) salt's crystal form, a preparation method and application are provided; specifically, the hydrochloride crystal form A, B, C, D, F, H, I, Sulphate crystal form A, Maleate crystal form A, Succinate crystal form A, Adipate crystal form A, Glycolate crystal form A, Malate crystal form A, Fumarate Salt crystal form A, besylate crystal form A, B, C, benzoate crystal form A, hippurate crystal form A and oxalate crystal form A of the quinazoline derivative represented by formula (I). The salt crystal form provided by the present invention has good stability, which can be used in the treatment of non-small cell lung cancer brain metastasis, meningeal metastasis, primary brain cancer or glioma, etc., and has good bioavailability, which is of great significance for further research on the efficacy of such solid drugs.
1. A crystal form of a hydrochloride salt of a quinazoline derivative represented by formula (I), wherein the crystal form is a first crystal form, a second crystal form, a third crystal form, a fourth crystal form, a fifth crystal form, a sixth crystal form or a seventh crystal form;
wherein, an XRPD pattern of the first crystal form has main characteristic peaks at the following 2θ: 6.5, 13.1, 9.4; has secondary characteristic peaks at the following 2θ: 7.3, 18.2, 20.0; and has characteristic peaks again at the following 2θ: 27.5, 26.6, 21.6;
an XRPD pattern of the second crystal form has main characteristic peaks at the following 2θ: 6.5, 17.7, 19.8; and has secondary characteristic peaks at the following 2θ: 7.3, 8.2, 10.5, 13.2;
an XRPD pattern of the third crystal form has main characteristic peaks at the following 2θ: 7.2, 17.6, 22.0; has secondary characteristic peaks at the following 2θ: 14.0, 13.6, 12.8; and has characteristic peaks again at the following 2θ: 24.6, 26.2, 27.3;
an XRPD pattern of the fourth crystal form has main characteristic peaks at the following 2θ: 13.4, 7.1, 25.4; has secondary characteristic peaks at the following 2θ: 6.7, 18.0, 19.8; and has characteristic peaks again at the following 2θ: 17.2, 27.3, 24.7;
an XRPD pattern of the fifth crystal form has main characteristic peaks at the following 2θ: 6.8, 20.5, 13.6; and has secondary characteristic peaks at the following 2θ: 14.8, 14.3, 17.9, 11.9;
an XRPD pattern of the sixth crystal form has main characteristic peaks at the following 2θ: 7.3, 18.0, 14.1; has secondary characteristic peaks at the following 2θ: 6.4, 13.2, 15.8; and has characteristic peaks again at the following 2θ: 16.8, 14.5, 20.3;
an XRPD pattern of the seventh crystal form has main characteristic peaks at the following 2θ: 18.6, 7.4, 6.9; has secondary characteristic peaks at the following 2θ: 13.2, 25.1, 12.3; and has characteristic peaks again at the following 2θ: 14.7, 28.1, 14.2;
an error range of a 2θ value is ±0.2.
2. A method for preparing the crystal form according to claim 1 , wherein:
a preparation method of the first crystal form comprises the following steps: adding 0.8 to 1.2 equivalents of a first organic solvent and hydrochloric acid to the quinazoline derivative represented by the formula (I), stirring at 22-28 degrees Celsius, and centrifugating to separate a lower solid to obtain the first crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the first organic solvent; the first organic solvent is methanol;
a preparation method of the second crystal form comprises the following steps: adding the quinazoline derivative represented by the formula (I) to a second organic solvent to obtain a suspension, and adding 0.8 to 1.2 equivalents of hydrochloric acid to the suspension, stirring at 22-28 degrees Celsius, and centrifugating to separate a lower layer of wet solid to obtain the second crystal form;
wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the second organic solvent; the second organic solvent is acetonitrile, ethyl acetate, or a tetrahydrofuran/water solution having a volume ratio of (15-20):1,
a preparation method of the third crystal form comprises the following steps: adding the quinazoline derivative represented by the formula (I) to a third organic solvent and adding 2 to 2.5 equivalents of hydrochloric acid, stirring at 22-28 degrees Celsius, centrifugating to separate a lower layer of wet solid to obtain the third crystal form of dihydrochloride; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the third organic solvent; the third organic solvent is acetone;
a preparation method of the fourth crystal form comprises the following steps: heating a sample of the quinazoline derivative represented by the formula (I) in the third crystal form of hydrochloride to 120-160 degrees Celsius and then cooling to 22-28 degrees Celsius to obtain the fourth crystal form of dihydrochloride salt;
a preparation method of the fifth crystal form comprises the following steps: adding the quinazoline derivative represented by the formula (I) in the second crystal form of hydrochloride to an alcoholic organic solvent and an ester organic solvent, and conducting a gas-liquid diffusion at 22-28 degrees Celsius until a solid precipitates to obtain the fifth crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) in the second crystal form of hydrochloride is added to each milliliter of the alcoholic organic solvent and the ester organic solvent; the alcoholic organic solvent is methanol, and the ester organic solvent is isopropyl acetate;
a preparation method of the sixth crystal form comprises the following steps: adding a fourth organic solvent to the quinazoline derivative represented by the formula (I) in the second crystal form of hydrochloride, filtering and volatilizing at 22-28 degrees Celsius to obtain the sixth crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) in the second crystal form of hydrochloride is added to each milliliter of the fourth organic solvent; the fourth organic solvent is ethanol;
a preparation method of the seventh crystal form comprises the following steps: heating a sample of the quinazoline derivative represented by the formula (I) in the sixth crystal form of hydrochloride to 120-130 degrees Celsius and then cooling to 22-28 degrees Celsius.
3. A crystal form of a fumarate of a quinazoline derivative represented by formula (I),
an XRPD pattern of the crystal form has main characteristic peaks at the following 2θ: 6.5, 17.8, 9.4; has secondary characteristic peaks at the following 2θ: 13.4, 7.5, 19.7; and has characteristic peaks again at the following 2θ: 14.6, 18.5; an error range of a 2θ value is ±0.2.
4. A method for preparing the crystal form according to claim 3 , wherein the method comprises: adding the quinazoline derivative of the formula (I) and 0.4-0.6 equivalent of fumaric acid to an organic solvent, stirring at 22-28 degrees Celsius, centrifugating to collect a solid to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the organic solvent.
5. A crystal form of a succinate of an quinazoline derivative represented by formula (I),
an XRPD pattern of the crystal form has main characteristic peaks at the following 2θ: 6.6, 17.8, 7.5; has secondary characteristic peaks at the following 2θ: 9.4, 20.3, 18.5; and has characteristic peaks again at the following 2θ: 21.0, 14.5, 19.5; an error range of a 2θ value is ±0.2.
6. A method for preparing the crystal form according to claim 5 , wherein the method comprises: adding an organic solvent to the quinazoline derivative of the formula (I) and 0.8-1.2 equivalents of succinic acid, then stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the organic solvent.
7. A crystal form of a maleate salt of a quinazoline derivative represented by formula (I),
an XRPD pattern of the crystal form has main characteristic peaks at the following 2θ: 6.3, 18.8, 16.7; and has secondary characteristic peaks at the following 2θ: 25.2, 21.2; wherein an error range of a 2θ value is ±0.2.
8. A method for preparing the crystal form according to claim 7 , wherein the method comprises: adding the quinazoline derivative of the formula (I) and 0.8-1.2 equivalents of maleic acid to an organic solvent, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the organic solvent.
9. A crystal form of a glycolate of a quinazoline derivative represented by formula (I),
an XRPD pattern of the crystal form has main characteristic peaks at the following 2θ: 6.6, 7.4, 17.9; and has secondary characteristic peaks at the following 2θ: 13.3; wherein an error range of a 2θ value is ±0.2.
10. A method for preparing the crystal form according to claim 9 , wherein the method comprises: after adding the quinazoline derivative represented by the formula (I) and 0.8-1.2 equivalents of glycolic acid to an organic solvent, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the organic solvent.
11. A crystal form of a sulfate salt of the quinazoline derivative represented by formula (I),
an XRPD pattern of the crystal form has main characteristic peaks at the following 2θ: 7.3, 18.2, 15.0; wherein an error range of a 2θ value is ±0.2.
12. A method for preparing the crystal form according to claim 11 , wherein the method comprises: adding a sample of the quinazoline derivative represented by the formula (I) to an organic solvent and 0.8-1.2 equivalents of sulfuric acid aqueous solution, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the organic solvent.
13. A crystal form of a malate salt of a quinazoline derivative represented by formula (I),
an XRPD pattern of the crystal form has main characteristic peaks at the following 2θ: 6.5, 18.8, 19.9; and has secondary characteristic peaks at the following 2θ: 7.5, 8.4, 9.2; wherein an error range of a 2θ value is ±0.2.
14. A method for preparing the crystal form according to claim 13 , wherein the method comprises: adding a sample of the quinazoline derivative represented by the formula (I) to an organic solvent and 0.8-1.2 equivalents of malic acid, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the organic solvent.
15. A crystal form of a benzenesulfonate of a quinazoline derivative represented by formula (I), wherein the crystal form is a first crystal form, a second crystal form or a third crystal form;
wherein, an XRPD pattern of the first crystal form has main characteristic peaks at the following 2θ: 6.6, 14.0, 15.3; has secondary characteristic peaks at the following 2θ: 7.1, 5.5, 19.7; and has characteristic peaks again at the following 2θ: 17.8, 16.9, 21.0;
an XRPD pattern of the second crystal form has main characteristic peaks at the following 2θ: 8.5, 14.5, 23.4; and has secondary characteristic peaks at the following 2θ: 18.3, 19.7;
an XRPD pattern of the third crystal form has main characteristic peaks at the following 2θ: 14.0, 14.7, 7.7; has secondary characteristic peaks at the following 2θ: 8.3, 21.2, 19.4; and has characteristic peaks again at the following 2θ: 27.5, 24.7;
an error range of a 2θ value is ±0.2.
16. A method for preparing the crystal form according to claim 15 , wherein a preparation method of the first crystal form comprises: adding a sample of the quinazoline derivative represented by the formula (I) to a first organic solvent and 0.8-1.2 equivalents of benzenesulfonic acid, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the first crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the first organic solvent; the first organic solvent is methanol;
a preparation method of the second crystal form comprises: adding a sample of the quinazoline derivative represented by the formula (I) to a second organic solvent and 0.8-1.2 equivalents of benzenesulfonic acid, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the second crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the second organic solvent; the second organic solvent is acetonitrile;
a preparation method of the third crystal form comprises: adding a sample of the quinazoline derivative represented by the formula (I) to a third organic solvent and 0.8-1.2 equivalents of benzenesulfonic acid, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the third crystal form; wherein 10 to 200 mg of the quinazoline derivative of the formula (I) is added to each milliliter of the third organic solvent; the third organic solvent is a mixed solvent of tetrahydrofuran and water at a volume ratio of (15-20):1.
17. A crystal form of a benzoate of a quinazoline derivative represented by formula (I),
an XRPD pattern of the crystal form has main characteristic peaks at the following 2θ: 7.3, 6.3, 16.8; and has secondary characteristic peaks at the following 2θ: 13.5, 18.7, 27.0; wherein an error range of a 2θ value is ±0.2.
18. A method for preparing the crystal form according to claim 17 , wherein the method comprises: adding a sample of the quinazoline derivative represented by the formula (I) to an organic solvent and 0.8-1.2 equivalents of benzoic acid, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the organic solvent.
19. A crystal form of a hippurate of a quinazoline derivative represented by formula (I),
an XRPD pattern of the crystal form has main characteristic peaks at the following 2θ: 5.6, 6.9, 20.0; has secondary characteristic peaks at the following 2θ: 16.0, 7.7, 13.7; and has characteristic peaks again at the following 2θ: 24.3, 26.4; an error range of a 2θ value is ±0.2.
20. A method for preparing the crystal form according to claim 19 , wherein the method comprises: adding a sample of the quinazoline derivative represented by the formula (I) to an organic solvent and 0.8-1.2 equivalents of hippuric acid, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the organic solvent.
21. A crystal form of an oxalate of a quinazoline derivative represented by formula (I),
an XRPD pattern of the crystal form has main characteristic peaks at the following 2θ: 6.4, 9.1, 17.5; has secondary characteristic peaks at the following 2θ: 12.9, 14.5, 26.4; and has characteristic peaks again at the following 2θ: 19.4, 18.3, 15.9; an error range of a 2θ value is ±0.2.
22. A method for preparing the crystal form according to claim 21 , wherein the method comprises: adding a sample of the quinazoline derivative represented by the formula (I) to an organic solvent and 0.8-1.2 equivalents of oxalic acid, stirring at 22-28 degrees Celsius, and centrifugating to collect a solid to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added to each milliliter of the organic solvent.
23. A pharmaceutical composition, wherein the pharmaceutical composition comprises the crystal form according to claim 1 , and pharmaceutically acceptable excipients or auxiliary components.
24. A method for treating or preventing diseases mediated by an epidermal growth factor receptor (EGFR) protein, comprising the step of administering to a subject the crystal form according to claim 1 or a pharmaceutical composition, wherein the pharmaceutical composition comprises the crystal form according to claim 1 and pharmaceutically acceptable excipients or auxiliary components.
25. The method according to claim 24 , wherein the diseases mediated by the epidermal growth factor receptor (EGFR) protein are caused by EGFRVIII activation mutations.
26. The method according to claim 24 , wherein the diseases mediated by the epidermal growth factor receptor (EGFR) protein are caused by EGFR Del19 and/or EGFR L858R activating mutations.
27. The method according to claim 24 , wherein the diseases mediated by an epidermal growth factor receptor (EGFR) protein are non-small cell lung cancer brain metastasis, meningeal metastasis, head and neck squamous cell carcinoma, squamous cell carcinoma, brain stem tumor, primary brain cancer or glioma.