NZ743659A - Crystalline forms of thienopyrimidine compound - Google Patents

Abstract

The present invention relates to crystalline forms of N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide, and pharmaceutical compositions containing the same. The crystalline forms can be easily used for the preparation of a pharmaceutical composition containing the same as an active ingredient. taining the same as an active ingredient.

Description

Description Title of Invention: CRYSTALLINE FORMS OF THIENOPY- RIMIDINE COMPOUND Technical Field The present invention relates to crystalline forms of a thienopyrimidine compound and pharmaceutical compositions containing the same. More specifically, the present invention relates to crystalline forms of N — (3-(2—(4—(4—methylpiperazin—1—yl)phenylamino)thieno[3,Z—d]pyrimidin—4—yloxy)phenyl )acrylamide, and ceutical itions containing the same.

Background Art The compound of Formula 1 below, whose compound name is N — (3-(2—(4—(4—methylpiperazin—l—yl)phenylamino)thieno[3,2—d]pyrimidin—4—yloxy)phenyl amide {INN2 2—propenamide, N — [3— [[2—[[4—(4—methyl— razinyl)phenyl] amino]thieno[3,2—d]pyrimidin—4—yl]oxy]phe nyl] }, is disclosed in PCT application . The compound has a selective inhibitory ty for a mutant epidermal growth factor receptor tyrosine kinase.

[Formula 1] \N/fi COMM K/N H N” S WI / Additionally, the above reference discloses the method of preparing the compound of Formula 1.

However, the nd of Formula 1 prepared in the above cited references was prepared as an amorphous solid, which is a form generally less suitable for a large— scale production of pharmaceutical drugs. For example, the thus-prepared form of the compound of Formula 1 was insufficient in the aspects of stability and non— hygroscopicity for pharmaceutical formulations. ingly, there is a need for the development of the compound of Formula 1 in crystalline forms which can fully comply with the strict ements and details thereof regarding pharmaceutical solid forms and formulations. onally, the compound of Formula 1 is preferably in a form that affords facile handling of the product upon sis such as ease of filtration and drying, and also for the e of economy, preferably enables long—term stable maintenance of a crystalline form t requiring particular storage conditions.

Under these circumstances, the present ors have made intensive efforts to develop a novel crystalline form of the compound of Formula 1, and have discovered that a particular crystalline form can provide excellent overall physicochemical properties such as stability, non-hygroscopicity, etc., and thus it can be easily used for the preparation of a pharmaceutical composition containing the same as an active in— nt, thereby completing the present invention.

Disclosure of Invention Technical Problem An object of the present invention is to provide a crystalline form of the compound of Formula 1, and a pharmaceutical ition containing the same.

Solution to Problem In order to achieve the above object, in one aspect of the t invention, there are provided crystalline forms of the compound of Formula 1 as shown below: [Formula 1] OQNMo \N’fi K/N H N” S WI / Specific examples of the above crystalline forms are as shown below: A crystalline form of a compound of Formula 1 having an X—ray powder ction (XRPD) pattern comprising peaks at diffraction angles of 26 = 8.6% 0.20, 16.0% 0.20 and 17.2% 0.20 when irradiated with a Cu—Kor light source. This crystalline form may further comprise diffraction peaks at 26 = 9.4% 02", 10.3% 0.20, 13.7% 0.20, 17.9% 0.20, 19.7% 02°, 22.1% 0.20, 23.6% 0.20, and 26.4% 0.20 when irradiated with a Cu- KOL light source; A crystalline form of a compound of a 1 having an X—ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles of 26 = 5.3% 02" and 16.2% 0.20 when irradiated with a Cu-KOt light source. This crystalline form may further comprise diffraction peaks at 26 = 20.7°i 0.20 when irradiated with a Cu—Ka light source; A crystalline form of a nd of a 1 having an X—ray powder diffraction (XRPD) pattern sing peaks at diffraction angles of 26 = 3.8% 02" and 11.6% 0.20 when irradiated with a Cu-Ka light source. This crystalline form may further comprise diffraction peaks at 26 = 980$ 02", l6.9°i 0.2°, and 19.8% 0.20 when irradiated with a Cu—Ka light source; and A crystalline form of a compound of Formula 1 having an X-ray powder diffraction (XRPD) pattern sing peaks at ction angles of 26 = 11. l°i 02°, 20.3% 0.20 and 20.8% 02" when irradiated with a Cu-Ka light source. This lline form may further comprise diffraction peaks at 26 = 14.601L 0.20, 15.5% 0.20, 21.0°i 0.20, and 22.2°i 02" when irradiated with a Cu—Ka light source.

In another , each crystalline form of the compound of Formula 1 as described herein is in substantially pure form.

The term "substantially pure" as used herein means at least 95% pure, preferably 99% pure, where 95% pure means not more than 5%, and 99% pure means not more than 1%, of any other form of the compound of Formula 1 being t (other crystalline form, amorphous form, etc).

In r aspect of the present invention, there is provided a pharmaceutical com— position containing any one selected from the above crystalline forms and at least one ceutically acceptable carrier and/or diluent.

The pharmaceutical composition can be used for the treatment of cancer induced by epidermal growth factor receptor tyrosine kinase or a mutant thereof.

Advantageous Effects of ion The crystalline forms of the nd of Formula 1 according to the present invention have excellent overall physicochemical characteristics, and thus the crystalline forms can be easily used for the preparation of a pharmaceutical com— position containing the same as an active ingredient.

Brief Description of Drawings FIGS. la to 1d show X—ray powder diffraction (XRPD) patterns of crystalline forms of the compound of Formula 1 prepared in Examples 1 to 4 of the present invention.

FIG. le shows an X—ray powder diffraction (XRPD) pattern of an amorphous form of the compound of Formula 1 prepared in Comparative Example 1 of the present invention.

FIGS. 2a to 2d show the graphs of differential scanning calorimetry (DSC) of crystalline forms of the compound of Formula 1 prepared in Examples 1 to 3 of the present invention. shows the graph of differential scanning calorimetry (DSC) of an amorphous form of the compound of Formula 1 prepared in Comparative Example 1 of the present invention.

FIGS. 3a to 3d show the graphs of dynamic vapor sorption (DVS) of crystalline forms of the compound of Formula 1 prepared in Examples 1 to 3 of the present invention. shows the graph of dynamic vapor sorption (DVS) of an amorphous form of the compound of Formula 1 prepared in Comparative Example 1 of the present invention.

Mode for the ion Hereinafter, the present ion will be bed in more detail with reference to the ing Examples. However, these Examples are for illustrative es only, and the invention is not intended to be d by these Examples.

Unless otherwise defined, all terms ing technical and scientific terms used herein have the same meanings as commonly understood within the t by one of ordinary skill in the art to which the invention belongs. However, unless otherwise specified, the term described below will have the meaning indicated below over the entire specification: As used herein, the term " refers to being within 5% of a particular value or range, and more preferably within 1% to 2%. For example, "about 10%" refers to 9.5% to 10.5%, and preferably, 9.8% to 10.2%. For another example, "about 100°C" refers to 95°C to 105°C, and preferably, 98°C to 102°C.

Unless otherwise specified, it must be apparent to a skilled practitioner that the values of peaks from X—ray powder diffraction studies reported in this invention are as— sociated with experimental errors typically observable in this field. ically, a peak is interpreted as to be located within i0.5° of the value reported herein. More specifically, a peak is interpreted as to be located within i0.2° of the value reported Crystalline forms of the compound of Formula 1 The present invention provides a crystalline form of the compound of Formula 1 below, i.e., N-(3-(2-(4-(4-methylpiperazinyl)phenylamino)thieno[3,2-d ]pyrimidin—4—yloxy)phenyl)acrylamide: [Formula 1] \N/fi OQNMO K/N H IV] S The compound of Formula 1 above (free base) may be prepared according to the con— ventional procedure described in , which is hereby incorporated by reference in its entirety.

The compound of Formula 1 may be prepared in a crystalline or amorphous form or a mixture thereof, and preferably in a lline form because the crystalline form has excellent stability and non—hygroscopicity, and thus has a physicochemical property which facilitates its formulation.

According to the present invention, the compound of Formula 1 can be prepared in various crystalline forms, and each of the possible crystalline forms will be described in detail herein below.

In one embodiment of the present ion, provided are crystalline forms of the compound of Formula 1. In a particular embodiment of the present invention, these lline forms are anhydrous. In r particular embodiment, the crystalline forms are hydrates. In a further specific embodiment, this hydrate is a dihydrate. In yet another specific ment, the crystalline form is a rate.

In an exemplary embodiment, the t invention provides a crystalline dihydrate form (Form A) of the compound of Formula 1. Form A exhibits an XRPD pattern comprising peaks at 26 = 8.6Oi0.2°, 16.00i0.2O and 17.2°i0.2O when irradiated with a Cu-ch light . More specifically, the crystalline form has an XRPD pattern comprising peaks at diffraction angles of 26 = 8.6Oi0.2°, 9.4Oi0.2°, 0.2°, 13.7°i0.2°, 16.0°iO.2°, 17.2°i0.2°, 17.9°i0.2°, 19.7Oi0.2°, 22.1°i0.2°, 23.6°i0.2°, and 26.4"i0.2O when irradiated with a Cu—Kd light source. More specifically, the above crystalline form (Form A) of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles of 26 = 8.6Oi0.2°, .2°, 10.30i0.2°, 13.7°i0.2°, 0.2°, 17.2Oi0.2°, 17.9°i0.2°, 19.7Oi0.20, 22.1Oi0.2°, 22.3°i0.2°, 23.2Oi0.2°, 0.2°, 26.4Oi0.2°, 29.7Oi0.2°, and 35.30i0.2° when irradiated with a Cu—Kor light source. These peaks may be those having a relative intensity (MD) of about 20% or more.

The above crystalline form may have an endothermic peak which has a starting point at about 75°C and its lowest point at about 93°C, an exothermic peak which has a starting point at about 141°C and its highest point at about 149°C, and an endothermic peak which has a starting point at about 199°C and its lowest point at about 205°C, in a DSC (10°C/min).

The above crystalline form may have a melting point of about 203°C to 204°C.

The above crystalline form may have an tion amount of about 1.5% to 2.5% in the region with a ve humidity of 10% to 90%, in a DVS.

In another exemplary embodiment, the present invention provides a trihydrate crystalline form (Form B) of the compound of Formula 1. Form B exhibits an XRPD pattern comprising peaks at 26 = 5 2° and l6.2°i0.2° when irradiated with a Cu— KOL light source. More specifically, the crystalline form has an XRPD pattern comprising peaks at diffraction angles of 20 = 5.3°i0.2°, 16.2°i0.2°, and 20.7°i0.2° when irradiated with a Cu—Ka light source. More specifically, the above crystalline form (Form B) of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles of 20 = 5.3°i0.2°, l6.2°J_r0.2°, 20.7°i0.2°, 25.4°i0.2°, and 28.5°i0.2° when irradiated with a Cu—Kor light . These peaks may be those having a relative intensity (1/10) of about 7% or more.

The above lline form may have an ermic peak which has a ng point at about 74°C and its lowest point at about 95°C, an exothermic peak which has a starting point at about 136°C and its highest point at about 145°C, and an endothermic peak which has a starting point at about 195°C and its lowest point at about 203°C, in a DSC (10°C/min).

The above crystalline form may have a melting point of about 204°C to 205°C.

The above crystalline form may have an absorption amount of about 5% to 6% in the region with a relative humidity of 10% to 90%, in a DVS.

In still r exemplary embodiment, the present invention provides an ous lline form (Form C) of the compound of Formula 1. Form C exhibits an XRPD pattern comprising peaks at 20 = 3.8°iO.2° and ll.6°i0.2° when irradiated with a Cu— Koz light source. More specifically, the crystalline form has an XRPD pattern comprising peaks at diffraction angles of 20 = 3.8°i0.2°, 9.8°i0.2°, ll.6°i0.2°, 16.9°i0.2°, and 19.8°i0.2° when irradiated with a Cu—Ka light source. More specifically, the above lline form (Form C) of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles of 20 = 3.8°i-0.2°, 9.8°i0.2°, ll.6°i0.2°, l6.9°i0.2°, 19.8°i0.2°, 20.2°i0.2°, 2l.9°i0.2°, 24.3°i0.2°, and 247° when irradiated with a Cu—Ka light . These peaks may be those having a relative intensity (1/10) of about 7% or more.

The above crystalline form may have an endothermic peak which has a starting point at about 194°C and its highest point at about 207°C in a °C/min).

The above crystalline form may have a melting point of about 204°C to 205°C.

The above lline form may have an tion amount of 0.9% to 1.1% in the region with a relative ty of 10% to 90%, in a DVS.

In still another exemplary embodiment, the present invention also provides an anhydrous crystalline form (Form D) of the compound of Formula 1. Form D exhibits an XRPD pattern comprising peaks at 20 = 11.1°iO.2°, 20.3°i0.2° and 20.8°i0.2° when irradiated with a Cu—Kd light source. More specifically, the crystalline form has an XRPD pattern comprising peaks at diffraction angles of 20 = ll.1°i0.2°, l4.6°i0.2°, 15.5°i0.2°, 20.3°i0.2°, 20.8°i0.2°, 21.0°i0.2°, and 22.2°i0.2° when irradiated with a Cu—Ka light source. More specifically, the above crystalline form (Form D) of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles of 20 = 8.8°i—0.2°, 10.5°iO.2°, ll.1°i0.2°, 14.6°i—0.2°, 15.5°i0.2°, l7.5°i0.2°, l9.2°i0.2°, l9.4°i0.2°, 20.3°i0.2°, 20.8°i0.2°, 21.0°i0.2°, 22.2°i0.2°, 23.1°i0.2°, 23.4°J_r0.2°, 25.0°i0.2°, and 25.2°i0.2° when irradiated with a Cu-Ka light . These peaks may be those having a relative intensity (MD) of about 10% or more.

The above crystalline form may have an ermic peak which has a starting point at about 204°C and its highest point at about 208°C in a DSC (10°C/min).

The above crystalline form may have a melting point of about 204°C to 205°C.

The above crystalline form may have an tion amount of 0.2% to 0.5% in the region with a relative humidity of 10% to 90%, in a DVS.

Medical use and pharmaceutical composition As disclosed in , the compound of Formula 1 has been shown to be useful for the selective and effective inhibitory activity against the growth of cancer cells and induced by a mutation in epidermal growth factor or (EGFR) tyrosine kinase or a mutant thereof, and drug resistance thereof.

In one aspect the ion further provides a crystalline form of the compound of Formula 1 as described herein for use in the treatment of a cancer harboring one or more EGFR mutation.

In a further aspect the ion provides a method for the treatment of cancer comprising administering to a patient in need thereof a therapeutically effective amount of a crystalline form of the nd of Formula 1 as described herein, wherein the cancer to be d is a cancer ing one or more EGFR mutation.

In a further aspect the cancer to be treated is a cancer harboring one or more EGFR mutations wherein at least one EGFR mutation is selected from De119 ion in exon 19), L858R and T790M.

In a further aspect the cancer to be treated is a cancer harboring a Dell9 EGFR mutation.

In a r aspect the cancer to be treated is a cancer harboring the EGFR on L858R.

In a further aspect the cancer to be treated is a cancer harboring the EGFR mutation T790M.

In a further aspect the cancer to be treated is a cancer harboring at least two EGFR mutations selected from the group consisting of De119/T790M and L858RfT790M.

In this aspect, the crystalline forms of the compound of Formula 1 may be used for the preparation of a pharmaceutical composition for preventing or treating cancers or tumors d by epidermal growth factor receptor tyrosine kinase or a mutant f. The pharmaceutical composition may be used to treat the same cancers ing EGFR mutation as described for the crystalline forms of the compound of Formula 1 hereinbefore.

Accordingly, the present invention provides a pharmaceutical composition containing a crystalline form of the compound of Formula 1 and at least one pharma— ceutically acceptable r or diluent. The pharmaceutical composition may be used for the treatment of cancers or tumors d by epidermal growth factor receptor tyrosine kinase or a mutant f.

The administration dose of the crystalline forms of the compound of Formula 1 or a pharmaceutical composition containing the same may vary depending on the subject to be treated, severity of illness or health state of the subject, administration rate, physician's decision, etc, but may be conventionally administered to a human subject having a body weight of e.g. 70 kg Via an oral or parenteral administration route in an amount of 10 mg to 2,000 mg as an active ingredient based on the nd of a 1, preferably in an amount of 50 mg to 1,000 mg, l to 4 times daily or on an on/off schedule. In some cases, it may be more appropriate to administer a lower dosage than that mentioned above, a higher dosage than the above may be ad— ministered if it does not cause harmful side effects, and in the case when a significantly larger dosage is to be administered, the administration may be performed daily by several divided doses with a lesser dosage per administration.

The pharmaceutical composition according to the present invention may be prepared in various ations for oral administration according to the conventional methods, e.g., tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc., or for parenteral stration, e.g., intramuscular, intravenous, or subcutaneous adminis— trations.

The pharmaceutical composition may contain any tional non—toxic, pharma— ally acceptable carrier, diluents, adjuvant, excipient, or vehicle.

When the pharmaceutical composition according to the present invention is prepared as a formulation for oral administration, the carrier to be used may include, e. g., cellulose, calcium silicate, corn starch, e, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, ts, etc. Additionally, when the pharmaceutical com— position is ed as a formulation for oral administration, the diluents to be used may include lactose, mannitol, saccharide, microcrystalline cellulose, cellulose derivative, corn , etc. When the ceutical composition according to the present invention is prepared as a formulation for injections, the carrier to be used may include, e.g., water, saline, an aqueous sugar—like solution, alcohols, ethers (e. g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifying agents, etc.

Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these Examples are for illustrative purposes only, and the invention is not intended to be limited by these Examples.

Analysis Apparatus and Method of Measurement 1. X-ray Powder Diffraction (XRPD) X—ray powder diffraction (XRPD) es of samples were performed in the range from 3° 20 to 40° 20 using a D8 e r ASX, Germany) analyzer. When the amount of a given sample was less than 100 mg, about 5 mg to 10 mg of the sample was gently compressed on a glass slide which was fit into a sample holder. When the amount of a given sample was greater than 100 mg, about 100 mg of the sample was gently compressed in a plastic sample holder so that the sample surface became flat and positioned immediately on top of the sample holder level.

F—lr—lf—lr—lf—lr—lf—lr—lF—lr—lF—lF—l OOOOOOOOOOOOOOOO\]\1\]\] flow-QWNt—‘OOOONQ P—! 00 00 |—l|—l|—l|—l|—l|—l|—l|—l|—l|—d|—d The measurement was performed as follows: Anode material (K01); Cu—ch (1.54056A) Scan range: 3° to 40° Generator settings: 100 mA, 40.0 kV Scan speed: 1 sec/step Diver slit: 0.3° catter slit: 0.3° ature: 20°C Step size: 002° 20 Rotation: use Goniometer radius: 435 mm 2. Differential ng Calorimeter (DSC) Differential scanning calorimeter (DSC) analysis was performed in as STA—1000 (Scinco, Korea) at 30°C to 350°C. A sample in an amount of 5 mg to 10 mg was weighed and added into an aluminum DSC fan, and the fan was sealed with a perforated aluminum lid in a non—sealing manner. Then, the sample was heated at a scan speed of 10°C/min from 30°C to 350°C, and the heat flow reaction generated was monitored in a DSC. 3. Dynamic Vapor Sorption (DVS) Dynamic vapor sorption (DVS) analysis was performed in a DVS age (Surface measurement system, United Kingdom) analyzer at 25°C with a relative humidity of 0% to 90%. A sample in an amount of 10 mg was placed into a wire-mesh vapor sorption balance pan and then attached to a DVS advantage c vapor sorption balance via surface measurement systems. Until a stable weight was achieved (99.5% completion of steps), the sample was applied to a g profile with a relative humidity of 10% to 90% with a 10% increase of the sample while maintaining the sample in each step. Upon completion of the sorption cycle, the sample was dried using the same process while ining a relative humidity of below 0%. The changes in the sample weight during the adsorption/desorption cycle (repeated 3 times) were ed and the hygroscopicity of the sample was measured. 4. High mance Liquid Chromatography (HPLC) High performance liquid chromatography (HPLC) analysis was performed for the purposes of ing purity and contents such as a stability test, etc., using an Agilent 1100/1200 series HPLC Systems (Agilent, USA) analyzer, and the conditions used for HPLC were as follows.

Purity and t analysis conditions: thienopyrimidine compound of Formula 1 Column: Hydrosphere C18 (YMC), 5 um (150 mm x 4.6 mm) Column temperature: 30°C Detector: UV spectrophotometer Detection wavelength: 254 nm Flow rate: 1.0 mL/min Time of analysis: 35 min : NaClO4—NaH2PO4 — phosphate buffer solution (pH 2.5 i 0.1)/CH3CN = 40/60 (v/v%) . Karl-Fischer Titrator: Metrohm, 795KFT Titrino 6. Melting Point Analyzer: Bastead electro thermal, 9300 7. Nuclear Magnetic Resonance (NMR): BRUKER, Advance DPX 300 (300 MHz) Preparation of lline forms of a nd of Formula 1 Comparative Example 1: Preparation of an amorphous form of a compound of Formula 1 An amorphous form of the compound of Formula 1 was obtained according to the method disclosed in WO 62515, or a similar method thereof, which is reference herein.

Water content: 0.3% Melting point: 203°C to 205°C MS Spectrum: m/z = 487.19 (M+1) 1H-NMR Spectrum (300MHz, DMSO-d6) 6 s, lH), 9.24(s, 1H), 8.27(d, lH), 7.71(d, 1H), 7.64(d, 1H), 7.49-7.41(m, 3H), 7.32(d, 1H), 7.07(dd, 1H), , 2H), 6.42(dd, 1H), 6.28(dd, lH), 5.78(dd, 1H), 2.99(t, 4H), 2.43(t, 4H), 2.2l(s, 3H).

Analysis of characteristics The results of XRPD, DSC, and DVS analyses of the amorphous form prepared in Comparative Example 1 are shown in FIGS. le, 2e, and 3e, respectively.

The amorphous form did not show any particular diffraction value in the XRPD pattern.

Additionally, the amorphous form was shown to have an endothermic peak which has a ng point at about 537°C and its highest point at about 73.64°C, and an exothermic peak which has a starting point at about l40.64°C and its highest point at about 150.l3°C, in a DSC min), and this was expected to be a phase tion.

An endothermic peak was shown at about 205.89°C.

In the DSC, the endothermic peak at about 73.64°C indicates the dehydration point, and the endothermic peak at about °C indicates a melting point. The melting point was ed to be between about 204°C and about 205°C.

Additionally, in the DVS, the amorphous form showed a continuous hygroscopic tendency in the region with a relative humidity of 10% to 90% up to a water content between about 5% and about 6%, and this is ed to be unstable from the hy— groscopic aspect.

Example 1: Preparation of a crystalline form (Form A) of a compound of Formula 1 The title compound prepared in Comparative Example 1 (100 g; 0.21 mol) was added into a mixed solvent of acetone (400 mL) and water (100 mL), and the mixture was heated under reflux for 2 hours. Then, the resultant was cooled to 15°C to 20°C or below, stirred for 12 hours, and the resulting solids were filtered, washed with a mixed solvent (acetone/water = 4/1), and dried at 50°C to obtain the compound of Formula 1 in a crystalline form (78g, yield: 78%).

Water t: 7.0% (theoretical value of a dihydrate: 6.90%) Analysis of characteristics The results of XRPD, DSC, and DVS analyses of the crystalline form prepared in e 1 are shown in FIGS. la, 2a, and 3a, respectively.

The peaks having a relative intensity (I/Io) of 3% or higher in the XRPD pattern of the above crystalline form are shown in Table 1 below. When the peaks had I/IO ratios equal to or higher than 20%, they appeared at diffraction angles of 86°, 94°, 10.3°, 137°, 160°, 172°, 179°, 197°, 221°, 223°, 232°, 236°, 264°, 297°, and 353° (20 i 0.2°).

[Table l] on (n 45m was“ Additionally, the above crystalline form showed an endothermic peak which has a starting point at about 75 .05°C and its highest point at about 93.01°C, and an exothermic peak which has a starting point at about 140.61°C and its highest point at about 148.80°C, in a DSC (10°C/min), and this was expected to be a phase transition.

Additionally, an endothermic peak which has a starting point at about 198.56°C and its highest point at about 204.67°C was shown.

In the DSC, the endothermic peak at about 93.01°C indicates the dehydration point, and the endothermic peak at about 204.67°C indicates a melting point. The melting point was ed to be between about 203°C and about 204°C.

Additionally, in the DVS, the above lline forms showed a continuous hy— groscopic tendency in the region with a relative humidity of 10% to 90% up to a water content of about 1.5%, and this is expected to be stable from the hygroscopic aspect.

Example 2: Preparation of a crystalline form (Form B) of a compound of Formula 1 The ous form of the compound of a 1 prepared in Comparative Example 1 (200 g; 0.42 mol) was added into a mixed solvent of acetone (2.2 L) and water (200 mL), and the mixture was dissolved by heating at 60°C for 1 hour. Then, the resultant was treated with active carbon, filtered with celite, and washed with e (400 mL).

The filtrate solution, at between 30°C and 40°C, was treated with water (600 mL), cooled slowly to room temperature, stirred for 3 hours, cooled again to a temperature between 5°C and 10°C, and d for 2 hours.

The ormed solids were filtered, washed with a mixed solvent (300 mL) of e and water (v/v = 2.5/1), and dried at 50°C to obtain the compound of Formula 1 in a crystalline form (152.0 g, yield: 76.0%).

Water content: 9.8% (theoretical value of a trihydrate: 10.0%) Analysis of characteristics The results of XRPD, DSC, and DVS analyses of the crystalline form prepared in Example 2 are shown in FIGS. 1b, 2b, and 3b, respectively.

The peaks having a relative intensity (MD) of 3% or higher in the XRPD pattern of the above crystalline forms are shown in Table 2 below. When the peaks had I/IO ratios equal to or higher than 7%, they appeared at diffraction angles of 53°, 162°, 207°, 254°, and 28.5°(20 i 0.2°).

[Table 2] 29 (10.2) “5 1/10 (as) 29 (520.2) 100 24 o —20 5 25 4 29' diffraction 2111316, (1' distance between crystal faces. 1/10 ($13 relative intensity (1 indicates the intensity of each peak; L, indicate Additionally, the above crystalline form showed an endothermic peak which has a ng point at about 74.17°C and its lowest point at about 95 .38°C, and an exothermic peak which has a starting point at about 135.8 1°C and its highest point at about 145.45°C, in a DSC (10°C/min), and this was expected to be a phase transition.

Additionally, an endothermic peak which has a starting point at about 194.71°C and its highest point at about 202.96°C was shown.

In the DSC, the endothermic peak at about 95.38°C indicates the dehydration point of the crystalline form of ate of the compound of Formula 1, and the ermic peak at about 194.71°C indicates a g point. The melting point was measured to be n about 204°C and about 205°C.

Additionally, in the DVS, the above crystalline forms showed a copic tendency in the region with a relative humidity of 10% to 90% up to a water content between about 5% and about 5.5%.

Example 3: ation of a crystalline form (Form C) of a compound of Formula 1 The title compound (5.0 g) obtained in Comparative Example 1 was dried at 170°C using a weight—reducing drying device (LOD) for 30 s to remove water, and the nd of Formula 1 was obtained in a crystalline form.

Analysis of characteristics The results of XRPD, DSC, and DVS analyses of the crystalline form prepared in Example 3 are shown in FIGS. 1c, 2c, and 3c, respectively. 2016/015536 The peaks having a relative intensity (Me) of 3% or higher in the XRPD n of the above crystalline forms are shown in Table 3 below. When the peaks had I/IO ratios equal to or higher than 7%, they appeared at ction angles of 38°, 98°, 116°, 169°, 198°, 202°, 219°, 243°, and 247° (20 i 0.2°).

[Table 3] 29 “1:02) (1 3.8 23.1 . : 8.5 10.41 . . “.m- ‘ .0 _. . 2 . . '. . 6.8 3.7 24.3 . 18.7 4.8 32 3 26 5 3.4 —_—|_ 2.9 26: diffraction angle, d2 distance between crystal faces, 1/10 (is): relative intensity (I indicates the intensity of each peak; L, indicate he intensity of the highest peak.

Additionally, the above crystalline form showed an endothermic peak which has a starting point at about 193.69°C and its highest point at about 207.25°C in a DSC (10°C/min). In the DSC, the endothermic peak indicates the dehydration point. The melting point was measured to be n about 204°C and about 205°C.

Additionally, in the DVS, the above crystalline form showed the hygroscopic level of about 0.8% to about 0.9% in the region with a relative humidity of 10% to 90%. From these results, the above crystalline forms were expected to be very stable from the hy— groscopic . Additionally, from these results, it was confirmed that they were very stable under a long—term storage condition (a temperature of 25°C and a relative humidity of 60%) and an accelerated condition (a temperature of 40°C and a relative humidity of 75%).

Example 4: Preparation of a crystalline form (Form D) of a compound of Formula 1 The title nd (5.0 g) ed in Examples 1 and 2 were added into iso— propanol (50 mL) and heated under reflux for 2 hours. Then, the reaction mixture was cooled to room temperature and stirred for 3 hours, and the resulting solids were filtered, washed with isopropanol (10 mL), dried at 50°C, and the compound of Formula 1 was obtained in an crystalline form (3.7 g, yield: 74%).

Water t: 0.2% Analysis of characteristics The results of XRPD, DSC, and DVS analyses of the crystalline form prepared in Example 4 are shown in FIGS. 1d, 2d, and 3d, respectively.

The peaks having a relative intensity (Me) of 5% or higher in the XRPD pattern of the above crystalline forms are shown in Table 4 below. When the peaks had I/IO ratios equal to or higher than 10%, they appeared at diffraction angles of 8.8°, 10.5 °, 11.1°, 146°, 155°, 175°, 192°, 194°, 203°, 208°, 210°, 222°, 231°, 234°, 250°, and 252° (26 i 0.2°).

[Table 4] 00 U16) 010.) at» 262 diffraction angte. d1 distance between crystal faces, {/19 ('12): relative intensity (I indicates the intensity of each peak; 10 indicate -_he_inLensitx 9f the highestflak.

Additionally, the above crystalline form showed an endothermic peak which has a ng point at about 204.32°C and its highest point at about 208.34°C in a DSC min). In the DSC, the endothermic peak indicates the g point. The melting point was measured to be between about 205°C and about 207°C.

Additionally, in the DVS, the above lline form showed the hygroscopic level of about 0.2% to about 0.5% in the region with a ve humidity of 10% to 90%. From these results, the above crystalline forms were expected to be very stable in terms of hygroscopicity. Additionally, from these results, it was confirmed that they were very stable under a long-term storage condition (a temperature of 25°C and a relative ty of 60%) and an accelerated condition (a temperature of 40°C and a relative humidity of 75%).

Those of ordinary skill in the art will recognize that the present invention may be embodied in other specific forms without departing from its spirit or essential charac— teristics. The described embodiments are to be considered in all respects only as il— lustrative and not ctive. The scope of the present invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within the scope of the present invention.

Claims (15)

Claims
1. [Claim 1] A crystalline form of the compound of Formula 1 shown below: [Formula 1] \N OQNJL/ wk“ I /
2. [Claim 2] The crystalline form of claim 1, wherein the lline form is anhydrous.
3. [Claim 3] The crystalline form of claim 1, wherein the crystalline form is a hydrate.
4. [Claim 4] The crystalline form of claim 3, n the hydrate is a dihydrate or a trihydrate.
5. [Claim 5] The crystalline form of claim 1, wherein the crystalline form is a dihydrate having an X—ray powder diffraction (XRPD) pattern comprising peaks at diffraction angle 26 values of 8.6% 0.20, l6.0°i 0.20 and 17.2% 0.20 when irradiated with a Cu—Kor light source.
6. [Claim 6] The crystalline form of claim 5, wherein the crystalline form further comprises peaks at diffraction angle 26 values of 9.4°i 0.20, 10.3% 0.20, 13.7% 0.20, 17.9% 0.20, 19.7% 0.20, 22.1% 0.20, 23.6% 0.20, and 26.4°i 0.20 when irradiated with a Cu-KOL light source.
7. [Claim 7] The crystalline form of claim 1, wherein the crystalline form is a trihydrate having an X—ray powder diffraction pattern comprising peaks at diffraction angle 26 values of 5.3% 0.20 and l6.2°i 0.20 when ir— radiated with a Cu—Kor light .
8. [Claim 8] The lline form of claim 7, wherein the crystalline form further comprises peaks at diffraction angle 26 values of 20.7°i 02°, 25 .4°i 0.20, and 28.50i 0.20 when irradiated with a Cu—Ka light source.
9. [Claim 9] The crystalline form of claim 1, wherein the crystalline form is an anhydrous form having an X—ray powder diffraction n comprising peaks at diffraction angle 26 values of 3.8% 0.20 and ll.6°i 0.20 when irradiated with a Cu—Koz light source.
10. [Claim 10] The crystalline form of claim 9, wherein the crystalline form further ses peaks at diffraction angle 26 values of 9.8°i 0.20, 16.9% 0.20, and 19.8% 0.20 when irradiated with a Cu-Ka light .
11. [Claim 11] The crystalline form of claim 1, wherein the crystalline form is an anhydrous form having an X-ray powder diffraction pattern comprising peaks at diffraction angle 26 values of ll.l°J_r 0.20, 20.3% 0.20 and 208°: 02" when irradiated with a Cu-Ka light .
12. [Claim 12] The crystalline form of claim 11, wherein the crystalline form further comprises peaks at diffraction angle 26 values of 14.601L 0.20, 15.5% 0.20, 21.0°i 0.2°, and 22.2°i 0.20 when irradiated with a Cu—Kd light source.
13. [Claim 13] The crystalline form of any one of claims 1 to 12, wherein the crystalline form is substantially pure.
14. [Claim 14] A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 13 and at least one pharmaceutically ac— le carrier or diluent.
15. [Claim 15] The pharmaceutical composition of claim 14, wherein the pharma— ceutical composition is used for treating cancer d by epidermal growth factor receptor tyrosine kinase or a mutant thereof. Hfig.1AJ 2000 (CPS) Intensity _L OOO 3 10 20 30 40 2Theta e) (CPS) CDOO Intensity I\) OO 2Theta (Degree) 3 1o 20 30 40 2Theta (Degree) [