Crystalline form of acid addition salts of phlopyrimidine compounds

Abstract

To provide a crystalline form of an acid addition salt of a novel furopyrimidine compound, for example, hydrochloride, methanesulfonate, or ethanesulfonate, and a pharmaceutical composition including the same.SOLUTION: Provided are crystalline forms of acid addition salts of N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)furo[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide, and a pharmaceutical composition including the same. The crystalline forms may be easily used in preparing the pharmaceutical composition including the same as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a crystalline form of an acid addition salt of a phlopyrimidine compound represented by the following chemical formula 1, which has a tyrosine kinase activity inhibitory effect useful for the treatment of cancer and autoimmune diseases such as rheumatoid arthritis, and to a pharmaceutical composition containing the same. More specifically, the present invention relates to a crystalline form of an acid addition salt of N-(3-(2-(4-(4-methylpiperazine-1-yl)phenylamino)phlo[3,2-d]pyrimidine-4-yloxy)phenyl)acrylamide and a pharmaceutical composition containing the same: [ka] [Background technology]

[0002] The compound name is N-(3-(2-(4-(4-methylpiperazine-1-yl)phenylamine It is (no)fl[3,2-d]pyrimidine-4-yloxy)phenyl)acrylamide. The compound of chemical formula 1 below is registered in the Republic of Korea as patent no. 1,589,114 and published internationally as patent no. Disclosed in Patent No. 2011162515. The compound is a mutant epidermal growth factor receptor. By having the activity to selectively inhibit somatic tyrosine kinase, good Sinus tumor or malignant tumor It is useful in treating ulcers, inflammatory diseases, or autoimmune diseases such as rheumatoid arthritis. [ka]

[0003] Furthermore, the aforementioned reference document discloses a method for producing the compound of chemical formula 1. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Republic of Korea Registered Patent No. 1,589,114 [Patent Document 2] International Patent Publication No. 2011162515 [Overview of the project] [Problems that the invention aims to solve]

[0005] However, the compound of chemical formula 1 produced according to the aforementioned reference is generally manufactured as an amorphous solid, a form that is not very suitable for large-scale pharmaceutical manufacturing processes. Furthermore, the compound of chemical formula 1 produced according to the aforementioned reference has the disadvantage of having very low solubility in water (less than 0.001 mg / mL).

[0006] Therefore, it is necessary to produce a crystalline salt of the compound of chemical formula 1 that has improved solubility in water while fully meeting the strict requirements and specific details for the drug dosage form.

[0007] To this end, the inventors explored the formation of acid addition salts of the compound of Chemical Formula 1 by utilizing various acids and solvents under diverse conditions and procedures. Furthermore, the inventors evaluated the physicochemical properties of these acid addition salts, such as solubility, hygroscopicity, and stability. As a result, they discovered that among the acid addition salts of the compound of Chemical Formula 1, the crystalline forms of hydrochloride, methanesulfonate, and ethanesulfonic acid exhibit excellent solubility in water, do not require specific storage conditions, and remain stable for long periods. These forms possess excellent physicochemical properties required for pharmaceutical production and can be easily utilized in the manufacture of pharmaceutical compositions containing them as active ingredients, leading to the completion of the present invention.

[0008] Accordingly, the object of the present invention is to provide crystalline forms of acid addition salts of the phlopyrimidine compound of chemical formula 1, such as hydrochloride, methanesulfonate, and ethanesulfonate, and pharmaceutical compositions containing the same. [Means for solving the problem]

[0009] In order to achieve the above object, one aspect provides a crystalline form of an acid addition salt of a compound represented by the following Chemical Formula 1:

Chemical Formula

[0010] In one specific embodiment, the acid addition salt of the compound of Chemical Formula 1 is a hydrochloride salt.

[0011] In one specific embodiment, the acid addition salt of the compound of Chemical Formula 1 is a methanesulfonate salt.

[0012] In one specific embodiment, the acid addition salt of the compound of Chemical Formula 1 is an ethanesulfonate salt.

[0013] In one specific embodiment, the acid addition salt of the compound of Chemical Formula 1 is also one or more selected from the group consisting of hydrochloride, methanesulfonate and ethanesulfonate.

[0014] In one specific embodiment, the acid addition salt of the compound of Chemical Formula 1 is also in the form of an anhydride or a hydrate. For example, the acid addition salt of the compound of Chemical Formula 1 may be a monohydrate, a dihydrate or a trihydrate, but is not limited thereto.

[0015] Specific examples of the crystalline form are as shown below: A crystalline form of dihydrochloride trihydrate (2HCl·3H₂O) of the compound of Chemical Formula 1, which has an X-ray powder diffraction (XRPD) spectrum comprising peaks at diffraction angles (2θ±0.2°) of 6.4°, 7.1°, 12.8° and 21.2° when irradiated with a Cu-Kα light source; A crystalline form of monohydrochloride dihydrate (1HCl·2H₂O) of the compound of Chemical Formula 1, which has an X-ray powder diffraction (XRPD) spectrum comprising peaks at diffraction angles (2θ±0.2°) of 7.0°, 7.9°, 15.8°, 17.2°, 18.6°, 20.6°, 21.3° and 23.2° when irradiated with a Cu-Kα light source; The monohydrochloride anhydride (1HCl·2H2O) crystalline form of the compound of chemical formula 1, which has an X-ray powder diffraction (XRPD) spectrum containing peaks at diffraction angles (2θ±0.2°) of 4.9°, 14.8°, and 21.2° when irradiated with a Cu-Kα light source. The methanesulfonic anhydride (1MsOH) crystalline form of the compound of chemical formula 1 having an X-ray powder diffraction (XRPD) spectrum containing peaks at diffraction angles (2θ±0.2°) of 11.8°, 17.2°, 19.0°, 20.0°, 22.8°, and 24.0° when irradiated with a Cu-Kα light source; The crystalline form of methanesulfonic acid monohydrate (1MsOH·1H2O) of the compound of chemical formula 1 having an X-ray powder diffraction (XRPD) spectrum containing peaks at diffraction angles (2θ±0.2°) of 7.6°, 15.2°, 17.0°, 18.7°, 20.8°, and 22.8° when irradiated with a Cu-Kα light source; and The ethanesulfone anhydride (1EsOH) crystalline form of the compound of chemical formula 1, having an X-ray powder diffraction (XRPD) spectrum that includes peaks at diffraction angles (2θ±0.2°) of 17.1°, 18.6°, 21.3°, 22.3°, 23.0°, and 23.6° when irradiated with a Cu-Kα light source.

[0016] In one specific example, the crystalline forms are each substantially pure forms.

[0017] As used herein, the term "substantially pure" means at least 95% pure, preferably 99% pure, and 95% pure means that the compound of chemical formula 1 is present in any other form (other crystalline, amorphous, etc.) in amounts of 5% or less, and 99% pure means that the compound of chemical formula 1 is present in any other form (other crystalline, amorphous, etc.) in amounts of 1% or less.

[0018] Another embodiment provides a pharmaceutical composition comprising one or more crystalline forms of the compound of chemical formula 1 and one or more pharmaceutically acceptable carriers or diluents.

[0019] The aforementioned pharmaceutical composition is induced by epidermal growth factor receptor tyrosine kinase or a variant thereof. goodIt is also used to treat uterine tumors or malignant tumors, inflammatory diseases, or autoimmune diseases such as rheumatoid arthritis. [Effects of the Invention]

[0020] The crystalline forms of the compound of chemical formula 1 in a single mode, such as hydrochloride, methanesulfonate, and ethanesulfonate, are excellent in terms of various physicochemical properties, namely solubility in water, hygroscopicity, and chemical stability, and are readily used in the manufacture of pharmaceutical compositions containing them as active ingredients. [Brief explanation of the drawing]

[0021] [Figure 1A] This figure shows the X-ray powder diffraction (XRPD) spectrum of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 1B] This figure shows the X-ray powder diffraction (XRPD) spectrum of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 1C] This figure shows the X-ray powder diffraction (XRPD) spectrum of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 1D] This figure shows the X-ray powder diffraction (XRPD) spectrum of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 1E] This figure shows the X-ray powder diffraction (XRPD) spectrum of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 1F] This figure shows the X-ray powder diffraction (XRPD) spectrum of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 2A] This is a differential scanning calorimetry (DSC) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 2B] This is a differential scanning calorimetry (DSC) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 2C] This is a differential scanning calorimetry (DSC) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 2D]This is a differential scanning calorimetry (DSC) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 2E] This is a differential scanning calorimetry (DSC) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 2F] This is a differential scanning calorimetry (DSC) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 3A] This is a dynamic vapor adsorption (DVS) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 3B] This is a dynamic vapor adsorption (DVS) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 3C] This is a dynamic vapor adsorption (DVS) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 3D] This is a dynamic vapor adsorption (DVS) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 3E] This is a dynamic vapor adsorption (DVS) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Figure 3F] This is a dynamic vapor adsorption (DVS) graph of the crystalline form of the acid addition salt of the compound of chemical formula 1 according to the examples. [Modes for carrying out the invention]

[0022] Terms not specifically defined herein shall have meanings as assigned by those skilled in the art in light of the description and context. However, unless otherwise specified, throughout this specification, the following terms shall have the meanings indicated below:

[0023] The term "approximately" means within 5%, preferably 1% to 2%, of a given value or range. For example, "approximately 10%" means 9.5% to 10.5%, preferably 9.8% to 10.2%. Another example is "approximately 100°C," which means 95°C to 105°C, preferably 98°C to 102°C.

[0024] Unless otherwise explicitly stated, those skilled in the art will understand that the peak values ​​from the X-ray powder diffraction studies reported in this invention are typically related to observable experimental error in the art. Specifically, the peaks are interpreted to be within ±0.5° of the values ​​reported herein. More specifically, the peaks are interpreted to be within ±0.2° of the values ​​reported herein.

[0025] The term "acid addition salt" refers to a salt formed by an acid-base reaction with an inorganic or organic acid of a compound of chemical formula 1. Examples of inorganic acids used in the formation of such acid addition salts include hydrochlorides, bromates, sulfates, phosphates, and nitrates. Examples of organic acids include maleates, fumarates, citrates, succinates, oxalic acid, tartaric acid, methanesulfonates, ethanesulfonic acid, benzenesulfonates, p-toluenesulfonates, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and (+)-camphor-10-sulfonates.

[0026] Hydrochloride, methanesulfonate, and ethanesulfonate salts of the compound of chemical formula 1, and their crystalline forms The following compounds of chemical formula 1, namely N-(3-(2-(4-(4-methylpiperazine-1-yl)phenylamino)fl[3,2-d]pyrimidine-4-yloxy)phenyl)acrylamide, are provided as hydrochloride, methanesulfonate, and ethanesulfonate, and their crystalline forms: [ka]

[0027] The compound of chemical formula 1 can also be produced by the general procedure described in Registered Patent No. 1,589,114 of the Republic of Korea and International Patent Publication No. 2011162515, both of which are incorporated herein by reference in their entirety.

[0028] The compound of chemical formula 1 described in the aforementioned document is amorphous and is a poorly soluble compound with a solubility in water of less than 0.001 mg / mL.

[0029] Generally, the conversion of free bases to salt forms is known to aid in the solubilization of poorly water-soluble drug substances. However, such salts must possess various physicochemical properties required for pharmaceutical production, such as reproducibility of specific crystalline forms, high crystallinity, crystalline stability, chemical stability, and non-hygroscopicity.

[0030] To select a suitable salt form of the compound of chemical formula 1, the salt formation of the compound of chemical formula 1 was explored using various acids and solvents under diverse conditions and procedures, and the physicochemical properties of the resulting salts, such as solubility, hygroscopicity, and stability, were evaluated. Among the salts thus produced, the crystalline forms of the hydrochloride, methanesulfonate, and ethanesulfonate of the compound of chemical formula 1 were the most superior in terms of various physicochemical properties such as reproducibility of specific crystal form production required for pharmaceutical purposes, improved purity, high crystallinity, crystal form stability, chemical stability, and non-hygroscopicity.

[0031] Crystalline forms of hydrochloride, methanesulfonate, and ethanesulfonate salts of the compound of chemical formula 1 The salts of the compound of chemical formula 1 can be produced in crystalline form, amorphous form, or as mixtures thereof, but the crystalline form is preferred. The crystalline forms of the hydrochloride, methanesulfonate, and ethanesulfonate salts of the compound of chemical formula 1 are preferred because they have excellent stability and physicochemical properties that facilitate formulation.

[0032] According to the present invention, the compound of chemical formula 1 can take various forms of crystalline acid addition salts, such as the dihydrochloride trihydrate (2HCl·3H2O) crystalline form, the monohydrochloride dihydrate (1HCl·2H2O) crystalline form, the monohydrochloride anhydride (1HCl) crystalline form, the methanesulfonate anhydride (1MsOH) crystalline form, the methanesulfonate monohydrate (1MsOH·1H2O) crystalline form, and the ethanesulfonate anhydride (1EsOH) crystalline form.

[0033] As a result of the test example 1 below, among the crystalline acid addition salts, the dihydrochloride trihydrate (2HCl·3H2O), methanesulfonate anhydride (1MsOH) crystalline form, methanesulfonate monohydrate (1MsOH·1H2O) crystalline form, and ethanesulfonate anhydride (1EsOH) crystalline form were excellent in terms of solubility in water, with the ethanesulfonate anhydride (1EsOH) crystalline form being the most excellent in terms of solubility. The aforementioned acid addition salts are advantageous in terms of non-hygroscopic / non-dehygroscopicity and stability, and are therefore useful as active ingredients in pharmaceutical compositions.

[0034] The following describes each of the crystal forms according to the present invention in more detail.

[0035] In one specific example, the present invention provides a crystalline form of the dihydrochloride trihydrate (2HCl·3H2O) of the compound of chemical formula 1, which, when irradiated with a Cu-Kα light source, has an X-ray powder diffraction (XRPD) spectrum including peaks at diffraction angles (2θ±0.2°) of 6.4°, 7.1°, 11.1°, 12.8°, and 21.2°. More specifically, the crystalline form of the dihydrochloride trihydrate (2HCl·3H2O) of the compound of chemical formula 1 may have an XRPD spectrum including peaks at diffraction angles (2θ±0.2°) of 6.4°, 7.1°, 12.8°, 15.6°, 19.6°, 21.2°, 27.9°, and 28.3° when irradiated with a Cu-Kα light source. These peaks also have a relative intensity of approximately 10% or more.

[0036] The crystalline form of the dihydrochloride trihydrate (2HCl·3H2O) of the compound of chemical formula 1 may have a water content of about 8.5% to 9.5% (theoretical water content of 9.04%) and a melting point of about 210°C to 220°C. The crystalline form may have two endothermic peaks in DSC (10°C / min) near about 75°C to 80°C and about 105°C to 110°C, which indicate the dehydration point of the trihydrate. An endothermic peak may be present at about 200°C to 220°C, which indicates the melting point. An exothermic peak may be present at about 240°C to 250°C, which indicates decomposition. In the dynamic vapor sorption (DVS) of the crystalline form, moisture absorption occurs in the relative humidity range of 10% to 20%, and moisture absorption in the relative humidity range of 30% to 90% may be measured to be very low.

[0037] In one specific example, the present invention provides a crystalline form of a monohydrochloride dihydrate (1HCl·2H2O) of the compound of chemical formula 1, the crystalline form having an X-ray powder diffraction (XRPD) spectrum that includes peaks at diffraction angles (2θ±0.2°) of 7.0°, 7.9°, 15.8°, 17.2°, 18.6°, 20.6°, 21.3°, and 23.2° when irradiated with a Cu-Kα light source. More specifically, the monohydrochloride dihydrate (1HCl·2H2O) crystalline form of the compound of chemical formula 1 can have an XRPD spectrum when irradiated with a Cu-Kα light source that includes peaks at diffraction angles (2θ±0.2°) of 7.0°, 7.9°, 12.6°, 15.8°, 17.2°, 18.6°, 20.2°, 20.6°, 21.0°, 21.3°, 23.2°, 26.9°, and 28.9°, and these peaks are also peaks with a relative intensity of approximately 25% or more.

[0038] The monohydrochloride dihydrate (1HCl·2H2O) crystalline form of the compound of chemical formula 1 may have an endothermic peak around 110°C to 140°C in DSC (10°C / min), which indicates the dehydration point of the dihydrate. It may also have an endothermic peak around 160°C to 170°C, which indicates the melting point. The crystalline form may have a water content of about 6.5% to 7.5% (theoretical water content of 6.63%) and a melting point of about 150°C to 170°C. The crystalline form may have very low moisture absorption in the relative humidity range of 10% to 90% in DVS.

[0039] In one specific example, the present invention provides a monohydrochloride anhydride (1HCl) crystalline form of the compound of chemical formula 1, which, when irradiated with a Cu-Kα light source, has an X-ray powder diffraction (XRPD) spectrum including peaks at diffraction angles (2θ±0.2) of 4.9°, 14.8°, and 21.2°. More specifically, the monohydrochloride anhydride (1HCl) crystalline form of the compound of chemical formula 1 can have an XRPD spectrum including peaks at diffraction angles (2θ±0.2) of 4.9°, 12.2°, 14.8°, 21.2°, 23.1°, and 24.9° when irradiated with a Cu-Kα light source, and these peaks are also peaks with a relative intensity of about 5% or more.

[0040] The monohydrochloride anhydride (1HCl) crystalline form of the compound of chemical formula 1 may have an endothermic peak at approximately 250°C to 270°C in DSC (10°C / min), which indicates the melting point. The crystalline form may have a water content of approximately 0.1% to 1.0% (theoretical water content of 0%) and a melting point of approximately 255°C to 270°C. The crystalline form may exhibit very low moisture absorption in the relative humidity range of 10% to 90% in DVS.

[0041] In one specific example, the present invention provides a methanesulfonic anhydride (1MsOH) crystalline form of the compound of chemical formula 1, which has an X-ray powder diffraction (XRPD) spectrum containing peaks at diffraction angles (2θ±0.2°) of 11.8°, 17.2°, 19.0°, 20.0°, 22.8°, and 24.0° when irradiated with a Cu-Kα light source. More specifically, the methanesulfonic anhydride (1MsOH) crystalline form of the compound of chemical formula 1 can have an XRPD spectrum containing peaks at diffraction angles (2θ±0.2°) of 10.7°, 11.3°, 11.8°, 12.2°, 15.0°, 17.2°, 17.6°, 18.6°, 19.0°, 20.0°, 22.3°, 22.8°, 23.3°, 23.7°, and 24.0° when irradiated with a Cu-Kα light source. These peaks also have a relative intensity of approximately 15% or more.

[0042] The methanesulfonic anhydride (1MsOH) crystalline form of the compound of chemical formula 1 may have a water content of about 0.5% to 1.5% (theoretical water content of 0%) and a melting point of about 235°C to 245°C. The crystalline form may have an endothermic peak at about 235°C to 240°C in DSC (10°C / min), which indicates the melting point. In DVS of the crystalline form, a water absorption of 2% to 3% may be measured in the range of relative humidity from 10% to 90%.

[0043] In one specific example, the present invention provides a crystalline form of methanesulfonic acid monohydrate (1MsOH·1H2O) of the compound of chemical formula 1, the crystalline form having an X-ray powder diffraction (XRPD) spectrum that includes peaks at diffraction angles (2θ±0.2°) of 7.6°, 15.2°, 17.0°, 18.7°, 20.8° and 22.8° when irradiated with a Cu-Kα light source. More specifically, the methanesulfonic acid monohydrate (1MsOH·1H2O) crystalline form of the compound of chemical formula 1 can have an XRPD spectrum when irradiated with a Cu-Kα light source that includes peaks at diffraction angles (2θ±0.2°) of 7.6°, 8.8°, 15.2°, 17.0°, 17.8°, 18.4°, 18.7°, 20.1°, 20.8°, 21.0°, 22.1°, 22.8°, 24.6°, 24.9°, 25.4°, 26.1°, 26.5°, 27.0°, and 28.4°, and these peaks are also peaks with a relative intensity of approximately 15% or more.

[0044] The crystalline form of methanesulfonic acid monohydrate (1MsOH·1H2O) of the compound of chemical formula 1 may have an endothermic peak around 90°C to 95°C in DSC (10°C / min), which indicates the dehydration point of the monohydrate. It may also have an endothermic peak around 205°C to 210°C, which indicates the melting point. The crystalline form may have a water content of about 2.5% to 3.5% (theoretical water content of 3.08%) and a melting point of about 200°C to 210°C. The crystalline form may have very low moisture absorption in the relative humidity range of 10% to 90% in DVS.

[0045] In one specific example, the present invention provides a crystalline form of the ethanesulfone salt anhydride (1EsOH) of the compound of chemical formula 1, the crystalline form having an X-ray powder diffraction (XRPD) spectrum that includes peaks at diffraction angles (2θ±0.2) of 17.1°, 18.6°, 21.3°, 22.3°, 23.0° and 23.6° when irradiated with a Cu-Kα light source. More specifically, the ethanesulfone anhydride (1EsOH) crystalline form of the compound of chemical formula 1 can have an XRPD spectrum when irradiated with a Cu-Kα light source that includes peaks at diffraction angles (2θ±0.2) of 7.1°, 11.1°, 11.7°, 14.2°, 17.1°, 18.1°, 18.6°, 19.8°, 20.0°, 21.3°, 22.3°, 23.0°, and 23.6°, and these peaks are also peaks with a relative intensity of approximately 15% or more.

[0046] The crystalline form of the ethanesulfone anhydride (1EsOH) of the compound of chemical formula 1 may have an endothermic peak at approximately 230°C to 240°C in DSC (10°C / min), which indicates the melting point. The crystalline form may have a water content of approximately 0.1% to 1.0% (theoretical water content of 0%) and a melting point of approximately 230°C to 240°C. The crystalline form may have a very low moisture absorption of less than 1% in the range of 10% to 90% relative humidity in DVS.

[0047] Pharmaceutical composition As disclosed in Registered Patent No. 1,589,114 of the Republic of Korea and International Patent Publication No. 2011162515, the compound of chemical formula 1 has been demonstrated to selectively and effectively inhibit cancer cell growth and drug resistance induced by epidermal growth factor receptor (EGFR) tyrosine kinase or its variants.

[0048] From this perspective, the crystalline hydrochloride, methanesulfonate, and ethanesulfonate of the compound of chemical formula 1 are induced by epidermal growth factor receptor (EGFR) tyrosine kinase or its variants. goodIt is also used to manufacture pharmaceutical compositions for the treatment or prevention of uterine tumors or malignant tumors, inflammatory diseases, or autoimmune diseases such as rheumatoid arthritis.

[0049] Accordingly, the present invention provides a pharmaceutical composition comprising crystalline hydrochloride, methanesulfonate, and ethanesulfonate of the compound of chemical formula 1, and one or more pharmaceutically acceptable carriers or diluents. The pharmaceutical composition can also be used for the treatment of cancer, tumors, inflammatory diseases, or autoimmune diseases such as rheumatoid arthritis induced by epidermal growth factor receptor tyrosine kinase or its variants.

[0050] The dosage of the crystalline hydrochloride, methanesulfonate, and ethanesulfonate of the compound of chemical formula 1, or a pharmaceutical composition containing them, varies depending on the subject being treated, the severity of the disease or condition, the rate of administration, and the judgment of the prescribing physician. Generally, based on the compound of chemical formula 1, a person may be administered 10 mg to 2,000 mg, preferably 50 mg to 1,000 mg, as the active ingredient, as free base of the compound of chemical formula 1, based on a body weight of 70 kg, once to four times daily, or on an on / off schedule, via oral or parenteral routes. In some cases, lower dosages than those described above may be more appropriate, and higher dosages may also be used without causing adverse side effects. If higher dosages are used, they may be divided into several smaller doses throughout the day.

[0051] The pharmaceutical compositions according to the present invention can be formulated by general methods and manufactured in a variety of oral administration forms such as tablets, pills, powders, capsules, syrups, emulsions, and microemulsions, or in parenteral administration forms such as intramuscular, intravenous, or subcutaneous administration.

[0052] The pharmaceutical composition may contain any common, non-toxic, pharmaceutically acceptable carriers, diluents, auxiliaries, excipients, etc. When the pharmaceutical composition according to the present invention is manufactured in the form of an oral dosage form, examples of carriers that can be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspensions, emulsifiers, and diluents. When the pharmaceutical composition according to the present invention is manufactured in the form of an oral dosage form, examples of diluents that can be used include lactose, mannitol, sugars, microcrystalline cellulose and cellulose derivatives, and dried corn starch. When the pharmaceutical composition according to the present invention is manufactured in the form of an injection, the carrier can be water, saline solution, glucose aqueous solution, sugar-like aqueous solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspension, emulsifier, etc.

[0053] Furthermore, a method for treating a disease is provided, comprising the step of administering a crystalline form of the compound of chemical formula 1, or a pharmaceutical composition, to an individual in a therapeutically effective amount. The disease is, good It can also be a sexually transmitted tumor or malignant tumor, an inflammatory disease, or an autoimmune disease such as rheumatoid arthritis.

[0054] The present invention will be described below with reference to specific examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited thereto. [Examples]

[0055] Analytical instruments and measurement methods 1. X-ray powder diffraction (XRPD) X-ray powder diffraction (XRPD) analysis was performed on a D8 Advance (Bruker ASX, Germany) analyzer at angles from 3°2θ to 40°2θ. For sample volumes less than 100 mg, approximately 5 mg to 10 mg of sample was gently pressed onto a glass slide fitted into a sample holder. For sample volumes exceeding 100 mg, approximately 100 mg of sample was gently pressed onto a plastic sample holder, ensuring the sample surface was smooth and directly above the sample holder level. The measurements were performed as follows: Anode material (Ka): Cu Ka (1.54056 Å) Scan range: 3° to 40° Generator setting: 100mA, 40.0kV Scan speed: 1 sec / step Diverging slit size: 0.3 degrees Anti-scatter slit: 0.3 degrees Temperature:20℃ Step size: 0.02 degrees 2θ Rotation: Use Goniometer radius: 435mm

[0056] 2. Differential Scanning Calorimetry (DSC) Differential scanning calorimetry (DSC) analysis was performed using an STA-1000 (Scinco, South Korea) analyzer at temperatures ranging from 30°C to 350°C. 5 mg to 10 mg of the sample was weighed and added to an aluminum DSC pan, sealed loosely with a perforated aluminum lid, and then heated from 30°C to 350°C at a scanning rate of 10°C / min to monitor the resulting heat flow reaction (DSC).

[0057] 3. Dynamic Vapor Adsorption (DVS) Dynamic vapor adsorption (DVS) analysis was performed using a DVS-advantage (surface measurement system, UK) analyzer at 25°C and 0% to 90% relative humidity. A 10 mg sample was placed in a wire mesh vapor adsorption balance pan and adsorbed onto a DVS-advantage dynamic vapor adsorption balance using a surface measurement system. The sample was maintained at each stage until a stable weight was achieved (99.5% stage completion), and the sample was applied to ramping profiles of 10% to 90% relative humidity (RH) in 10% increments. After the adsorption cycle was completed, the sample was dried using the same process, but maintained at a relative humidity of 0% or less. The weight change between adsorption / desorption cycles (3 repetitions) was recorded to measure the hygroscopicity of the sample.

[0058] 4. High-performance liquid chromatography (HPLC) High-performance liquid chromatography (HPLC) analysis is performed using Agilent 1100 / 1200 series HPLC Systems (Agilent, USA) for purposes such as purity and content analysis, including stability testing. The HPLC analysis conditions are as follows: Conditions for purity and content analysis: Flupyrimidine compound of chemical formula 1 Column: Hydrosphere C18 (YMC), 5 μm (150 mm x 4.6 mm) Column temperature: 30℃ Detector: Ultraviolet absorbance spectrophotometer Detection wavelength: 254nm Flow rate: 1.0mL / min Analysis time: 35 minutes Eluent: NaClO4-NaH2PO4-phosphate buffer solution (pH 2.5 ± 0.1) / CH3CN = 65 / 35 (v / v%)

[0059] 5. Ion Chromatography (IC) Ion chromatography (IC) analysis was performed using a Thermo Fisher Scientific ICS-2500 series IC systems (Thermo Fisher Scientific, USA) analyzer for the purpose of analyzing the hydrochloric acid content of hydrochloride salts. The IC analysis conditions were as follows: Content analysis conditions: Flupyrimidine compound of chemical formula 1 Column: IonPac AS19 (Dionex), (25mm x 4mm), Guard (50mm x mm) Column temperature: 30℃ Detector: Electrical conductivity detector (CD) Suppressor: ASRS 4mm, 40mA current Flow rate: 1.0mL / min Analysis time: 30 minutes Eluent: 10 mM potassium hydroxide solution

[0060] 6. Moisture Measurement Moisture content was measured using a Carl Fischer 795KFT Titrino (Metrohm, Switzerland) moisture meter.

[0061] 7. Melting point measurement The melting point was measured using an IA9200 (Electrothermal, UK) melting point analyzer.

[0062] Examples: Preparation and analysis of the crystalline form of the acid addition salt of the compound of chemical formula 1.

[0063] Example 1. Dihydrochloride trihydrate of the compound of chemical formula 1 (2HCl·3H 2 O) Production of crystal forms 690 g (1.47 mol) of the compound of Chemical Formula 1, prepared by the method of Registered Korean Patent No. 1,589,114 and International Patent Publication No. 2011162515 cited herein, or by a similar method, was added to 6,900 mL of an 80% aqueous solution of isopropanol (isopropanol / water = 8 / 2). 240 mL (2.93 mol) of concentrated hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was cooled to 10°C, and the precipitated solid was filtered. After washing with 690 mL of an 80% aqueous solution of isopropanol (isopropanol / water = 8 / 2), the solid was dried to obtain 650 g of the title compound (yield: 82.0%). Moisture content: 8.8% (Theoretical value for trihydrate: 9.04%) Ion chromatography: 13.6% (Theoretical value for dihydrochloride: 13.4%)

[0064] Characteristic analysis The results of XRPD analysis, DSC analysis, and DVS analysis of the crystal form produced in Example 1 are shown in Figures 1A, 2A, and 3A, respectively. In the XRPD spectrum of the aforementioned crystal form, the relative intensity (I / I) o The peaks where the ratio was 3% or higher are listed in Table 1 below. o For peaks where the ratio was 10% or more, the diffraction angles (2θ±0.2°) were 6.4°, 7.1°, 12.8°, 15.6°, 19.6°, 21.2°, 27.9°, and 28.3°.

[0065] [Table 1]

[0066] In the DSC (10°C / min) of the crystalline form, endothermic peaks were observed starting at approximately 58.7°C, with minimum points at approximately 77.4°C and 109.4°C, further endothermic peaks at approximately 200.1°C and 218.7°C, and an exothermic peak at approximately 250°C. The endothermic peaks at approximately 77.4°C and 109.4°C in the DSC represent the dehydration points of the dihydrochloride trihydrate crystalline form, the endothermic peaks at approximately 200.08°C and 218.69°C represent the melting points, and the exothermic peak at approximately 250°C represents thermal decomposition.

[0067] The aforementioned crystalline form showed a moisture content of approximately 8.8% (theoretical moisture content of 9.04%) using a Karl Fischer moisture analyzer, and exhibited a melting point of approximately 210°C to 218°C.

[0068] In the aforementioned crystalline form of DVS, moisture absorption occurs in the range of relative humidity from 0% to 20%, but the degree of moisture absorption is very low in the range of relative humidity above 30%. The aforementioned crystalline form was sufficiently stable under long-term storage conditions (e.g., temperature of 25°C and relative humidity of 60%), accelerated conditions (e.g., temperature of 40°C and relative humidity of 75%), and harsh conditions (e.g., temperature of 40°C and relative humidity of 75%).

[0069] Example 2. Monohydrochloride dihydrate of the compound of chemical formula 1 (1HCl·2H 2 O) Production of crystal forms Example 2.1. Compound dihydrochloride trihydrate of chemical formula 1 (2HCl·3H 2 Manufactured from O) 460 g (0.85 mol) of the dihydrochloride trihydrate of the compound of chemical formula 1 (2HCl·3H2O) was added to 4,600 mL of a 50% ethanol aqueous solution (ethanol / water = 5 / 5). The reaction mixture was heated to 40°C to 45°C, and an aqueous solution prepared by dissolving 67.7 g (1.69 mol) of sodium hydroxide in 460 mL of water was added. The mixture was then stirred at 40°C to 45°C for 30 minutes. 89.7 mL (1.02 mol) of concentrated hydrochloric acid was added to the reaction mixture, and the mixture was stirred at 40°C to 45°C for 1 hour. The reaction mixture was gradually cooled to 20°C to 25°C and stirred at 20°C to 25°C for 12 hours. The precipitated solid was filtered, washed with 460 mL of cooled 50% ethanol aqueous solution (ethanol / water = 5 / 5), and dried to obtain 398 g of the title compound (yield: 87.0%). Moisture content: 7.5% (Theoretical value for dihydrate: 6.63%) Ion chromatography: 7.4% (Theoretical value for monohydrochloride: 7.2%)

[0070] Example 2.2. Preparation from the compound of chemical formula 1 53 g (0.11 mol) of the compound of chemical formula 1 was added to 530 mL of an 80% methanol aqueous solution (methanol / water = 8 / 2). After adding 10.9 mL (0.12 mol) of concentrated hydrochloric acid to the reaction mixture, the mixture was stirred at 20°C to 25°C for 12 hours. The precipitated solid was filtered, washed with 53 mL of an 80% methanol aqueous solution (methanol / water = 8 / 2), and dried at 50°C to obtain 49 g of the title compound (yield: 80.0%). Moisture content: 6.2% (Theoretical value for dihydrate: 6.63%) Ion chromatography: 7.0% (Theoretical value for monohydrochloride: 7.2%)

[0071] Characteristic analysis The results of XRPD analysis, DSC analysis, and DVS analysis of the crystal forms produced in Example 2 are shown in Figures 1Bb, 2B, and 3B, respectively. In the XRPD spectrum of the aforementioned crystal form, the relative intensity (I / I) o The peaks where the ratio was 5% or higher are listed in Table 2 below. o For peaks where the ratio was 10% or more, the diffraction angles (2θ±0.2°) were shown as 7.0°, 7.9°, 12.6°, 13.4°, 15.5°, 15.8°, 17.2°, 18.2°, 18.6°, 19.1°, 20.2°, 20.6°, 21.0°, 21.3°, 22.1°, 23.2°, 23.8°, 24.1°, 24.8°, 25.0°, 25.3°, 25.9°, 26.9°, 28.1°, 28.9°, 30.1°, 30.7°, 31.2°, 32.2°, and 33.9°.

[0072] [Table 2]

[0073] In the DSC (10°C / min) of the aforementioned crystalline form, endothermic peaks were observed at approximately 115.0°C and 135.8°C, and at approximately 165.1°C. The endothermic peaks at approximately 115.0°C and 135.8°C in the DSC represent the dehydration points of the monohydrochloride dihydrate crystalline form, while the endothermic peak at approximately 165.1°C represents the melting point. The aforementioned crystalline form showed a moisture content of approximately 7.5% (theoretical moisture content of 6.63%) using a Karl Fischer moisture analyzer, and exhibited a melting point of approximately 154°C to 165°C. In the DVS of the crystalline form, the degree of moisture absorption was measured to be low, approximately 0.8%, in the relative humidity range of 10% to 90%. The crystalline form was sufficiently stable under both long-term storage conditions (e.g., 25°C and 60% relative humidity) and accelerated conditions (e.g., 40°C and 75% relative humidity).

[0074] Example 3. Preparation of the monohydrochloride anhydride (1HCl·anhydrate) crystalline form of the compound of chemical formula 1. Example 3.1. Compound dihydrochloride trihydrate of chemical formula 1 (2HCl·3H 2 Manufactured from O) 70 g of the dihydrochloride trihydrate (2HCl·3H2O) of the compound of chemical formula 1 was added to 2,100 mL of water. The reaction mixture was stirred at room temperature for 2 hours, and the precipitated solid was filtered. After washing with 70 mL of water and drying, 25 g of the title compound (yield: 35.7%) was obtained. Moisture content: 0.3% Ion chromatography: 7.1% (Theoretical value for monohydrochloride: 7.2%)

[0075] Example 3.2. Preparation from the compound of chemical formula 1 53 g (0.11 mol) of the compound of chemical formula 1 was added to 530 mL of methanol. After adding 10.9 mL (0.12 mol) of concentrated hydrochloric acid to the reaction mixture, the mixture was stirred at 20°C to 25°C for 12 hours. The precipitated solid was filtered, washed with 53 mL of methanol, and dried at 50°C to obtain 46 g of the title compound (yield: 81.0%). Moisture content: 0.4% Ion chromatography: 7.2% (Theoretical value for monohydrochloride: 7.2%)

[0076] Characteristic analysis The results of XRPD analysis, DSC analysis, and DVS analysis of the crystal forms produced in Example 3 are shown in Figures 1C, 2C, and 3C, respectively. In the XRPD spectrum of the aforementioned crystal form, the relative intensity (I / I) o The peaks where the ratio was 2% or higher are listed in Table 3 below. o For peaks where the ratio was 5% or more, the diffraction angles were indicated as 4.9°, 12.2°, 14.8°, 21.2°, 23.1°, and 24.9° (2θ±0.2°).

[0077] [Table 3]

[0078] In the DSC (10°C / min) analysis of the aforementioned crystalline form, an endothermic peak was observed at approximately 264.2°C. The endothermic peak at approximately 264.2°C in the DSC analysis indicates the melting point.

[0079] The aforementioned crystalline form showed a moisture content of approximately 0.3% and a melting point of approximately 259 to 264°C, as measured by a Karl Fischer moisture meter.

[0080] In the DVS of the crystalline form, the degree of moisture absorption was measured to be low, approximately 1%, in the relative humidity range of 10% to 90%. The crystalline form was sufficiently stable under long-term storage conditions (e.g., 25°C and 60% relative humidity) and accelerated conditions (e.g., 40°C and 75% relative humidity).

[0081] Example 4. Preparation of mesylate anhydrate of the compound of chemical formula 1. 10 g (21.26 mmol) of the compound of chemical formula 1 was added to 100 mL of ethanol. 1.52 mL (23.38 mmol) of methanesulfonic acid was added dropwise to the reaction mixture, and the mixture was stirred at 20°C to 25°C for 12 hours. The precipitated solid was then filtered. The filtrate was washed with 10 mL of ethanol and dried at 50°C to obtain 10 g of the title compound (yield: 83.0%). Moisture content: 1.0%

[0082] Characteristic analysis The results of XRPD analysis, DSC analysis, and DVS analysis of the crystalline form of the methanesulfonate anhydride (MsOH·anhydrate) of the compound of chemical formula 1 produced in Example 4 are shown in Figures 1D, 2D, and 3D, respectively. In the XRPD spectrum of the aforementioned crystal form, the relative intensity (I / I) o The peaks where the ratio was 5% or higher are listed in Table 4 below. o For peaks where the ratio was 10% or more, the diffraction angles (2θ±0.2°) were shown as 7.1°, 10.7°, 11.3°, 11.8°, 12.2°, 14.2°, 15.0°, 17.2°, 17.6°, 18.1°, 18.6°, 19.0°, 20.0°, 21.4°, 22.3°, 22.8°, 23.3°, 23.7°, 24.0°, 24.7°, 27.5°, 27.7°, and 30.3°.

[0083] [Table 4]

[0084] In the DSC (10°C / min) of the aforementioned crystalline form, an endothermic peak was observed at approximately 242.5°C. The endothermic peak at approximately 242.5°C in the DSC indicates the melting point.

[0085] The aforementioned crystalline form showed a moisture content of approximately 1.0% and a melting point of approximately 237 to 242°C, as measured by a Karl Fischer moisture meter.

[0086] In the DVS of the crystalline form, the degree of moisture absorption was measured to be low, approximately 2%, in the relative humidity range of 10% to 90%. The crystalline form was sufficiently stable under long-term storage conditions (e.g., 25°C and 60% relative humidity) and accelerated conditions (e.g., 40°C and 75% relative humidity).

[0087] Example 5. Methanesulfonate monohydrate of the compound of chemical formula 1 (mesylate·1H 2 O) Manufacturing 10 g (21.26 mmol) of the compound of Chemical Formula 1 was added to 100 mL of 90% aqueous ethanol solution (ethanol / water=9 / 1). 1.52 mL (23.38 mmol) of methanesulfonic acid was added dropwise to the reaction solution, the mixture was stirred at 20°C to 25°C for 12 hours, and the precipitated solid was collected by filtration. The filtered product was washed with 10 mL of ethanol and dried at 50°C to obtain 10.9 g of the title compound (yield: 91.0%). Water content: 3.1% (theoretical value for monohydrate: 3.08%)

[0088] Characteristic analysis The results of XRPD analysis, DSC analysis and DVS analysis of the crystalline form of the methanesulfonate monohydrate (MsOH·1H₂O) of the compound of Chemical Formula 1 prepared in Example 5 above are shown in Figure 1E, Figure 2E and Figure 3E, respectively.

[0089] In the XRPD spectrum of the crystalline form, the relative intensity (I / I o ) of 5% or more are listed in Table 5 below. For peaks with a ratio of I / I o of 10% or more, peaks are shown at diffraction angles (2θ±0.2°) of 7.6°, 8.8°, 12.3°, 13.1°, 14.9°, 15.2°, 17.0°, 17.8°, 18.4°, 18.7°, 19.7°, 20.1°, 20.8°, 21.0°, 22.1°, 22.8°, 24.6°, 24.9°, 25.4°, 26.1°, 26.5°, 27.0°, 27.4°, 28.4°, 28.8°, 29.7° and 30.5°.

[0090]

Table 5

[0091] In DSC (10°C / min) of the crystalline form, an endothermic peak is shown at about 92.0°C, and an endothermic peak is shown at about 209.0°C. The endothermic peak at about 92.0°C in DSC corresponds to the dehydration point of the methanesulfonate monohydrate crystalline form, and the endothermic peak at about 209.0°C corresponds to the melting point.

[0092] The aforementioned crystalline form showed a moisture content of approximately 3.1% (theoretical moisture content of 3.08%) using a Karl Fischer moisture analyzer, and exhibited a melting point of approximately 204°C to 208°C.

[0093] In the DVS of the crystalline form, the degree of moisture absorption was measured to be low, approximately 1%, in the relative humidity range of 10% to 90%. The crystalline form was sufficiently stable under long-term storage conditions (e.g., 25°C and 60% relative humidity) and accelerated conditions (e.g., 40°C and 75% relative humidity).

[0094] Example 6. Preparation of the ethanesulfonate anhydride crystalline form of the compound of Chemical Formula 1. Example 6.1. Production using anhydrous ethanol 10 g (21.26 mmol) of the compound of chemical formula 1 was added to 100 mL of ethanol. 1.92 mL (23.38 mmol) of ethanesulfonic acid was added dropwise to the reaction mixture, and the mixture was stirred at 20°C to 25°C for 3 hours. The precipitated solid was then filtered. The filtrate was washed with 10 mL of ethanol and dried at 50°C to obtain 10.5 g of the title compound (yield: 85.0%). Moisture content: 0.3%

[0095] Example 6.2. Production in an aqueous ethanol solution 10 g (21.26 mmol) of the compound of chemical formula 1 was added to 100 mL of a 90% ethanol aqueous solution (ethanol / water = 9 / 1). 1.92 mL (23.38 mmol) of ethanesulfonic acid was added dropwise to the reaction mixture, and the mixture was stirred at 20°C to 25°C for 3 hours. The precipitated solid was then filtered. The filtrate was washed with 10 mL of ethanol and dried at 50°C to obtain 8.9 g of the title compound (yield: 73.0%). Moisture content: 0.2%

[0096] Characteristic analysis The results of XRPD analysis, DSC analysis, and DVS analysis of the ethanesulfonate anhydride (esylate·anhydrate) crystalline form of the compound of chemical formula 1 produced in Example 6 are shown in Figures 1F, 2F, and 3F, respectively.

[0097] In the XRPD spectrum of the aforementioned crystal form, the relative intensity (I / I) o The peaks where the ratio was 10% or higher are listed in Table 6 below. o For peaks where the ratio was 10% or more, the diffraction angles (2θ±0.2) were shown as 7.1°, 11.1°, 11.7°, 12.2°, 14.2°, 14.9°, 17.1°, 18.1°, 18.6°, 19.8°, 20.0°, 21.3°, 22.3°, 23.0°, 23.6°, and 27.6°.

[0098] [Table 6]

[0099] In the DSC (10°C / min) of the aforementioned crystalline form, an endothermic peak was observed at approximately 235.2°C. The endothermic peak at approximately 235.2°C in the DSC indicates the melting point.

[0100] The aforementioned crystalline form showed a moisture content of 0.3% using a Karl Fischer moisture analyzer, and its melting point was measured at approximately 229 to 235°C.

[0101] In the aforementioned crystalline form of DVS, the degree of moisture absorption was measured to be low, approximately 1%, in the relative humidity range of 10% to 90%. Through this, the crystalline form was sufficiently stable under both long-term storage conditions (temperature of 25°C and relative humidity of 60%) and accelerated conditions (e.g., temperature of 40°C and relative humidity of 75%).

[0102] Test Example 1. Water Solubility Measurement Test To measure the water solubility, samples of the acid addition salts of the compound of chemical formula 1 produced in Examples 1 to 6 were prepared in non-ionized water under the following conditions. Each solution was then analyzed by high-performance liquid chromatography (HPLC) under the same conditions as for measuring the content of the compound of chemical formula 1. The amount dissolved was measured relative to the compound of chemical formula 1 (LOD: exceeding 0.001 mg / mL), and this value was converted. The results are shown in Tables 7 and 8 below.

[0103] Specifically, 100 mg of each polymorph was added to 5 mL of water, mixed using a voltamixer at 20°C to 25°C, and the filtrate was filtered using a GH Polypro membrane Acrodisc and PALL (pore size 0.2 μm). The filtrate was then diluted with a diluent for high-performance liquid chromatography (HPLC) analysis.

[0104] [Table 7]

[0105] [Table 8]

[0106] As can be seen from Table 7 above, when compared with the solubility of the compound of chemical formula 1 (free base), the hydrochloride salt of the compound of chemical formula 1 showed higher solubility, and in particular, the dihydrochloride salt of the compound of chemical formula 1 showed higher solubility than the crystalline form of monohydrochloric acid.

[0107] Therefore, among the hydrochloride salts of the compound of chemical formula 1, the dihydrochloride trihydrate crystalline form is expected to be the most advantageous in terms of pharmaceutical composition, considering factors such as dissolution.

[0108] Furthermore, as can be seen from Table 8 above, when compared with the solubility of the compound of chemical formula 1 (free base), the sulfonate salt of the compound of chemical formula 1 showed remarkably high solubility, and in particular, the crystalline form of ethanesulfonic anhydride of the compound of chemical formula 1 showed remarkably high solubility.

[0109] Therefore, among the sulfonates of the compound of chemical formula 1, the crystalline form of ethanesulfonic anhydride is expected to be the most advantageous in terms of pharmaceutical composition, considering factors such as elution.

Claims

1. The crystalline form of the acid addition salt of the compound shown in chemical formula 1 below: 【Chemistry 1】 And, The aforementioned crystal form is When irradiated with a Cu-Kα light source, the dihydrochloride trihydrate (2HCl·3H) of the compound of chemical formula 1 has an X-ray powder diffraction (XRPD) spectrum that includes peaks at diffraction angles (2θ ± 0.2°) of 6.4°, 7.1°, 12.8°, 15.6°, and 21.2°. ２ O) It is a crystalline form, a crystalline form.

2. A pharmaceutical composition comprising the crystalline form described in claim 1 and one or more pharmaceutically acceptable carriers or diluents.

3. The pharmaceutical composition according to claim 2, characterized in that the pharmaceutical composition is used for the treatment or prevention of benign or malignant tumors, inflammatory diseases, or autoimmune diseases induced by epidermal growth factor receptor tyrosine kinase or a variant thereof.

4. The pharmaceutical composition according to claim 3, characterized in that the autoimmune disease is rheumatoid arthritis.

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