Crystal Form of Acid Addition Salt of Flopyrimidine Compound

Abstract

One aspect relates to a crystalline form of an acid addition salt of N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)furo[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide, and a pharmaceutical composition containing the same, which can be easily used to prepare a pharmaceutical composition containing the same as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a crystalline form of an acid addition salt of a fluoropyrimidine compound having an inhibitory effect on tyrosine kinase activity represented by the following Chemical Formula 1, which is useful for the treatment of cancer and autoimmune diseases such as rheumatoid arthritis, and 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-methylpiperazin-1-yl)phenylamino)furo[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide, and a pharmaceutical composition containing the same:

Chemical Formula

Background Art

[0002] The compound of the following Chemical Formula 1, whose compound name is N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)furo[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide, is disclosed in Korean Registered Patent No. 1,589,114 and International Patent Publication No. 2011162515. Since the compound has an activity of selectively inhibiting mutant epidermal growth factor receptor tyrosine kinase, Benign it is useful for the treatment of tumors or malignant tumors, inflammatory diseases, or autoimmune diseases such as rheumatoid arthritis.

Chemical Formula

[0003] In addition, the above reference discloses a method for producing the compound of Chemical Formula 1.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

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

[0006] Therefore, it is necessary to produce a salt of the compound of Chemical Formula 1 in crystalline form that meets the strict requirements for pharmaceutical dosage forms and specific matters thereof while improving the solubility in water.

[0007] For this purpose, the present inventors explored the formation of acid addition salts of the compound of Chemical Formula 1 using various acids and solvents under various conditions and procedures. Further, the present inventors evaluated physicochemical properties such as solubility, hygroscopicity, and stability related to the acid addition salts. As a result, among the acid addition salts of the compound of Chemical Formula 1, the crystalline forms of hydrochloride, methanesulfonate, and ethanesulfonate are excellent in solubility in water, do not require specific storage conditions, and are stably maintained for a long time. Thus, they are excellent in various physicochemical properties required in pharmacy and can be easily used for the production of pharmaceutical compositions containing the same as an active ingredient, leading to the completion of the present invention.

[0008] Therefore, an object of the present invention is to provide crystalline forms of acid addition salts of the flopyrimidine compound of Chemical Formula 1, such as hydrochloride, methanesulfonate, and ethanesulfonate, and pharmaceutical compositions containing the same.

MEANS FOR SOLVING THE PROBLEMS

[0009] In accordance with the above object, one aspect provides a crystalline form of an acid addition salt of a compound of the following Chemical Formula 1:

CHEM.

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

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

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

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

[0014] In one specific example, 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 is also a monohydrate, a dihydrate, or a trihydrate, but is not limited thereto.

[0015] Specific examples of the crystal form are as follows: The dihydrochloride trihydrate (2HCl·3H2O) crystal form of the compound of Chemical Formula 1 having an X-ray powder diffraction (XRPD) spectrum including 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; The monohydrochloride dihydrate (1HCl·2H2O) crystal form of the compound of Chemical Formula 1 having an X-ray powder diffraction (XRPD) spectrum including 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) crystal form of the compound of Chemical Formula 1 having an X-ray powder diffraction (XRPD) spectrum including 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) crystal form of the compound of Chemical Formula 1 having an X-ray powder diffraction (XRPD) spectrum including 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 methanesulfonic acid monohydrate (1MsOH·1H2O) crystal form of the compound of Chemical Formula 1 having an X-ray powder diffraction (XRPD) spectrum including 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 ethanesulfonic anhydride (1EsOH) crystal form of the compound of Chemical Formula 1 having an X-ray powder diffraction (XRPD) spectrum including 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 crystal forms are each in a substantially pure form.

[0017] As used herein, the term "substantially pure" means at least 95% pure, desirably 99% pure, and 95% pure means that 5% or less, and 99% pure means that 1% or less of the compound of Chemical Formula 1 is present in any other form (such as other crystal forms, amorphous forms, etc.).

[0018] Another aspect provides a pharmaceutical composition comprising one or more of the crystal forms of the compound of Chemical Formula 1 and one or more pharmaceutically acceptable carriers or diluents.

[0019] The pharmaceutical composition is also used for the treatment of tumors or malignancies, inflammatory diseases, or autoimmune diseases such as rheumatoid arthritis induced by epidermal growth factor receptor tyrosine kinase or variants thereof. Benign

Advantages of the Invention

[0020] ​The crystal forms of the compound of Chemical Formula 1 according to one aspect, for example, hydrochloride, methanesulfonate, and ethanesulfonate, are excellent in various physicochemical properties, that is, solubility in water, hygroscopicity, chemical stability, etc., and are also easily used in the production of pharmaceutical compositions containing the same as an active ingredient.

Brief Description of Drawings

[0021]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 1E

Figure 1F

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Figure 2E

Figure 2F

Figure 3A

Figure 3B

Figure 3C

Figure 3D

Figure 3E

Figure 3F

Mode for Carrying Out the Invention

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

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

[0024] Unless otherwise indicated, those skilled in the art will understand that the peak values from the X-ray powder diffraction studies reported in the present invention are typically associated with observable experimental errors in the art. Specifically, the peak is interpreted to be located within ±0.5° of the value reported herein. More specifically, the peak is interpreted to be located within ±0.2° of the value reported herein.

[0025] The term "acid addition salt" means a salt with an inorganic acid or an organic acid that can form a salt by an acid-base reaction with the compound of Chemical Formula 1. Examples of the inorganic acids used for the formation of the acid addition salt include hydrochloride, bromate, sulfate, phosphate, nitrate, etc., and examples of the organic acids include maleate, fumarate, citrate, succinate, oxalic acid, tartaric acid, methanesulfonate, ethanesulfonic acid, benzenesulfonate, p-toluenesulfonate, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and (+)-camphor-10-sulfonate, etc.

[0026] Hydrochloride, methanesulfonate and ethanesulfonate salts of the compound of Chemical Formula 1, and crystal forms thereof There are provided hydrochloride, methanesulfonate, and ethanesulfonate salts of the compound of the following Chemical Formula 1, i.e., N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)furo[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide, and crystal forms thereof:

Chemical Formula

[0027] The compound of Chemical Formula 1 can also be produced by the general procedures described in Korean Registered Patent No. 1,589,114 and International Patent Publication No. 2011162515, the entire texts of which are incorporated herein by reference.

[0028] The compound of Chemical Formula 1 described in the above-mentioned documents is amorphous and is a poorly soluble compound having a solubility in water of less than 0.001 mg / mL.

[0029] Generally, the conversion of a free base to a salt form is known to assist in solubilizing a water-insoluble drug substance. However, such salts must possess various physicochemical properties such as reproducibility in the production of a specific crystalline form required in pharmacy, high crystallinity, stability of the crystalline form, chemical stability, and non-hygroscopicity.

[0030] To select a suitable salt form of the compound of Formula 1, various acids and solvents were utilized under various conditions and procedures to explore the salt formation of the compound of Formula 1, and physicochemical properties such as the solubility, hygroscopicity, and stability of the generated salts were evaluated. Among the salts thus produced, the crystalline forms of the hydrochloride, methanesulfonate, and ethanesulfonate of the compound of Formula 1 were the most excellent in terms of various physicochemical properties such as reproducibility in the production of a specific crystalline form required in pharmacy, improvement in purity, high crystallinity, stability of the crystalline form, chemical stability, and non-hygroscopicity.

[0031] Crystal forms of hydrochloride, methanesulfonate and ethanesulfonate salts of the compound of Chemical Formula 1 The salts of the compound of Formula 1 are produced in crystalline or amorphous forms, or mixtures thereof, but it is desirable that they be in crystalline form. The crystalline forms of the hydrochloride, methanesulfonate, and ethanesulfonate of the compound of Formula 1 are desirable in that they have excellent stability and physicochemical properties that facilitate formulation.

[0032] According to the present invention, the compound of Formula 1 can be in the form of various crystalline acid addition salts, for example, 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 of the compound of Formula 1.

[0033] As a result of the examination in Test Example 1 below, among the crystalline acid addition salts, the dihydrochloride trihydrate (2HCl·3H2O), the methanesulfonate anhydrate (1MsOH) crystal form, the methanesulfonate monohydrate (1MsOH·1H2O) crystal form, and the ethanesulfonate anhydrate (1EsOH) crystal form are excellent in terms of solubility in water, and the ethanesulfonate anhydrate (1EsOH) crystal form is the most excellent in solubility. Since the above-mentioned acid addition salts are advantageous in terms of non-hygroscopicity / non-desiccation and stability, they are also substances useful as active ingredients of pharmaceutical compositions.

[0034] Hereinafter, each crystal form according to the present invention described above will be described in more detail.

[0035] By way of a specific example, the present invention provides a crystal form of the dihydrochloride trihydrate (2HCl·3H2O) of the compound of Chemical Formula 1, and when irradiated with a Cu-Kα light source, the crystal form 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 crystal form of the dihydrochloride trihydrate (2HCl·3H2O) of the compound of Chemical Formula 1 can 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°. These peaks are also peaks with a relative intensity of about 10% or more.

[0036] The dihydrochloride trihydrate (2HCl·3H2O) crystalline form of the compound of Formula 1 can have a water content of about 8.5% to 9.5% (theoretical water content 9.04%) and a melting point of about 210°C to 220°C. The crystalline form can have two endothermic peaks in the vicinity of about 75°C to 80°C and about 105°C to 110°C in DSC (10°C / min), and these endothermic peaks represent the dehydration points of the trihydrate. It can have an endothermic peak at about 200°C to 220°C, which represents the melting point. It can have an exothermic peak at about 240°C to 250°C, which means thermal decomposition. In the DVS (dynamic vapor sorption) of the crystalline form, moisture absorption occurs in the range of relative humidity from 10% to 20%, and the moisture absorption in the range of relative humidity from 30% to 90% can be measured to be very low.

[0037] In one specific example, the present invention provides a monohydrochloride dihydrate (1HCl·2H2O) crystalline form of the compound of Formula 1. When irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) spectrum including 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°. More specifically, the monohydrochloride dihydrate (1HCl·2H2O) crystalline form of the compound of Formula 1 can have an XRPD spectrum including 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 about 25% or more.

[0038] The monohydrochloride dihydrate (1HCl·2H2O) crystal form of the compound of Formula 1 can have an endothermic peak in the vicinity of about 110 °C to 140 °C in DSC (10 °C / min), and this endothermic peak means the dehydration point of the dihydrate. It can have an endothermic peak at about 160 °C to 170 °C, which means the melting point. The crystal form can have a moisture content of about 6.5% to 7.5% (theoretical moisture content 6.63%) and a melting point of about 150 °C to 170 °C. In DVS, the crystal form can be measured to have a very low hygroscopicity in the range of relative humidity of 10% to 90%.

[0039] By way of a specific example, the present invention provides a crystal form of the monohydrochloride anhydride (1HCl) of the compound of Formula 1, and when irradiated with a Cu-Kα light source, the crystal form 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 crystal form of the monohydrochloride anhydride (1HCl) of the compound of 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°, and these peaks are also peaks with a relative intensity of about 5% or more.

[0040] The crystal form of the monohydrochloride anhydride (1HCl) of the compound of Formula 1 can have an endothermic peak at about 250 °C to 270 °C in DSC (10 °C / min), which means the melting point. The crystal form can have a moisture content of about 0.1% to 1.0% (theoretical moisture content 0%) and a melting point of about 255 °C to 270 °C. In DVS, the crystal form can be measured to have a very low hygroscopicity in the range of relative humidity of 10% to 90%.

[0041] By way of a specific example, the present invention provides a methanesulfonic anhydride (1MsOH) crystal form of the compound of Chemical Formula 1, and when irradiated with a Cu-Kα light source, the crystal form has an X-ray powder diffraction (XRPD) spectrum including peaks at diffraction angles (2θ±0.2°) of 11.8°, 17.2°, 19.0°, 20.0°, 22.8°, and 24.0°. More specifically, the methanesulfonic anhydride (1MsOH) crystal form of the compound of Chemical Formula 1 can have an XRPD spectrum including 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. Those peaks are also peaks with a relative intensity of about 15% or more.

[0042] The methanesulfonic anhydride (1MsOH) crystal form of the compound of Chemical Formula 1 can have a moisture content of about 0.5% to 1.5% (theoretical moisture content 0%) and a melting point of about 235°C to 245°C. The crystal form can have an endothermic peak at about 235°C to 240°C in DSC (10°C / min), which means the melting point. In the DVS of the crystal form, moisture absorption of 2% to 3% can be measured in the range where the relative humidity is 10% to 90%.

[0043] According to a specific example, the present invention provides a methanesulfonic acid monohydrate (1MsOH·1H2O) crystal form of the compound of formula 1, and when irradiated with a Cu-Kα light source, the crystal form has an X-ray powder diffraction (XRPD) spectrum including peaks at diffraction angles (2θ±0.2°) of 7.6°, 15.2°, 17.0°, 18.7°, 20.8°, and 22.8°. More specifically, the methanesulfonic acid monohydrate (1MsOH·1H2O) crystal form of the compound of formula 1 can have an XRPD spectrum including 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 about 15% or more.

[0044] The methanesulfonic acid monohydrate (1MsOH·1H2O) crystal form of the compound of formula 1 can have an endothermic peak in DSC (10°C / min) in the vicinity of about 90°C to 95°C, and this endothermic peak means the dehydration point of the monohydrate. It can have an endothermic peak at about 205°C to 210°C, which means the melting point. The crystal form can have a moisture content of about 2.5% to 3.5% (theoretical moisture content 3.08%) and a melting point of about 200°C to 210°C. In DVS, the moisture absorption of the crystal form can be measured to be very low in the range of relative humidity from 10% to 90%.

[0045] According to a specific example, the present invention provides an ethanesulfonic acid anhydride (1EsOH) crystal form of the compound of Chemical Formula 1, and when irradiated with a Cu-Kα light source, the crystal form has an X-ray powder diffraction (XRPD) spectrum including peaks at diffraction angles (2θ±0.2) of 17.1°, 18.6°, 21.3°, 22.3°, 23.0° and 23.6°. More specifically, the ethanesulfonic acid anhydride (1EsOH) crystal form of the compound of Chemical Formula 1 can have an XRPD spectrum including 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 about 15% or more.

[0046] The ethanesulfonic acid anhydride (1EsOH) crystal form of the compound of Chemical Formula 1 can have an endothermic peak at about 230°C to 240°C in DSC (10°C / min), which means the melting point. The crystal form can have a moisture content of about 0.1% to 1.0% (theoretical moisture content 0%), and a melting point of about 230°C to 240°C. In DVS, the hygroscopicity of the crystal form can be measured to be very low, less than 1% in the range of relative humidity from 10% to 90%.

[0047] Pharmaceutical composition As disclosed in Korean Registered Patent No. 1,589,114 and International Patent Publication No. 2011162515, the compound of Chemical Formula 1 has been proven to have an activity of selectively and effectively suppressing the growth and drug resistance of cancer cells induced by epidermal growth factor receptor (EGFR) tyrosine kinase or its variants.

[0048] From such a 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 BenignIt is also used for manufacturing a pharmaceutical composition for treating or preventing tumors or malignant tumors, inflammatory diseases, or autoimmune diseases such as rheumatoid arthritis.

[0049] Accordingly, the present invention provides a pharmaceutical composition comprising a crystalline hydrochloride, methanesulfonate, and ethanesulfonate of the compound of Chemical Formula 1, and one or more pharmaceutically acceptable carriers or diluents. The pharmaceutical composition is also used for treating cancers, tumors, inflammatory diseases, or autoimmune diseases such as rheumatoid arthritis induced by epidermal growth factor receptor tyrosine kinase or a variant thereof.

[0050] The dosage of the crystalline hydrochloride, methanesulfonate, and ethanesulfonate of the compound of Chemical Formula 1, or a pharmaceutical composition containing the same, varies depending on the subject to be 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, for humans, as an active ingredient, when based on a body weight of 70 kg, as a free base of the compound of Chemical Formula 1, in an amount of 10 mg to 2,000 mg, preferably 50 mg to 1,000 mg, once to four times a day, or on an on / off schedule, it is also administered via oral or parenteral routes. In some cases, a dosage less than the aforementioned range is more suitable, and even more dosages are used without causing harmful side effects. If more dosages are used, they are distributed into several smaller dosages over a day.

[0051] The pharmaceutical composition according to the present invention can be formulated by a general method and is also manufactured into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or parenteral dosage forms such as intramuscular administration, intravenous administration, or subcutaneous administration.

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

[0053] Also provided is a method for treating a disease, comprising the step of administering to an individual a therapeutically effective amount of the crystalline form of the compound of Chemical Formula 1, or the pharmaceutical composition. The disease is Benign also a tumor or malignant tumor, an inflammatory disease or an autoimmune disease such as rheumatoid arthritis.

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

Example

[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 from 3° 2θ to 40° 2θ. When the sample amount was less than 100 mg, a sample of about 5 mg to 10 mg was gently pressed onto a glass slide fitted in the sample holder. When the sample amount exceeded 100 mg, about 100 mg of the sample was gently pressed onto a plastic sample holder so that the sample surface was smooth and directly above the sample holder level. The measurement was carried out as follows: Anode material (Ka): Cu Ka (1.54056 Å) Scan range: 3° to 40° Generator setting: 100 mA, 40.0 kV Scan speed: 1 sec / step Divergence slit size: 0.3 degrees Anti-scatter slit: 0.3 degrees Temperature: 20 °C Step size: 0.02 deg 2θ Rotation: Used Goniometer radius: 435 mm

[0056] 2. Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC) analysis was performed on a STA-1000 (Scinco, Korea) analyzer at 30 °C to 350 °C. A sample of 5 mg to 10 mg was weighed into an aluminum DSC pan, sealed non-hermetically with a perforated aluminum lid, and then the sample was heated from 30 °C to 350 °C at a scan speed of 10 °C / min to monitor the heat flow reaction (DSC) generated.

[0057] 3. Dynamic vapor sorption (DVS) Dynamic vapor sorption (DVS) analysis was performed using a DVS advantage (surface measurement system, UK) analyzer at 25 °C and relative humidity (RH) from 0% to 90%. A 10 mg sample was placed on a wire mesh vapor sorption balance pan and attached to a DVS-advantage dynamic vapor sorption balance by a surface measurement system (surface measurement systems). The sample was maintained at each stage until a stable weight was achieved (99.5% stage completion), and then applied to a ramping profile of 10% to 90% relative humidity (RH) in 10% increments. After completing the adsorption cycle, the sample was dried using the same process but maintained at a relative humidity of 0% or less. The weight change during the adsorption / desorption cycle (repeated 3 times) was recorded to measure the hygroscopicity of the sample.

[0058] 4. High performance liquid chromatography (HPLC) High performance liquid chromatography (HPLC) analysis was performed using an Agilent 1100 / 1200 series HPLC Systems (Agilent, USA) analyzer for purity analysis and content analysis, such as stability tests. The HPLC analysis conditions are as follows. Conditions for purity analysis and content analysis: flupyrimidine compound of Chemical Formula 1 Column: Hydrosphere C18 (YMC), 5 μm (150 mm × 4.6 mm) Column temperature: 30 °C Detector: ultraviolet absorption photometer Detection wavelength: 254 nm Flow rate: 1.0 mL / min Analysis time: 35 min 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 system (Thermo Fisher Scientific, USA) analyzer for the purpose of analyzing the hydrochloric acid content of hydrochloride salts. The IC analysis conditions are as follows respectively. Content analysis conditions: flopyrimidine compound of Chemical Formula 1 Column: IonPac AS19 (Dionex), (25 mm × 4 mm), guard (50 mm × mm) Column temperature: 30 °C Detector: Conductivity detector (CD) Suppressor: ASRS 4 mm, current 40 mA Flow rate: 1.0 mL / min Analysis time: 30 minutes Eluent: 10 mM potassium hydroxide solution

[0060] 6. Moisture measurement Water content measurement was performed using a 795 KFT Titrino (Metrohm, Switzerland) Karl Fischer moisture meter.

[0061] 7. Melting point measurement Melting point measurement was performed using an IA9200 (Electrothermal, UK) melting point meter.

[0062] Examples: Production and analysis of crystal forms of acid addition salts of the compound of Chemical Formula 1

[0063] Example 1. Production of dihydrochloride trihydrate (2HCl·3H₂O) crystal form of the compound of Chemical Formula 1 2 Characteristic analysis 690 g (1.47 mol) of the compound of Chemical Formula 1 produced by the method of Republic of Korea Patent Registration No. 1,589,114 and International Patent Publication No. 2011 / 162515 cited in this specification, or a method similar thereto, was added to 6,900 mL of an 80% aqueous isopropanol solution (isopropanol / water = 8 / 2). After adding 240 mL (2.93 mol) of concentrated hydrochloric acid to the reaction solution, the mixture was stirred at room temperature for 12 hours. The reaction solution was cooled to 10 °C, and the precipitated solid was filtered. After washing with 690 mL of an 80% aqueous isopropanol solution (isopropanol / water = 8 / 2) and drying, 650 g of the title compound (yield: 82.0%) was obtained. Water content: 8.8% (theoretical value for trihydrate: 9.04%) Ion chromatography: 13.6% (theoretical value for dihydrochloride: 13.4%)

[0064] Example 2. Production of monohydrochloride dihydrate (1HCl·2H₂O) crystal form of the compound of Chemical Formula 1 The results of XRPD analysis, DSC analysis, and DVS analysis of the crystalline form produced in Example 1 above are shown in Figures 1A, 2A, and 3A, respectively. In the XRPD spectrum of the crystalline form, peaks with a relative intensity (I / I o ) of 3% or more are listed in Table 1 below. For peaks with a ratio of I / I o of 10% or more, the diffraction angles (2θ ± 0.2°) are 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, an endothermic peak starting at about 58.7 °C with lowest points at about 77.4 °C and about 109.4 °C was shown, an endothermic peak was shown at about 200.1 °C and about 218.7 °C, and an exothermic peak was shown at about 250 °C. The endothermic peaks at about 77.4 °C and about 109.4 °C in the DSC mean the dehydration points of the dihydrochloride trihydrate crystalline form, the endothermic peaks between about 200.08 °C and about 218.69 °C mean the melting points, and the exothermic peak at about 250 °C means thermal decomposition.

[0067] The crystalline form showed a water content of about 8.8% (theoretical water content 9.04%) with a Karl Fischer moisture meter and a melting point between about 210 °C and 218 °C.

[0068] In the DVS of the crystalline form, moisture absorption occurred in the range of relative humidity from 0% to 20%, but the degree of moisture absorption was very low in the range of relative humidity of 30% or more. The 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 2.1. Production from dihydrochloride trihydrate (2HCl·3H₂O) of the compound of Chemical Formula 1 2 Example 2.2. Production from the compound of Chemical Formula 1 Characteristic analysis 2 Example 3. Production of monohydrochloride anhydride (1HCl·anhydrate) crystal form of the compound of Chemical Formula 1 460 g (0.85 mol) of the dihydrochloride trihydrate (2HCl·3H₂O) of the compound of Chemical Formula 1 was added to 4,600 mL of a 50% ethanol aqueous solution (ethanol / water = 5 / 5). The reaction solution was heated to 40 °C to 45 °C, and after adding an aqueous solution in which 67.7 g (1.69 mol) of sodium hydroxide was dissolved in 460 mL of water, it was stirred at 40 °C to 45 °C for 30 minutes. After adding 89.7 mL (1.02 mol) of concentrated hydrochloric acid to the reaction solution, it was stirred at 40 °C to 45 °C for 1 hour. The reaction solution 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 a cooled 50% ethanol aqueous solution (ethanol / water = 5 / 5), and then dried to obtain 398 g of the title compound (yield: 87.0%). Water content: 7.5% (theoretical value for dihydrate: 6.63%) Ion chromatography: 7.4% (theoretical value for monohydrochloride: 7.2%)

[0070] Example 3.1. Production from dihydrochloride trihydrate (2HCl·3H₂O) of 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% aqueous methanol solution (methanol / water = 8 / 2). After adding 10.9 mL (0.12 mol) of concentrated hydrochloric acid to the reaction solution, 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% aqueous methanol solution (methanol / water = 8 / 2), and then dried at 50 °C to obtain 49 g of the title compound (yield: 80.0%). Water content: 6.2% (theoretical value for dihydrate: 6.63%) Ion chromatography: 7.0% (theoretical value for monohydrochloride: 7.2%)

[0071] Example 3.2. Production from the compound of Chemical Formula 1 The results of XRPD analysis, DSC analysis, and DVS analysis of the crystalline form produced in Example 2 above are shown in Figure 1Bb, Figure 2B, and Figure 3B, respectively. In the XRPD spectrum of the crystalline form, peaks with a relative intensity (I / I o ) of 5% or more are listed in Table 2 below. For peaks with a ratio of I / I o of 10% or more, the diffraction angles (2θ ± 0.2°) are 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 crystalline form, endothermic peaks were shown at approximately 115.0 °C and 135.8 °C, and an endothermic peak was shown 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, and the endothermic peak at approximately 165.1 °C represents the melting point. The crystalline form showed a water content of approximately 7.5% (theoretical water content 6.63%) using a Karl Fischer moisture meter, and showed a melting point of approximately 154 °C to 165 °C. In the DVS of the crystalline form, in the range of relative humidity from 10% to 90%, the degree of moisture absorption was measured to be as low as approximately 0.8%. The crystalline form was sufficiently stable under long-term storage conditions (e.g., a temperature of 25 °C and a relative humidity of 60%) and accelerated conditions (e.g., a temperature of 40 °C and a relative humidity of 75%).

[0074] Characteristic analysis Example 4. Production of methanesulfonate anhydride (mesylate·anhydrate) of the compound of Chemical Formula 1 2 Characteristic analysis 70 g of the dihydrochloride trihydrate (2HCl·3H2O) of the compound of Chemical Formula 1 was added to 2,100 mL of water. After stirring the reaction solution at room temperature for 2 hours, 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. Water content: 0.3% Ion chromatography: 7.1% (theoretical value for monohydrochloride: 7.2%)

[0075] Example 5. Production of methanesulfonate monohydrate (mesylate·1H₂O) of 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 solution, it 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%). Water 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 crystalline form produced in Example 3 were shown in FIGS. 1C, 2C, and 3C, respectively. In the XRPD spectrum of the crystalline form, peaks with a relative intensity (I / I o ) of 2% or more are listed in Table 3 below. For peaks with a ratio of I / I o of 5% or more, diffraction angles (2θ ± 0.2°) of 4.9°, 12.2°, 14.8°, 21.2°, 23.1°, and 24.9° were shown.

[0077]

Table 3

[0078] In the DSC (10°C / min) of the crystalline form, an endothermic peak was shown at about 264.2°C. The endothermic peak at about 264.2°C in DSC means the melting point.

[0079] The crystalline form showed a water content of about 0.3% and a melting point of about 259 to 264°C using a Karl Fischer moisture meter.

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

[0081] Example 6. Production of ethanesulfonate anhydride (esylate·anhydrate) crystal form 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 solution, and after stirring at 20°C to 25°C for 12 hours, the precipitated solid was 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%). Water: 1.0%

[0082] Example 6.1. Production in absolute ethanol The results of XRPD analysis, DSC analysis, and DVS analysis of the crystalline form of the methanesulfonate anhydrate (MsOH·anhydrate) of the compound of Chemical Formula 1 produced in Example 4 above are shown in FIGS. 1D, 2D, and 3D, respectively. In the XRPD spectrum of the crystalline form, peaks with a relative intensity (I / I o ) of 5% or more are listed in Table 4 below. For peaks where the ratio of I / I o is 10% or more, the diffraction angles (2θ ± 0.2°) are 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 crystalline form, an endothermic peak was shown at approximately 242.5°C. The endothermic peak at approximately 242.5°C in the DSC means the melting point.

[0085] The crystalline form showed a water content of approximately 1.0% with a Karl Fischer moisture meter and a melting point of approximately 237 to 242°C.

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

[0087] Example 6.2. Production in aqueous ethanol solution 2 Characteristic analysis 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). 1.52 mL (23.38 mmol) of methanesulfonic acid was added dropwise to the reaction solution, and after stirring at 20°C to 25°C for 12 hours, the precipitated solid was filtered. The filtrate 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] Test Example 1. Water solubility measurement test The results of XRPD analysis, DSC analysis, and DVS analysis of the crystal form of the methanesulfonate monohydrate (MsOH·1H2O) of the compound of Chemical Formula 1 produced in Example 5 were shown in Figure 1E, Figure 2E, and Figure 3E, respectively.

[0089] In the XRPD spectrum of the crystal form, peaks with a 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, the diffraction angles (2θ ± 0.2°) were 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 the DSC (10°C / min) of the crystal form, an endothermic peak was shown at about 92.0°C and an endothermic peak was shown at about 209.0°C. The endothermic peak at about 92.0°C in DSC means the dehydration point of the methanesulfonate monohydrate crystal form, and the endothermic peak at about 209.0°C means the melting point.

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

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

[0094] ​ ​ 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 solution, and after stirring at 20°C to 25°C for 3 hours, the precipitated solid was 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: 0.3%

[0095] ​ 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 solution, and after stirring at 20°C to 25°C for 3 hours, the precipitated solid was 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: 0.2%

[0096] ​ The results of XRPD analysis, DSC analysis, and DVS analysis of the esylate·anhydrate crystalline form of the compound of Chemical Formula 1 prepared in Example 6 are shown in Figure 1F, Figure 2F, and Figure 3F, respectively.

[0097] In the XRPD spectrum of the crystalline form, peaks with a relative intensity (I / I o ) of 10% or more are listed in Table 6 below. For peaks where the ratio of I / I o is 10% or more, the diffraction angles (2θ ± 0.2) are 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 crystalline form, an endothermic peak was shown at about 235.2°C. The endothermic peak at about 235.2°C in the DSC means the melting point.

[0100] The crystalline form showed a moisture content of 0.3% with a Karl Fischer moisture meter, and the melting point was measured to be about 229 to 235°C.

[0101] In the DVS of the crystalline form, in the range of relative humidity from 10% to 90%, the degree of moisture absorption was measured to be as low as about 1%. Through this, the crystalline form was sufficiently stable under 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] ​ To measure the water solubility, each acid addition salt of the compound of Chemical Formula 1 produced in Examples 1 to 6 above was used to prepare samples in deionized water under the following conditions, and then each solution was analyzed by high performance liquid chromatography (HPLC) according to the content measurement conditions of the compound of Chemical Formula 1. Based on the compound of Chemical Formula 1, the dissolved amount was measured (LOD: exceeding 0.001 mg / mL), and after converting the value, the resulting values are shown in Tables 7 and 8 below.

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

[0104]

Table 7

[0105]

Table 8

[0106] As can be seen from Table 7 above, when comparing with the solubility of the compound of Chemical Formula 1 (free base), the hydrochloride salt of the compound of Chemical Formula 1 was high, and in particular, the dihydrochloride salt of the compound of Chemical Formula 1 showed a higher solubility than the crystalline form of the monohydrochloride, indicating such a result.

[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 also in terms of the pharmaceutical composition when considering elution and the like.

[0108] Also, as can be seen from Table 8 above, when comparing with the solubility of the compound of Chemical Formula 1 (free base), the sulfonate salt of the compound of Chemical Formula 1 was significantly high, and in particular, the crystalline form of the ethane sulfonic anhydride of the compound of Chemical Formula 1 showed a significantly high solubility, indicating such a result.

[0109] Therefore, among the sulfonate salts of the compound of Chemical Formula 1, the crystalline form of the ethane sulfonic anhydride is expected to be the most advantageous also in terms of the pharmaceutical composition when considering elution and the like.

Claims

1. The crystalline form of the acid addition salt of the compound of the following Chemical Formula 1: 【Chemical 1】 which is the ethanesulfonate anhydride (1EsOH) crystalline form of the compound of Chemical Formula 1, and has an X-ray powder diffraction (XRPD) spectrum including 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. A crystalline form characterized by that.

2. A pharmaceutical composition comprising the crystalline form according to Claim 1 and one or more pharmaceutically acceptable carriers or diluents.

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

4. The pharmaceutical composition according to Claim 3, wherein the autoimmune disease is rheumatoid arthritis.

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