HK1254393B - Novel crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1h-pyrrol-3-yl)-n-methylmethanamine salt - Google Patents

Description

New Crystalline Form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy- 1H-pyrrol-3-yl)-N-methylmethanamine Salt

Technical Field

The present invention relates to a new crystalline form of a pharmaceutically acceptable salt of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine.

Background Art

The selection of pharmaceutically acceptable salts and their crystalline polymorphs is a critical step in the development of new drugs. This is because the salts or crystalline polymorphs of certain drugs are often important determinants of the ease of preparation of the drug substance, solubility, stability during distribution and storage, ease of formulation, and pharmacokinetic properties. Crystalline polymorphs are produced when the same corresponding composition is crystallized in different lattice arrangements that result in specific differences in thermodynamic properties and stability. When two or more crystalline polymorphs can be prepared, it is preferred to use a method that produces the pharmaceutically superior crystalline polymorph in a very pure form.

When selecting a desired crystalline polymorph, the properties of the various crystalline polymorphs should be compared and the preferred crystalline polymorph selected based on various types of physical properties. In some cases, where ease of manufacture, stability, etc. are considered important, one crystalline polymorph may be desired, while in other cases, other crystalline polymorphs may be desired for greater solubility and/or primary pharmacokinetic properties.

In particular, there is a constant need for pharmaceutical formulations that exhibit higher bioavailability or higher stability, and therefore a constant need to investigate new acceptable salts or purer salts of existing drug molecules and their crystalline forms.

Therefore, the present inventors have discovered that a new active pharmaceutical substance, 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine, salt and new crystalline forms thereof can be prepared and can be used in pharmacy based on their physicochemical properties and stability, thereby completing the present invention.

Summary of the Invention

Technical issues

The object of the present invention is to provide a new crystalline form of a pharmaceutically acceptable salt of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine having high water solubility and excellent stability.

Technical Solution

To achieve the above objectives, the present invention provides:

Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride;

Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride;

A crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine succinate;

A crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate;

Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate, and

Crystalline Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate.

Hereinafter, the present invention will be described in detail.

The new active pharmaceutical substance 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine is a compound represented by the following chemical formula (1), which corresponds to a 4-methoxypyrrole derivative:

[Chemical Formula 1]

The above-mentioned 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine and its pharmaceutically acceptable salts not only have proton pump inhibitory activity, gastric damage inhibitory activity and defense factor enhancing effect, but also have excellent eradication activity against Helicobacter pylori. Therefore, 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine and its pharmaceutically acceptable salts can be effectively used to prevent and treat gastrointestinal damage caused by gastrointestinal ulcers, gastritis, reflux esophagitis or Helicobacter pylori.

Crystalline forms of pharmaceutically acceptable salts of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine can be prepared by different crystallization methods, such as evaporative crystallization, dissolution crystallization, reactive crystallization, solvent-mediated polymorphic transformation, and solid-state polymorphic transformation, which are selected based on the thermodynamic and kinetic properties of the salt.

In addition, the crystalline form of the pharmaceutically acceptable salt of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine prepared in this way can be identified by X-ray powder diffraction analysis and differential scanning calorimetry analysis.

Specifically, the above-mentioned crystal forms can be classified based on the diffraction angle (2θ) showing a characteristic peak in the X-ray powder diffraction pattern and the peak intensity of each diffraction angle (2θ). Here, due to various factors such as the preparation technology of the measurement sample, the fixing step of the measurement sample, and the measurement instrument, the diffraction angle (2θ) may vary by ±0.2°, or preferably by ±0.1°.

In addition, the crystal form can be distinguished by the endothermic onset temperature and the endothermic temperature representing the maximum endothermic peak in differential scanning calorimetry analysis. Here, the temperature may vary by ±3°C, preferably by ±2°C, and more preferably by ±1°C, depending on various factors such as the sample preparation technique, the measuring instrument, and the temperature change rate.

Crystalline Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride

In the X-ray powder diffraction pattern, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride may have peaks at diffraction angles (2θ±0.2°) of 5.8°, 9.7°, 10.0°, 12.8°, 13.2°, 17.4°, and 18.5°.

In particular, in the X-ray powder diffraction pattern, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride may have peaks at diffraction angles (2θ±0.2°) of 5.8°, 9.7°, 10.0°, 12.8°, 13.2°, 17.4°, 18.5°, 19.5°, 19.8°, 20.1°, 25.9° and 28.2°.

More particularly, in the X-ray powder diffraction pattern, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride may have peaks at diffraction angles (2θ±0.2°) of 5.8°, 9.7°, 10.0°, 12.8°, 13.2°, 17.4°, 18.5°, 19.5°, 19.8°, 20.1°, 21.8°, 25.9°, 26.5° and 28.2°.

In addition, in differential scanning calorimetry analysis, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride can have an endothermic onset temperature of 215.02±3°C and exhibit a maximum endothermic peak at an endothermic temperature of 217.11±3°C.

Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride can be prepared by an evaporative crystallization method comprising the following steps:

1) dissolving 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride in one or more solvents selected from the group consisting of _C1-8 aliphatic alcohols, pentane, hexane, heptane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, dichloromethane, chloroform, diethyl ether, petroleum ether, ethylene glycol, propylene glycol, butanediol, acetonitrile and acetone to prepare a solution; and

2) The solvent was evaporated from the above solution to crystallize the hydrochloride salt.

Step 1) is a step of dissolving the hydrochloride using a good solvent that can completely dissolve the hydrochloride, and can be performed at room temperature. Alternatively, in step 1), 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base and hydrochloric acid can be used instead of the hydrochloride.

In this case, as the C _1-8 aliphatic alcohol, methanol, ethanol, propanol, isopropanol, n-butanol, or n-octanol can be used.

For example, the solvent may be methanol, ethanol, ethyl acetate, dichloromethane or acetone, and may be used in 1 to 20 times volume (ml/g), or preferably 5 to 20 times volume (ml/g) relative to the weight of the hydrochloride.

Step 2) is a step of evaporating the solvent from the solution prepared in step 1) and making the solution supersaturated to crystallize the hydrochloride, which can be performed at a temperature of 23° C. to 28° C. for 1 to 4 days.

Alternatively, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride can be prepared by a dissolution crystallization method comprising the following steps:

1) dissolving 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride in one or more solvents selected from the group consisting of _C1-8 aliphatic alcohols, pentane, hexane, heptane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, dichloromethane, chloroform, diethyl ether, petroleum ether, ethylene glycol, propylene glycol, butanediol, acetonitrile and acetone to prepare a solution; and

2) adding one or more crystallization solvents selected from the group consisting of C _1-8 fatty alcohols, water and organic solvents to the solution and stirring to crystallize the hydrochloride.

Step 1) can be carried out in the same manner as step 1) of the above-mentioned evaporative crystallization method.

Step 2) is to add an antisolvent to the solution prepared in step 1) to change the solubility, thereby crystallizing the hydrochloride, wherein stirring can be performed at a temperature of 23° C. to 28° C. and a speed of 50 rpm to 300 rpm for 1 hour to 1 day.

In this case, as the C _1-8 aliphatic alcohol, methanol, ethanol, propanol, isopropanol, n-butanol, or n-octanol can be used. As the organic solvent, n-hexane, ethyl acetate, butyl acetate, acetonitrile, chloroform, diethyl ether, or acetone can be used.

In addition, the crystallization solvent may be used in a volume (ml/g) of 1 to 20 times, or preferably 5 to 20 times, relative to the weight of the hydrochloride, and the volume ratio of the crystallization solvent in step 2 to the solvent in step 1 may be 1: 1 to 1: 2. Within the above range, since the crystal generation time is prolonged and an excess solvent is used, crystals can be prepared in high yield and high purity without economic loss.

Crystals prepared by evaporative crystallization and solution crystallization can be recovered from the solution by vacuum filtration. If necessary, the recovered crystals can be washed and dried under vacuum to obtain a high-purity hydrochloride salt form. In addition, the reaction conditions described in the above preparation method, such as the solvent ratio, temperature range, reaction time, etc., can be adjusted according to the selected solvent.

Crystalline Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride

In the X-ray powder diffraction pattern, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride may have peaks at diffraction angles (2θ±0.2°) of 9.2°, 10.0°, 12.9°, and 20.2°.

In particular, in the X-ray powder diffraction pattern, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride may have peaks at diffraction angles (2θ±0.2°) of 9.2°, 9.8°, 10.0°, 12.9°, 13.2°, 13.4°, 13.8°, 15.0°, 18.4°, 19.6° and 20.2°.

In addition, in differential scanning calorimetry analysis, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride can have an endothermic onset temperature of 213.14±3°C and exhibit a maximum endothermic peak at an endothermic temperature of 215.7±3°C.

Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride can be prepared by evaporative crystallization, wherein the solvent in step 1) can be used in an amount of 5 to 50 times the volume (ml/g), or preferably 30 to 50 times the volume (ml/g), relative to the weight of the hydrochloride.

Crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate

In the X-ray powder diffraction pattern, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate may have peaks at diffraction angles (2θ±0.2°) of 8.0°, 11.2°, 12.0°, 14.9°, 22.1° and 24.1°.

In particular, in the X-ray powder diffraction pattern, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate may have peaks at diffraction angles (2θ±0.2°) of 8.0°, 11.2°, 12.0°, 14.9°, 20.0°, 22.1° and 24.1°.

In addition, in differential scanning calorimetry analysis, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate can have an endothermic onset temperature of 132.3±3°C and exhibit a maximum endothermic peak at an endothermic temperature of 133.9±3°C.

The crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate can be prepared by evaporation crystallization or solution crystallization similar to Form I of the hydrochloride salt, except that succinate is used instead of hydrochloride.

Crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate

In the X-ray powder diffraction pattern, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate may have peaks at diffraction angles (2θ±0.2°) of 11.7°, 21.5°, and 23.5°.

In particular, in the X-ray powder diffraction pattern, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate may have peaks at diffraction angles (2θ±0.2°) of 11.7°, 13.0°, 13.5°, 14.5°, 18.3°, 19.5°, 20.3°, 21.5° and 23.5°.

In addition, in differential scanning calorimetry analysis, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate can have an endothermic onset temperature of 146.34±3°C and exhibit a maximum endothermic peak at an endothermic temperature of 148.27±3°C.

The crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate can be prepared by evaporation crystallization or dissolution crystallization similar to Form I of the hydrochloride salt, except that the tartrate salt is used instead of the hydrochloride salt.

Crystalline Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate

In the X-ray powder diffraction pattern, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate may have peaks at diffraction angles (2θ±0.2°) of 7.9°, 11.9°, and 24.0°.

In particular, in the X-ray powder diffraction pattern, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate may have peaks at diffraction angles (2θ±0.2°) of 7.9°, 11.9°, 20.0°, and 24.0°.

In addition, in differential scanning calorimetry analysis, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate may have an endothermic onset temperature of 164.97±3°C and exhibit a maximum endothermic peak at an endothermic temperature of 167.46±3°C.

Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate can be prepared by an evaporative crystallization method similar to that of Form I of the hydrochloride salt, except that the fumarate salt is used instead of the hydrochloride salt.

Alternatively, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate can be prepared by a reactive crystallization method comprising the following steps:

1) dissolving 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base and fumaric acid in a _C1-8 fatty alcohol to prepare a 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base solution and a fumaric acid solution, respectively; and

2) The 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base solution and the fumaric acid solution were mixed, and the mixed solution was stirred to crystallize the fumarate.

Step 1) is a step of preparing a solution using a good solvent capable of completely dissolving the free base and fumaric acid, and can be performed at room temperature.

In this case, methanol, ethanol, propanol, isopropanol, n-butanol, or n-octanol can be used as the C _1-8 aliphatic alcohol. Preferably, ethanol can be used as the C _1-8 aliphatic alcohol.

The C _1-8 fatty alcohol can be used in a volume (ml/g) of 5 to 20 times relative to the weight of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base, and the C _1-8 fatty alcohol can be used in a volume (ml/g) of 5 to 30 times relative to the weight of fumaric acid.

Step 2) is a step of mixing the solutions prepared in step 1) and stirring the mixture to produce crystals through a chemical reaction, wherein the stirring can be performed at a temperature of 24° C. to 28° C. and a speed of 50 to 300 rpm for 2 to 4 hours. Within this range, crystals can be efficiently produced while the fumarate is formed.

Crystals prepared by reactive crystallization can be recovered from the solution by vacuum filtration. If necessary, the recovered crystals can be washed and dried under vacuum to obtain a high-purity crystalline form. In addition, the reaction conditions described in the above preparation method, such as solvent ratio, temperature range, reaction time, etc., can be adjusted according to the selected solvent.

Crystalline Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate

In the X-ray powder diffraction pattern, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate may have peaks at diffraction angles (2θ±0.2°) of 8.4°, 10.5°, 18.3°, and 19.02°.

In particular, in differential scanning calorimetry analysis, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate may have an endothermic onset temperature of 179.47±3°C and exhibit a maximum endothermic peak at an endothermic temperature of 189.05±3°C.

Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate can be prepared by a polymorphic transformation method in which Form I of the fumarate salt changes to Form II of the fumarate salt.

For example, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate can be prepared by a solvent-mediated polymorphic transformation method comprising the following steps:

1) dissolving Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine fumarate in a C _1-8 fatty alcohol to prepare a solution; and

2) The solution was stirred to allow the crystalline form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate to undergo polymorphic transformation.

Step 1) is a step of preparing a solution using a good solvent that can completely dissolve the crystalline form I, and can be performed at room temperature.

In this case, methanol, ethanol, propanol, isopropanol, n-butanol, or n-octanol can be used as the C _1-8 aliphatic alcohol. Preferably, ethanol can be used as the C _1-8 aliphatic alcohol.

The solvent may be used in an amount of 1 to 20 times the weight of Form I (ml/g), preferably 5 to 20 times the weight (ml/g).

Step 2) is a step of stirring the solution prepared in step 1) and changing the crystal structure of Form I in the solution to convert it into Form II, wherein the stirring is carried out at a temperature of 24° C. to 28° C. and a speed of 50 rpm to 300 rpm for 12 to 16 hours.

Alternatively, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate can be prepared by a solid-state polymorphic transformation method comprising the following steps:

Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate was vacuum dried at 40°C to 50°C and subjected to polymorphic transformation.

The vacuum drying in the above step can be performed for 12 to 24 hours, and the crystal structure of Form I can be changed by vacuum drying to produce Form II.

Crystals prepared by the polymorphic transformation method can be recovered from the solution through a vacuum filtration process. If necessary, the recovered crystals can be washed and dried under vacuum to obtain a high-purity crystalline form. In addition, the reaction conditions described in the above preparation method, such as the solvent ratio, temperature range, and reaction time, can be adjusted according to the selected solvent.

On the other hand, the present invention provides a pharmaceutical composition comprising: one or more crystalline forms selected from the group consisting of crystalline form I of the hydrochloride salt of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine, crystalline form II of the hydrochloride salt, crystalline form of the succinate salt, crystalline form of the tartrate salt, crystalline form I of the fumarate salt, and crystalline form II of the fumarate salt.

Such pharmaceutical compositions may include commonly used pharmaceutically acceptable carriers. Carriers are carriers commonly used in formulations, including but not limited to lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, etc. In addition to the above components, the pharmaceutical composition may further include lubricants, wetting agents, sweeteners, flavorings, emulsifiers, suspending agents, preservatives, etc.

The above-mentioned pharmaceutical composition can be administered orally or parenterally, including intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection and transdermal administration.

In this case, the pharmaceutical composition can be administered in a therapeutically effective amount, for example, an effective amount ranging from about 0.001 mg/kg to about 100 mg/kg per day. The dosage can vary depending on the formulation method, administration method, patient age, weight, sexually transmitted infection, diet, administration time, administration route, excretion rate or susceptibility.

By using a pharmaceutically acceptable carrier and/or excipient in a unit dose form or in a multidose container, the pharmaceutical composition can be formulated by methods readily implemented by those skilled in the art. In this case, any formulation can be used without limitation, as long as the formulation is in any form suitable for pharmaceutical formulations, including oral dosage forms (e.g., powders, granules, tablets, capsules, suspensions, emulsions, syrups, or sprays), topical formulations (e.g., ointments or creams, suppositories, and sterile injections). In addition, a dispersant or stabilizer may be further included.

Beneficial effects

The new crystalline form of the 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine salt according to the present invention has high water solubility and excellent stability under moisture-proof conditions and high humidity exposure conditions, and can therefore be used pharmaceutically.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 shows an X-ray powder diffraction pattern of Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Example 1-1.

2 shows the X-ray powder diffraction pattern of Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Example 2.

FIG3 shows an X-ray powder diffraction pattern of the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate prepared in Example 3-1.

FIG4 shows an X-ray powder diffraction pattern of the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate prepared in Example 4-1.

FIG5 shows an X-ray powder diffraction pattern of Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate prepared in Example 5-1.

FIG6 shows the X-ray powder diffraction pattern of Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate prepared in Example 6-1.

7 shows an X-ray powder diffraction pattern of the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base prepared in Comparative Example 1.

FIG8 shows the differential scanning calorimetry analysis results of Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Example 1-1.

9 shows the differential scanning calorimetry analysis results of Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Example 2.

FIG10 shows the differential scanning calorimetry analysis results of the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate prepared in Example 3-1.

FIG11 shows the differential scanning calorimetry analysis results of the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate prepared in Example 4-1.

FIG12 shows the differential scanning calorimetry analysis results of Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate prepared in Example 5-1.

FIG13 shows the differential scanning calorimetry analysis results of Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate prepared in Example 6-1.

Figure 14 shows the differential scanning calorimetry analysis results and thermogravimetric analysis results of the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base prepared in Comparative Example 1.

DETAILED DESCRIPTION

The following provides preferred embodiments to help understand the present invention. However, these embodiments are provided only for illustrative purposes and should not be construed as limiting the present invention to these embodiments.

Preparation Example 1: Preparation of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine (free base)

Step 1-1) Preparation of 2-(2,4-difluorophenyl)-2-((3-methoxy-2-(methoxycarbonyl)-3-oxoprop-1-en-1-yl)amino)acetic acid

2,4-Difluorophenylglycine (150.0 g, 801.5 mmol), dimethyl 2-(methoxymethylene)malonate (126.9 g, 728.6 mmol) and sodium acetate (65.8 g, 801.5 mmol) were added to methanol (800.0 ml) and the mixture was refluxed at 60° C. for 4 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to remove approximately 70% of the methanol, followed by filtration. The resulting solid was dried under reduced pressure to give 190.0 g of the title compound (yield: 79.2%).

¹ H-NMR (500MHz, CDCl ₃ ): 8.02-7.99 (m, 1H), 7.45-7.40 (m, 1H), 7.00-6.95 (m, 2H), 5.16 (s, 1H), 3.74 (s, 3H), 3.76 (s, 3H).

Step 1-2) Preparation of 5-(2,4-difluorophenyl)-4-hydroxy-1H-pyrrole-3-carboxylic acid methyl ester

Acetic anhydride (1731.2 ml) and triethylamine (577.1 ml) were added to 2-(2,4-difluorophenyl)-2-((3-methoxy-2-(methoxycarbonyl)-3-oxoprop-1-en-1-yl)amino)acetic acid (190.0 g, 577.1 mmol) prepared in step 1-1. The reaction mixture was refluxed at 140° C. for 30 minutes and then cooled to 0° C. Ice water (577.1 ml) was added to the reaction mixture at 0° C., stirred at room temperature for 1 hour, and then extracted with ethyl acetate. The resulting extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting compound was filtered using silica gel to remove solids and then concentrated under reduced pressure.

Tetrahydrofuran (140.0ml) and water (120.0ml) are added to the obtained residue, and the mixture is cooled at 0°C, and then sodium hydroxide (46.17g, 1154.2mmol) is added to the above mixture. The reaction mixture is stirred at 0°C for 30 minutes, neutralized with 1N aqueous hydrochloric acid solution, and then extracted with ethyl acetate. The obtained extract is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Silica gel column chromatography (ethyl acetate: normal hexane=1:4 (v/v)) is used to purify the obtained residue to obtain 22.0g of the title compound (yield: 15.1%).

¹ H-NMR (500MHz, CDCl ₃ ): 8.80 (s, 1H), 8.17-8.12 (m, 2H), 7.13 (d, 1H), 6.95 (t, 1H), 6.86-6.83 (m, 1H), 3.88 (s, 3H).

Step 1-3) Preparation of 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester

5-(2,4-difluorophenyl)-4-hydroxy-1H-pyrrole-3-carboxylic acid methyl ester (22.0 g, 86.9 mmol) prepared in step 1-2 was dissolved in tetrahydrofuran (434.5 ml) and methanol (173.9 ml). (Trimethylsilyl)diazomethane (2.0 M ether solution, 173.8 ml) was added to the reaction mixture and stirred at room temperature for 48 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 (v/v)) to give 18.1 g of the title compound (yield: 75.3%).

¹ H-NMR (500MHz, CDCl ₃ ): 8.78 (s, 1H), 8.12 (m, 1H), 7.30 (d, 1H), 6.95 (t, 1H), 6.88 (t, 1H), 3.87 (s, 3H), 3.85 (s, 3H).

Step 1-4) Preparation of 5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxylic acid methyl ester

5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester (18.0 g, 67.4 mmol) prepared in step 1-3 was dissolved in dimethylformamide (335.0 ml). Sodium hydride (60%, dispersion in liquid wax) (4.0 g, 101.0 mmol) was added to the resulting solution at room temperature, and the mixture was stirred at room temperature for 10 minutes. 3-Fluorobenzenesulfonyl chloride (13.37 ml, 101.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 (v/v)) to give the title compound (26.1 g) (yield: 91.1%).

¹ H-NMR (500MHz, CDCl ₃ ):7.98(s,1H),7.43-7.39(m,1H),7.30(t,1H),7.23(d,1H),7.15(q,1H),7.67(q,1H),6.91(t,1H),6.77(t,1H),3.87(s,3H),3.61(s,3H).

Step 1-5) Preparation of 5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde

Methyl 5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxylate prepared in Step 1-4 was dissolved in tetrahydrofuran (300.0 ml). Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution) (183.4 ml, 183.4 mmol) was added to the resulting solution at 0°C, and the mixture was stirred at room temperature for 1 hour, neutralized with 1N hydrochloric acid solution, and then extracted with ethyl acetate. The resulting extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.

The obtained residue was dissolved in dichloromethane (300ml), and diatomaceous earth (26.0g) and pyridinium chlorochromate (39.5g, 183.4mmol) were then added thereto. The reaction mixture was stirred at room temperature for 1 hour, then filtered to remove solids, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (ethyl acetate: normal hexane=1:2 (v/v)) was used to purify the obtained residue to obtain the title compound (17.2g) (yield: 70.9%).

¹ H-NMR (500MHz, CDCl ₃ ):9.89(s,1H),7.99(s,1H),7.45-7.41(m,1H),7.33(s,1H),7.25(d,1H),7.18(q,1H),7.05(s,1H),6.92(t,1H),6.77(t,1H),3.63(s,3H).

Step 1-6) Preparation of 1-(5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-lH-pyrrole-3-carbaldehyde (17.0 g, 43.0 mmol) prepared in step 1-5 was dissolved in methanol (430.0 ml). Methylamine (9.8 M methanol solution) (87.8 ml, 860.0 mmol) was added to the resulting solution, and the mixture was stirred at room temperature for 30 minutes. Sodium borohydride (16.3 g, 430.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) to give the title compound (15.2 g) (yield: 86.1%).

¹ H-NMR (500MHz, CDCl ₃ ):7.39-7.35(m,1H),7.26-7.20(m,2H),7.15(q,1H),7.06(d,1H),6.87(t,1H),6.78(t,1H),3.60(d,2H),3.44(s,3H),2.45(s,3H).

Preparation Example 2: Preparation of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride

1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine (15.0 g, 36.6 mmol) prepared in Preparation Example 1 was dissolved in ethyl acetate (36.6 ml), and a hydrochloric acid solution (2.0 M diethyl ether solution) (36.6 ml, 73.1 mmol) was added thereto. The reaction mixture was stirred at room temperature for 1 hour and then filtered, and the resulting solid was dried under reduced pressure to give the title compound (15.1 g) (yield: 92.5%).

Molecular weight: 446.87.

¹ H-NMR (500MHz, MeOD):7.69(s,1H),7.58-7.53(m,1H),7.45(t,1H),7.30(d,1H) ),7.20-7.15(m,2H),7.02-6.94(m,2H),4.07(d,2H),3.46(s,3H),2.71(s,3H).

Hereinafter, in the following examples, 1-(5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (free base) prepared in Preparation Example 1 and 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Preparation Example 2 were used.

Example 1-1: Preparation of Form I of Hydrochloride by Evaporative Crystallization

300 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride was dissolved in 5 ml of ethanol to prepare a solution. Then, ethanol was evaporated from the prepared solution at room temperature for 1 day. After crystal formation, the crystals were separated by filtration under reduced pressure to obtain 250 mg of Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride.

Example 1-2: Preparation of Form I of Hydrochloride by Dissolution Crystallization

300 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride was dissolved in 5 ml of ethanol to prepare a solution. Then, 5 ml of n-hexane was added to the prepared solution and stirred at 50 rpm for 1 day at room temperature. After crystal formation, the crystals were separated by filtration under reduced pressure to obtain 235 mg of crystalline Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride.

Example 2: Preparation of Form II of Hydrochloride by Evaporative Crystallization

20 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride was dissolved in 1 ml of methanol to prepare a solution. Methanol was then evaporated from the prepared solution at room temperature for 1 day. After crystals were generated, the crystals were separated by filtration under reduced pressure to obtain 15 mg of Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride.

Example 3-1: Preparation of crystalline form of succinate using evaporative crystallization

300 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base and 86.3 mg of succinic acid were dissolved in 5 ml of methanol to prepare a solution. Methanol was then evaporated from the prepared solution at room temperature for 2 days. After crystals were generated, the crystals were separated by filtration under reduced pressure to obtain 340 mg of crystalline 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine succinate.

Example 3-2: Preparation of succinate crystalline form using solution crystallization

300 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine free base and 86.3 mg of succinic acid were dissolved in 5 ml of methanol to prepare a solution. Then, 5 ml of n-hexane was added to the prepared solution and stirred at 50 rpm for 4 hours at room temperature. After crystal formation, the crystals were separated by filtration under reduced pressure to obtain 300 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate.

Example 4-1: Preparation of crystalline form of tartrate using evaporative crystallization

300 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base and 109.7 mg of tartaric acid were dissolved in 5 ml of methanol to prepare a solution. Methanol was then evaporated from the prepared solution at room temperature for 2 days. After crystal formation, the crystals were separated by filtration under reduced pressure to obtain 385 mg of a crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate.

Example 4-2: Preparation of tartrate crystals using a solution crystallization method

300mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine free base and 109.7mg of tartaric acid were dissolved in 5ml of methanol to prepare a solution. Then, 5ml of n-hexane was added to the prepared solution and stirred at room temperature for 4 hours at 50rpm. After crystal formation, the crystal was separated by filtration under reduced pressure to obtain 340mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine tartrate.

Example 5-1: Preparation of Form I of Fumarate by Evaporative Crystallization

300 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base and 84.8 mg of fumaric acid were dissolved in 5 ml of ethanol to prepare a solution. Then, ethanol was evaporated from the prepared solution at room temperature for 2 days. After crystal formation, the crystals were separated by filtration under reduced pressure to obtain 340 mg of crystalline Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate.

Example 5-2: Preparation of Form I of Fumarate by Reactive Crystallization

300 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine free base was dissolved in 5 ml of ethanol, and 109.7 mg of fumaric acid was dissolved in 3 ml of ethanol to prepare solutions respectively. Then, the two solutions prepared above were mixed and stirred at room temperature at 50 rpm for 2 hours. After crystal formation, the crystals were separated by filtration under reduced pressure to obtain 314 mg of crystalline Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine fumarate.

Example 6-1: Preparation of Form II of Fumarate Salt Using Solvent-Mediated Polymorphic Transformation

300 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine fumarate crystalline form I was dissolved in 5 ml of ethanol to prepare a solution. The prepared solution was then stirred at room temperature at 50 rpm for 16 hours. After crystal formation, the crystals were separated by filtration under reduced pressure to obtain 250 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine fumarate crystalline form II.

Example 6-2: Preparation of Form II of Fumarate Salt Using Solid-State Polymorphism

300 mg of crystalline form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine fumarate was vacuum dried at 50° C. for 24 hours. After crystals were generated, the crystals were separated by filtration under reduced pressure to obtain 300 mg of crystalline form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine fumarate.

Comparative Example 1: Preparation of free base crystalline form using cooling crystallization method

100 mg of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base was cooled at a low temperature of 4° C. for 2 weeks. After crystals were generated, the crystals were separated by filtration under reduced pressure to obtain 100 mg of a crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base.

Test Example 1: Inhibitory effect on proton pump (H+/K+-ATPase) activity

The inhibitory effect of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Preparation Example 2 on the proton pump (H+/K+-ATPase) activity was measured as follows:

Gastric vesicles were prepared using porcine stomach according to a known method (Edd C. Rabon et al., Preparation of Gastric H+, K+-ATPase., Methods in Enzymology, vol. 157 Academic Press Inc., (1988), pp. 649-654). The protein content of the prepared gastric vesicles was quantitatively measured using a bicinchoninic acid (BCA) kit (Thermo). 80 μl of a test compound (predetermined concentration, 0.5% DMSO, 2.5 mM _MgCl2 , 12.5 mM KCl, 1.25 mM EDTA, 60 mM Tris-HCl, pH 7.4) was added to each well of a 96-well plate. 10 μl of a reaction solution containing gastric vesicles (60 mmol/l, Tris-HCl buffer, pH 7.4) and 10 μl of a Tris buffer solution containing adenosine triphosphate (10 mM ATP, Tris-HCl buffer, pH 7.4) were added to each well and the enzymatic reaction was carried out at 37°C for 40 minutes. 50 μl of malachite green solution (0.12% malachite green solution in 6.2N sulfuric acid, 5.8% ammonium molybdate, and 11% Tween 20 mixed in a ratio of 100:67:2) was added to terminate the enzymatic reaction, and 50 μl of 15.1% sodium citrate was added thereto. The amount of monophosphate (Pi) in the reaction solution was measured at 570 nm using a microplate reader (FLUOstar Omega, BMG). The inhibition rate (%) was determined based on the activity values of the control group and the activity values of the test compound at different concentrations. The concentration that inhibits H + / K + -ATPase activity by 50% (IC ₅₀ ) was calculated from each inhibition % value of the compound using the Logistic 4-parameter function of the Sigmaplot 8.0 program. As a result, the 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Preparation Example 2 showed an IC ₅₀ value of 0.024 μM. Therefore, the salt of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine according to one embodiment of the present invention has excellent proton pump inhibitory activity and can therefore be used as a pharmaceutical composition for preventing and treating gastrointestinal damage caused by gastrointestinal ulcers, gastritis, reflux esophagitis or Helicobacter pylori.

Test Example 2: X-ray powder diffraction analysis

X-ray powder diffraction analysis was performed on the crystalline forms prepared in the Examples and Comparative Examples, and the results are shown in Figures 1 to 7. In this example, X-ray powder diffraction analysis was performed using an X-ray powder diffraction spectrometer (D8 Advance, Bruker) at a voltage of 45 kV, a current of 40 mA, a divergence and scattering slit of 1°, a light receiving slit of 0.2 mm, and a scanning speed of 3°/min (0.4 sec/0.02° interval) over a diffraction angle (2θ) range of 5° to 35° using a CuKα target.

1 , it can be confirmed that in the X-ray powder diffraction pattern, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Example 1-1 has peaks at diffraction angles (2θ) of 5.8°, 9.7°, 10.0°, 12.8°, 13.2°, 17.4°, 18.5°, 19.5°, 19.8°, 20.1°, 21.8°, 25.9°, 26.5°, and 28.2°.

2 , it can be confirmed that in the X-ray powder diffraction pattern, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Example 2 has peaks at diffraction angles (2θ) of 9.2°, 9.8°, 10.0°, 12.9°, 13.2°, 13.4°, 13.8°, 15.0°, 18.4°, 19.6°, and 20.2°.

Referring to Figure 3, it can be confirmed that in the X-ray powder diffraction pattern, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate prepared in Example 3-1 has peaks at diffraction angles (2θ) of 8.0°, 11.2°, 12.0°, 14.9°, 20.0°, 22.1° and 24.1°.

4 , it can be confirmed that in the X-ray powder diffraction pattern, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate prepared in Example 4-1 has peaks at diffraction angles (2θ) of 11.7°, 13.0°, 13.5°, 14.5°, 18.3°, 19.5°, 20.3°, 21.5°, and 23.5°.

5 , it can be confirmed that in the X-ray powder diffraction pattern, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine fumarate prepared in Example 5-1 has peaks at diffraction angles (2θ) of 7.9°, 11.9°, 20.0°, and 24.0°.

6 , it can be confirmed that in the X-ray powder diffraction pattern, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine fumarate prepared in Example 6-1 has peaks at diffraction angles (2θ) of 8.4°, 10.5°, 18.3°, and 19.02°.

7 , it can be confirmed that in the X-ray powder diffraction pattern, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base prepared in Comparative Example 1 has peaks at diffraction angles (2θ) of 8.7°, 10.4°, 12.4°, 17.08°, 17.48°, 21.6°, 25.06°, 26.03°, 28.7°, and 29.6°.

Test Example 3: Differential Scanning Calorimetry

Differential scanning calorimetry (DSC) was performed on the crystalline forms prepared in the Examples and Comparative Examples, and the results are shown in Figures 8 to 14. In this example, differential scanning calorimetry (DSC Q20, TA Instruments Co., Ltd.) was performed in a sealed pan under nitrogen purification with a temperature increase from 200°C to 300°C at a scan rate of 10°C/min.

8 , it can be confirmed that in differential scanning calorimetry analysis, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Example 1-1 has an endothermic onset temperature of 215.02° C. and exhibits a maximum endothermic peak at an endothermic temperature of 217.11° C.

9 , it can be confirmed that in differential scanning calorimetry analysis, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Example 2 has an endothermic onset temperature of 213.14° C. and exhibits a maximum endothermic peak at an endothermic temperature of 215.7° C.

10 , it can be confirmed that in differential scanning calorimetry analysis, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethylamine succinate prepared in Example 3-1 has an endothermic onset temperature of 132.3° C. and exhibits a maximum endothermic peak at an endothermic temperature of 133.9° C.

11 , it can be confirmed that in differential scanning calorimetry analysis, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine tartrate prepared in Example 4-1 has an endothermic onset temperature of 146.34° C. and exhibits a maximum endothermic peak at an endothermic temperature of 148.27° C.

12 , it can be confirmed that in differential scanning calorimetry analysis, Form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate prepared in Example 5-1 has an endothermic onset temperature of 164.97° C. and exhibits a maximum endothermic peak at an endothermic temperature of 167.46° C.

13 , it can be confirmed that in differential scanning calorimetry analysis, Form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate prepared in Example 6-1 has an endothermic onset temperature of 179.47° C. and exhibits a maximum endothermic peak at an endothermic temperature of 189.05° C.

14 , it can be confirmed that in differential scanning calorimetry analysis, the crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base prepared in Comparative Example 1 has an endothermic onset temperature of 79.76° C. and exhibits a maximum endothermic peak at an endothermic temperature of 83.45° C.

As can be seen from Figures 8 to 14, it can be confirmed that the crystal form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base prepared in Comparative Example 1 has a lower endothermic onset temperature and a lower endothermic temperature of the maximum endothermic peak compared to the crystal form of the salt prepared in the examples. Therefore, it can be confirmed that 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base is not suitable for pharmaceutical use due to its low melting point, while the crystal form of the salt according to the examples is pharmaceutically applicable.

Test Example 4: Hygroscopicity test

The crystalline forms prepared in the above examples were tested for hygroscopicity. First, 40 mg of the crystalline forms in the examples were sealed and stored in separate glass desiccators containing saturated aqueous solutions of several salts for at least two days under the constant relative humidity conditions shown in Table 1 below. Subsequently, weight change measurements of each of these crystalline forms revealed no observed weight change due to humidity. Therefore, it can be seen that the crystalline forms prepared in the examples are not hygroscopic.

【Table 1】

Test Example 5: Stability Confirmation Test

The crystalline form prepared in the embodiment was subjected to stability testing to evaluate the degree of impurities formed during storage under harsh conditions (moisture-proof conditions and high humidity exposure conditions). The results of the stability test under moisture-proof conditions are shown in Table 2 below, and the results of the stability test under high humidity exposure conditions are shown in Table 3 below.

For the stability test, vials containing 10 mg of each sample accurately weighed were prepared in the planned quantity and stored under conditions divided into moisture-proof conditions (60°C and relative humidity <10%) and high humidity exposure conditions (60°C and relative humidity of 95%). However, under high humidity exposure conditions, the vial stoppers were not used to allow the samples to fully contact the moisture in the air. At fixed time points after the start of the test, two vials were taken at each time point (n=2 samples per test). 10 ml of methanol was added to each vial to dissolve the sample, followed by centrifugation. The resulting supernatant was analyzed by liquid chromatography. The peak area was determined by integrating all detected peaks, and the relative peak areas of the main components and total impurities were calculated and expressed as an average value.

【Table 2】

【Table 3】

As shown in Tables 2 and 3, it can be confirmed that the crystalline forms prepared in the Examples do not show a decrease in the peak area of the main component and an increase in the peak area of the total impurities, a phenomenon that is extremely significant under moisture-proof conditions and high humidity exposure conditions in the prior art. Therefore, it was confirmed that the crystalline forms prepared in the Examples suppress the increase of impurities and exhibit excellent chemical stability, regardless of the influence of humidity under harsh conditions.

Test Example 6: Water Solubility Test

The crystalline forms prepared in the examples were tested for water solubility, and the results are shown in Table 4 below. For the water solubility test, first, less than 10 mg of sample was accurately weighed and placed in a vial. 50 μl of deionized water was added, and the mixture was shaken for 30 seconds and ultrasonically shaken for 1 minute. This process was repeated several times. The water solubility was calculated by measuring the amount of water used to dissolve all the samples.

【Table 4】

As shown in Table 4, it can be seen that the water solubility of the crystalline forms prepared in the Examples is 10 times or more than that of the crystalline form of the free base prepared in Comparative Example 1. In addition, the crystalline forms prepared in the Examples exhibit high solubility in the order of crystalline form I of the hydrochloride salt, crystalline form of the succinate salt, crystalline form of the tartrate salt, and crystalline form I of the fumarate salt.

Claims (12)

1. A crystal form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine hydrochloride, wherein, in an X-ray powder diffraction pattern, crystal form I has peaks at diffraction angles of 2θ ± 0.2° at 5.8°, 9.7°, 10.0°, 12.8°, 13.2°, 17.4°, and 18.5°. 2. The crystal form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine hydrochloride according to claim 1, wherein, in differential scanning calorimetry, the crystal form I has an endothermic onset temperature of 215.02±3℃ and exhibits a maximum endothermic peak at an endothermic temperature of 217.11±3℃. 3. A crystal form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine hydrochloride, wherein, in an X-ray powder diffraction pattern, crystal form II has peaks at diffraction angles of 2θ±0.2° at 9.2°, 10.0°, 12.9°, and 20.2°. 4. Crystal form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine hydrochloride according to claim 3, wherein, in differential scanning calorimetry, crystal form II has an endothermic onset temperature of 213.14±3℃ and exhibits a maximum endothermic peak at an endothermic temperature of 215.7±3℃. 5. A crystal form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine succinate, wherein the crystal form has peaks at diffraction angles of 2θ±0.2° at 8.0°, 11.2°, 12.0°, 14.9°, 22.1° and 24.1° in X-ray powder diffraction patterns. 6. The crystal form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine succinate according to claim 5, wherein, in differential scanning calorimetry, the crystal form has an endothermic onset temperature of 132.3±3℃ and exhibits a maximum endothermic peak at an endothermic temperature of 133.9±3℃. 7. A crystal form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine tartrate, wherein the crystal form has peaks at diffraction angles of 2θ±0.2° at 11.7°, 13.0°, 13.5°, 14.5°, 18.3°, 19.5°, 20.3°, 21.5° and 23.5° in an X-ray powder diffraction pattern. 8. The crystal form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine tartrate according to claim 7, wherein, in differential scanning calorimetry, the crystal form has an endothermic onset temperature of 146.34±3℃ and exhibits a maximum endothermic peak at an endothermic temperature of 148.27±3℃. 9. A crystal form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine fumarate, wherein, in an X-ray powder diffraction pattern, crystal form I has peaks at diffraction angles of 2θ ± 0.2° at 7.9°, 11.9°, 20.0°, and 24.0°. 10. Crystal form I of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine fumarate according to claim 9, wherein, in differential scanning calorimetry, crystal form I has an endothermic onset temperature of 164.97±3℃ and exhibits a maximum endothermic peak at an endothermic temperature of 167.46±3℃. 11. A crystal form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine fumarate, wherein, in an X-ray powder diffraction pattern, crystal form II has peaks at diffraction angles of 2θ ± 0.2° at 8.4°, 10.5°, and 19.02°. 12. Crystal form II of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethylamine fumarate according to claim 11, wherein, in differential scanning calorimetry, crystal form II has an endothermic onset temperature of 179.47±3℃ and exhibits a maximum endothermic peak at an endothermic temperature of 189.05±3℃.