KR102221856B1 - Novel crystalline polymorph of fimasartan - Google Patents

Abstract

The present inventors have developed a novel fimasartan free base crystalline form and a polymorph thereof, in which a hydrate form is not properly maintained at room temperature and in a drying process, which is a problem with the potassium hydrate of fimasartan, and has improved low stability due to heat. The present invention can be used as a composition for preventing and/or treatment of hypertensive diseases.

Description

Novel fimasartan crystalline polymorph {NOVEL CRYSTALLINE POLYMORPH OF FIMASARTAN}

The present invention provides a novel crystalline form of fimasartan free base and a polymorph thereof in which the hydrate form is not properly maintained at room temperature and during drying, which is a problem of potassium hydrate of fimasartan, and has improved low stability due to heat.

Fimasartan is an angiotensin II receptor antagonist whose molecular structure is described in Korean Patent Publication No. 10-0354654, and is a useful compound as a prophylactic and/or therapeutic agent for hypertensive diseases. It is sold as a main component of fimasartan potassium trihydrate in Korean Patent Publication No. 10-0521980, which is the main component of a tablet product marketed under the trade name of Kanab tablet.

Korean Patent Publication No. 10-1490329 discloses a crystal form of fimasartan potassium monohydrate. It was reported that the stability was improved.

However, it was predicted that the potassium pimasartan hydrates of Korean Patent Publication Nos. 10-1490329 and 10-0521980 may be phase-transferred to an anhydrous crystal form due to their moisture content dropping by temperature or during storage and storage at room temperature. Therefore, it was required that a new crystal structure of fimasartan is required, which is more stable by temperature, and the moisture content is constant during storage and storage at room temperature.

Korean Patent Application Laid-Open No. 10-2017-0061615 discloses a methanesulfonate, a benzenesulfonate, a campasulfonic acid salt, a toluenesulfonate, an ethane disulfonate or a pimasatan organic acid salt of a naphthalenedisulfonate or a hydrate or solvate thereof. have. This is a new salt that has improved the solubility of fimasartan potassium trihydrate in Korean Patent Publication No. 10-0521980, but there is no significant difference in bioavailability, and the result of measuring the bioavailability is also campasulfonate and benzenesulfoate. Only the results of are specified.

In addition, in the patent for a new salt of fimasartan in Korean Laid-Open Patent Publication No. 10-2017-0061615, the contents of the stability with the potassium salt currently reported are not properly described.

However, since the fimasartan new salt has a problem of being decomposed by water, it is very difficult to secure the polymorphism of fimasartan by water and stability in storage and storage without overcoming this problem.

Korean Registered Patent Publication No. 10-0354654 Korean Registered Patent Publication No. 10-0521980 Korean Patent Publication No. 10-1490329 Republic of Korea Patent Publication No. 10-2017-0061615

The present inventors have tried to overcome the problem of polymorphic transition due to a change in water content, which is a problem of fimasartan potassium trihydrate, and stability during storage and storage.

As a result, the present inventors intend to disclose a novel polymorph of fimasartan that does not undergo polymorphism due to a change in water content, and has excellent stability during storage and storage, and moisture change and stability results due to temperature thereof. do.

The inventors of the present invention have tried to develop a crystalline form of fimasartan as a neutral component in order to improve the problem of polymorphic conversion due to moisture change during storage and storage of fimasartan potassium trihydrate, or its low stability, as a result of research efforts to develop a fimasartan crystalline form even when the temperature is high. A polymorph of Parmasartan of Formula 1 with no change in water content and higher stability was developed.

[Formula 1]

According to an embodiment of the present invention, the present invention is powder X having characteristic peaks at 2θ diffraction angles of 11.332±0.2, 24.001±0.2, 20.594±0.2, 13.501±0.2 and 21.637±0.2 in powder X-ray diffraction (PXRD) analysis. It provides a fimasartan monohydrate crystal form 1, characterized in that it has a line diffraction pattern. According to another embodiment of the present invention, fimasartan monohydrate crystal 1 form of the present invention is 11.332±0.2, 13.501±0.2, 16.598±0.2, 19.736±0.2, 20.305±0.2, 20.594±0.2, 21.637±0.2, 22.552±0.2, 22.552±0.2 It may have characteristic peaks at 0.2, 24.001±0.2 and 24.636±0.2.

For example, the intensity and peak position of the powder X-ray diffraction of the embodiment of the fimasartan monohydrate crystal 1 form according to the present invention may be as shown in Table 1 below.

(Intensity and peak position of PXRD of fimasartan monohydrate crystal type 1)

In addition, the present invention shows the dehydration temperature between 40 ℃ and 120 ℃ in temperature differential scanning calorimetry (DSC) analysis using a sealed fan, the endothermic start temperature 149.99 ℃ ± 3 ℃ and the endothermic temperature of 158.06 ℃ ± 3 ℃ endothermic curve. Provides visible fimasartan monohydrate crystal form 1.

In addition, the present invention provides a fimasartan monohydrate crystal form 1 showing a mass reduction in the range of 3% to 4% in mass reduction due to moisture in thermogravimetric analysis (TGA).

In addition, the present invention provides a crystal 1 form of fimasartan monohydrate having a moisture content of 3% to 4% in a moisture Karl Fischer analysis.

According to another embodiment of the present invention, the present invention is powder X having characteristic peaks at 2θ diffraction angles of 16.849±0.2, 11.371±0.2, 13.585±0.2, 11.657±0.2 and 24.144±0.2 in powder X-ray diffraction (PXRD) analysis. It provides a fimasartan anhydride crystal form 2, characterized in that it has a line diffraction pattern. According to another embodiment of the present invention, the fimasartan anhydride crystalline form 2 of the present invention is 11.371±0.2, 11.657±0.2, 13.585±0.2, 16.849±0.2, 20.381±0.2, 20.827±0.2, 21.689±0.2, 22.560±0.2 It may have characteristic peaks at 0.2 and 24.144±0.2.

For example, the intensity and peak position of the powder X-ray diffraction of the embodiment of the fimasartan anhydride crystal type 2 according to the present invention may be as shown in Table 2 below.

(Intensity and peak position of PXRD of fimasartan anhydride crystal 2 form)

In addition, the present invention does not have a dehydration peak in a temperature differential scanning calorimetry (DSC) analysis using a sealed fan, and fimasartan anhydride showing an endothermic curve of an endothermic initiation temperature of 150.55°C±3°C and an endothermic temperature of 158.83°C±3°C. Provides crystal type 2.

In addition, the present invention provides fimasartan anhydride crystal form 2 having a moisture content of 1% or less in a moisture Karl Fischer analysis.

According to another embodiment of the present invention, the present invention provides fimasartan amorphous, characterized in that the 2θ diffraction angle has a characteristic powder X-ray diffraction pattern of an amorphous form in powder X-ray diffraction (PXRD) analysis.

The effects of the present invention are as follows.

The fimasartan polymorph according to the present invention can be used as a useful active ingredient in a pharmaceutical composition capable of securing stability against polymorphism because there is no change in water content compared to fimasartan potassium trihydrate.

In addition, the fimasartan polymorph according to the present invention has increased stability compared to fimasartan acid addition salts, and thus can be used as a useful active ingredient in storage and storage processes.

1 shows a powder X-ray diffraction pattern of the fimasartan monohydrate crystal type 1 prepared according to an embodiment of the present invention.
2 is a temperature differential scanning calorimeter (DSC) result of the fimasartan monohydrate crystal type 1 prepared according to an embodiment of the present invention.
3 shows the results of thermogravimetric analysis (TGA) of crystal 1 form of fimasartan monohydrate prepared according to an embodiment of the present invention. In these results, fimasartan monohydrate crystal type 1 contains about 3% or more of moisture.
Figure 4 shows a powder X-ray diffraction pattern of the fimasartan anhydride crystal type 2 prepared according to an embodiment of the present invention.
5 shows the results of a temperature differential scanning calorimeter (DSC) of the fimasartan anhydride crystal type 2 prepared according to an embodiment of the present invention.
6 shows an X-ray diffraction pattern of fimasartan amorphous powder prepared according to an embodiment of the present invention.
7 is a result of thermogravimetric analysis (TGA) in order to observe the change in water content by drying the fimasartan monohydrate crystal 1 form of the present invention from room temperature to 60 degrees for 24 hours. Here, it was confirmed that the water content of the fimasartan monohydrate crystal type 1 did not change even when the temperature was increased.

The present invention will be described in more detail through the following examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

[Example 1] Preparation of Fimasartan Monohydrate Crystal Form 1

At room temperature, 10 g of fimasartan potassium trihydrate was added to 100 mL of methylene chloride and dissolved. A 10% aqueous sodium hydrogen carbonate solution was added and stirred for 10 minutes, while the pH was adjusted to about 9-10, and the organic layer was separated. After removing moisture from the organic layer using magnesium sulfate, it was filtered and concentrated under reduced pressure at 45°C. Thereafter, 50 mL of isopropanol was added, stirred at room temperature for 2 hours, filtered (washed with 5 mL of isopropanol), and dried under reduced pressure at 40° C. for 16 hours to obtain 8.2 g of fimasartan monohydrate crystal 1 form.

[Example 2] Preparation of Fimasartan Anhydride Crystal Form 2

At room temperature, 10 g of fimasartan potassium trihydrate was added to 100 mL of ethyl acetate and dissolved. A 10% aqueous sodium hydrogen carbonate solution was added and stirred for 10 minutes, while the pH was adjusted to about 9-10, and the organic layer was separated. After removing moisture from the organic layer using magnesium sulfate, it was filtered and concentrated under reduced pressure at 45°C. Thereafter, 50 mL of isopropanol was added, stirred at room temperature for 2 hours, filtered (washed with 5 mL of isopropanol), and dried under reduced pressure at 70° C. for 48 hours to obtain 7.6 g of fimasartan anhydride crystal 2 form.

[Example 3] Fimasartan amorphous preparation using vacuum evaporation crystallization

After adding 10 g of fimasartan and 200 ml of tetrahydrofuran, stirred at room temperature for 40 minutes to completely dissolve. After that, the solids are simultaneously precipitated by using a diffraction evaporator at a water bath temperature of 50 degrees. After that, the diffraction evaporator was stirred for 20 minutes at a diffraction rate of 90 to obtain a solid. After that, it vacuum-dried at room temperature for 12 hours to obtain fimasartan amorphous in 96% yield.

[Experimental Example 1] Powder X-ray diffraction (PXRD)

PXRD analysis (see Figs. 1, 4, 6) was performed on an X-ray powder diffractometer (D8 Advance) using Cu Kα radiation. The instrument was equipped with tube power, and the amount of current was set at 45 kV and 40 mA. The divergence and scattering slits were set to 1°, and the light-receiving slits were set to 0.2 mm. A θ-2θ continuous scan of 3°/min (0.4 sec/0.02° interval) from 5 to 35° 2θ was used.

[Experimental Example 2] Temperature Differential Scanning Calorimetry (DSC)

DSC Q20 obtained from TA company was used to perform DSC measurements (see Figs. 2 and 5) in a closed pan at a scan rate of 10°C/min from 30°C to 350°C under nitrogen purification.

[Experimental Example 3] Thermogravimetric Analysis (DSC)

Measurements (see Figs. 3 and 7) were performed using a TGA fan at a scan rate of 10° C./min from 30° C. to 350° C. under nitrogen purification using DSC Q50 obtained from TA Corporation.

[Experimental Example 4] Changes in water content of fimasartan monohydrate crystal type 1 and fimasartan potassium trihydrate according to temperature change

Fimasartan monohydrate crystal type 1 and fimasartan potassium trihydrate of the present invention were placed in a vacuum dryer under vacuum drying by 5 g and the change in water content was observed using the KF method every 6 hours at 25 degrees, 40 degrees, and 60 degrees. I did.

Early 6h 12h 18h 24h 25 degrees 3.42% 3.45% 3.48% 3.46% 3.48% 40 degrees 3.42% 3.39% 3.37% 3.38% 3.40% 60 degrees 3.42% 3.40% 3.38% 3.36% 3.38%

(Moisture content change according to temperature change of fimasartan monohydrate crystal type 1)

As shown in Table 3, the problem of the polymorphic transition phenomenon of the hydrate due to the change in water content, which is the problem of the fimasartan potassium hydrate, was confirmed that the fimasartan monohydrate crystal type 1 of the present invention can be solved. In order to analyze this result in more detail, as a result of analyzing samples of fimasartan monohydrate crystal type 1 after 24 hours at 25 degrees, 40 degrees, and 60 degrees through thermogravimetric analysis (TGA), the moisture content was changed as 3%. Did not show.

Therefore, it is believed that the stability of fimasartan potassium hydrate against polymorphism can be solved by the fimasartan monohydrate crystal form 1 of the present invention.

Early 6h 12h 18h 24h 25 degrees 9.45% 9.42% 9.38% 9.25% 9.08% 40 degrees 9.45% 0.38% 0.38% 0.36% 0.32% 60 degrees 9.45% 0.33% 0.33% 0.33% 0.32%

(Moisture content change according to temperature change of conventional fimasartan potassium trihydrate)

The results in Table 4 can be confirmed that the fimasartan potassium trihydrate polymorphism transitions to anhydride due to temperature without maintaining the hydrate by increasing the temperature. This causes a problem that the desired crystal form cannot be properly obtained during the storage and storage process, and thereby can be said to be a fatal problem affecting the absorption rate in the body. However, the fimasartan monohydrate crystalline form 1 of the present invention in Table 3 can be determined to be a more stable crystalline form in a polymorphic transition phenomenon capable of solving this problem.

[Experimental Example 5] Acceleration and Severe Stability Comparison Evaluation of Fimasartan Polymorph and Fimasartan Potassium Trihydrate

The stability test of a drug is to set the storage method and the period of use of the drug, after setting an appropriate standard, and then determining a significant change based on the determined test method and setting the expiration date, thus ensuring the appropriate stability of the drug. Is one of the very important factors in the commercialization of drugs.

Therefore, in order to confirm the possibility of commercialization of the fimasartan polymorph of the present invention, the fimasartan potassium trihydrate was used as a control and accelerated and severely stabilized according to the ICH guidelines, and liquid chromatography (HPLC) described in the US Pharmacopoeia (USP) ) After analysis using the analysis method, the results are shown in Tables 5 and 6.

Early 3 days 7 days Fimasartan potassium trihydrate 99.78% 99.24% 99.08% Fimasartan monohydrate type 1 99.85% 99.84% 99.82% Fimasartan anhydride type 2 99.83% 99.85% 99.84% Fimasartan amorphous 99.78% 99.76% 99.74%

{Accelerated Stability Results of Fimasartan Polymorph and Fimasartan Potassium Trihydrate (40℃± 2℃, RH 75%)}

Early 3 days 7 days Fimasartan potassium trihydrate 99.78% 99.08% 98.5% Fimasartan monohydrate type 1 99.85% 99.83% 99.81% Fimasartan anhydride type 2 99.83% 99.80% 99.78% Fimasartan amorphous 99.78% 99.68% 99.64%

{Severe Stability Results of Fimasartan Polymorph and Fimasartan Potassium Trihydrate (60℃± 2℃, RH 75%)}

Stability tests under accelerated and severe conditions of the fimasartan polymorph and fimasartan potassium trihydrate prepared according to the examples were performed. As a result, as shown in Tables 5 and 6, the fimasartan polymorph according to the present invention was stably maintained without the influence of the purity, but it was confirmed that the conventional fimasartan potassium trihydrate has low purity and poor stability.

Therefore, the fimasartan polymorph of the present invention has improved stability, suggesting a possibility as a new fimasartan raw material pharmaceutical substance.

As described above, specific parts of the present invention have been described in detail, and it is obvious that these specific techniques are only preferred embodiments and are not intended to limit the scope of the present invention to those of ordinary skill in the art. Accordingly, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (4)

In powder X-ray diffraction (PXRD) analysis, it has a powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles of 11.332±0.2, 13.501±0.2, 20.594±0.2, 21.637±0.2, and 24.001±0.2. In DSC) analysis, the dehydration temperature appears between 40°C and 120°C, the endothermic start temperature is 149.99°C±3°C and the endothermic temperature is 158.06°C±3°C, showing an endothermic curve. The fimasartan monohydrate crystalline form 1 according to claim 1, wherein the moisture content is 3 to 4% in the Moisture Karl Fischer analysis. Powder X-ray diffraction (PXRD) analysis has a powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles of 11.371±0.2, 11.657±0.2, 13.585±0.2, 16.849±0.2, and 24.144±0.2. In DSC) analysis, there is no dehydration peak, and fimasartan anhydride crystalline form 2 showing an endothermic curve with an endothermic initiation temperature of 150.55℃±3℃ and an endothermic temperature of 158.83℃±3℃. Fimasartan amorphous, characterized in that the 2θ diffraction angle in powder X-ray diffraction (PXRD) analysis has a characteristic powder X-ray diffraction pattern in the amorphous form of FIG. 6 below:
[Figure 6]

Images