KR100536786B1 - Crystalline polymorph of nafamostat mesilate and method for preparing the same - Google Patents

Abstract

In the powder X-ray diffraction plot, the crystalline polymorph of mesylic acid napamosat exhibiting strong diffraction peaks at 17.0, 18.4, 19.3, 19.9, 20.9, 24.3 and 26.3 degrees at diffraction angles (2θ ± 0.1 degrees) is a very stable crystal. As a result, the quality does not change even during long-term preservation, so that the quality of the drug can be maintained in high purity, and the concern of side effects due to degradation products can be avoided.

Description

Crystalline polymorph of mesylic acid napamostat and its manufacturing method {CRYSTALLINE POLYMORPH OF NAFAMOSTAT MESILATE AND METHOD FOR PREPARING THE SAME}

The present invention relates to a crystalline polymorph of mesylic acid napamosat useful as a pharmaceutical. More specifically, the present invention has a protease inhibitory effect, a blood coagulation, a genesis system, a kallikrein-quinine system, and an inhibitory effect on trypsin, pancreatic kallikrein, and the like, and acute pancreatitis. , Mesylyl, which is useful for preventing intravascular blood clotting (DIC) and coagulation of perfusion blood during circulating blood, and is very stable, so that the quality does not change even during long-term preservation and maintains high quality as a medicine It is about the crystalline polymorph of San Napamosat.

Although a method for producing mesylic acid napamosat is described in Japanese Laid-Open Patent Publication No. 61-1063, no detailed examination of the purification method has been made. For the purification method of mesylic acid napamostat, see Chem. Pharm. Bull., 33 (4), 1470-1471 (1985) describes that a colorless powder having a melting point of 260 ° C. (decomposition) is obtained by recrystallization from water. However, no literature has been described on the crystal polymorphism of mesylic acid napamostat, so far, no knowledge of the crystal polymorphism of mesylic acid napamostat is known.

As a result of the study of mesylic acid napamostat, the present inventors found that various types of crystalline forms exist in mesylic acid napamostat, and the obtained crystalline form differs depending on the production method and production conditions.

For example, in the recrystallization method in which mesolic acid napamostat is dissolved in water and then cooled and crystallized, two kinds of solids (types I and II) are generated depending on the crystallization conditions, and in particular, semi-amorphous Form II crystals are likely to be separated in an aqueous solution, and in a conventional method, it is difficult to filter the separated solids and to obtain a certain quality one.

As another crystallization method, mesyl acid napamosat may be dissolved in an aqueous solvent, followed by crystallization by adding a solvent such as acetone. In this case, two kinds of solids (types I and III) are generated depending on crystallization conditions. It is also conceivable to make it precipitate as a mixture.

Usually, since the compound in which a crystal polymorph exists differs in various properties according to a crystal form, even the same compound may show completely different stability. In particular, pharmaceuticals require high purity and constant quality regardless of the original medicine and pharmaceuticals, and there is a need to stably manufacture and provide a crystalline form having a uniform and high stability as a compound. In order to ensure the uniform and stable quality required as a medicine, it is absolutely necessary to always provide a single crystalline compound constantly.

An amorphous mesylic acid napamostat, which does not have an X-ray diffraction angle obtained by freeze drying currently used as a formulation, has low stability and causes a decrease in content due to long-term storage. As a result, there is a problem that it produces a decomposition product such as p-guanidinobenzoic acid or 6-amidino-2-naphthol, which has been pointed out as a potential cause of hyperkalemia, one of the side effects of mesylic acid napamosat. have. Regardless of the preparation and the original drug, a stable crystalline drug which does not cause any content degradation during long-term storage and does not generate undesirable impurities is preferable.

Disclosure of the Invention

The present inventors have diligently investigated the crystalline polymorph of mesylic acid napamostat, which is useful for acute pancreatitis, diffuse intravascular coagulation (DIC), and the prevention of coagulation of perfusion blood during blood circulation. Several types of polymorphs exist, and it has been found that any kind of crystals have excellent stability in the long-term stability test and have completed the present invention.

The present invention is a crystalline polymorph of mesylic acid napamosat which exhibits strong diffraction peaks at 17.0, 18.4, 19.3, 19.9, 20.9, 24.3 and 26.3 degrees at diffraction angles (2θ ± 0.1 degrees) in a powder X-ray diffraction graph.

Moreover, this invention crystallizes the aqueous solution of the mesylic acid napamosat at 25-45 degreeC in acetone, The manufacturing method of the said crystal polymorphism characterized by the above-mentioned.

The present invention is characterized by strong diffraction peaks or characteristic at 9.0, 13.0, 16.3, 17.1, 18.1, 19.3, 19.8, 20.2, 21.4, 22.4, 23.4 and 23.7 at diffraction angles (2θ ± 0.1 degrees) in powder X-ray diffraction figures. Methalic acid napamosat showing a peak is a process for producing the above-mentioned crystal polymorph, characterized in that phase conversion in a suspended state in alcohol.

The present invention exhibits strong diffraction peaks or characteristic peaks at 16.6, 17.0, 18.4, 19.3, 19.8, 20.2, 22.6, 23.4, 24.2 and 25.8 degrees at diffraction angles (2θ ± 0.1 degrees) in powder X-ray diffraction plots. It is a manufacturing method of the said crystal polymorph, The mesylic acid napamostat is phase-converted in suspension state in alcohol.

Moreover, this invention is the manufacturing method of the said crystal polymorphism characterized by converting amorphous mesylic acid napamostat which does not show a diffraction peak in a powder X-ray diffraction figure in suspension state in alcohol.

Best Mode for Carrying Out the Invention

Mesyl acid napamostat is the following structural formula

6'-Amidino-2'-naphthyl 4-guanidinobenzoate-2 methanesulfonic acid salt, which is represented by the acute pancreatitis, diffuse intravascular coagulation (DIC), perfusion during blood circulation This medicine is used for the prevention of blood clotting.

The crystal polymorph of the novel mesylic acid napamosat provided in the present invention exhibits strong diffraction peaks at 17.0, 18.4, 19.3, 19.9, 20.9, 24.3 and 26.3 degrees at diffraction angles (2θ ± 0.1 degrees) in powder X-ray diffraction diagrams. It is a crystal polymorph (type I crystal). The powder X-ray diffraction diagram of the crystal polymorph (form I crystal) of the present invention is as shown in FIG. This powder X-ray diffraction data is measured using Cu-Kα rays by RINT 2500 V manufactured by Rigaku Electric Co., Ltd.

The crystal polymorph of the novel mesylic acid napamostat provided in the present invention is a very stable crystal, and the quality does not change even during long-term storage, so that the quality of the pharmaceutical product can be maintained in high purity, and the concern of side effects due to degradation products can be avoided. have. More specifically, the crystalline polymorph of mesylic acid napamostat of the present invention was subjected to a 6% accelerated stability test (40 ° C., 75% humidity), in which the freeze-dried mesylic acid napamostat formulation caused a decrease in content of about 1%. It is very stable without causing decomposition at all.

In addition, by formulating the crystalline polymorphic powder of mesylic acid napamostat, there is no need to perform the low temperature, inefficient freeze-drying for a long time, which has the advantage of easy formulation. In addition, because of the good flowability of the crystalline powder is easy to handle and is very suitable for formulation.

The crystal polymorph of the present invention can be produced as follows.

The crystal polymorph of this invention can be obtained by crystallizing the aqueous solution of mesylic acid napamosat in 25-45 degreeC in acetone.

Moreover, different crystal polymorphs can be obtained by changing the temperature conditions at the time of crystallization in acetone. In other words, when the aqueous solution of nafamostat of mesylic acid is crystallized at 20 ° C. or lower in acetone, in the powder X-ray diffraction diagram, 9.0, 13.0, 16.3, 17.1, 18.1, 19.3, 19.8, and 20.2 at a diffraction angle (2θ ± 0.1 degrees) Form III crystals of mesylic acid napamosat showing strong diffraction peaks or characteristic peaks at 21.4, 22.4, 23.4 and 23.7 degrees can be obtained. The powder X-ray diffraction pattern of this III crystal is as shown in FIG. This powder X-ray diffraction data is measured using Cu-Kα rays by RINT 2500 V manufactured by Rigaku Electric Co., Ltd.

The crystalline polymorph of the present invention can also be obtained by phase-converting to the crystalline polymorph of the present invention by suspending this type III crystal in an alcohol such as methanol, ethanol, isopropyl alcohol, preferably isopropyl alcohol.

Mesylic acid napamosat was purified in water to show strong diffraction peaks at 16.6, 17.0, 18.4, 19.3, 19.8, 20.2, 22.6, 23.4, 24.2 and 25.8 degrees at diffraction angles (2θ ± 0.1 degrees) in powder X-ray diffraction plots. Alternatively, a semi-crystalline form II crystal having a characteristic peak can be obtained. The powder X-ray diffraction pattern of this type II crystal is as shown in FIG. This powder X-ray diffraction data is measured using Cu-Kα rays by RINT 2500 V manufactured by Rigaku Electric Co., Ltd.

This type II crystal can be suspended in an alcohol such as methanol, ethanol or isopropyl alcohol, preferably isopropyl alcohol, to be phase-converted to the crystal polymorph of the present invention to obtain the polymorph of the present invention.

Furthermore, amorphous methamic acid napamosat, which does not exhibit a diffraction angle in powder X-ray diffraction, is suspended in an alcohol such as methanol, ethanol, isopropyl alcohol, preferably ethanol to phase-convert to the crystalline polymorph of the present invention. Crystal polymorphs can also be obtained. Amorphous mesylic acid napamosat can be obtained by freeze-drying an aqueous solution of mesylic acid napamosat.

Hereinafter, the present invention will be described in more detail by reference examples, examples, and test examples, but the present invention is not limited to these reference examples, examples, and test examples.

EXAMPLE

Reference Example 1

15 ml of purified water was added to 10 g of mesyl acid napamostat, and it was dissolved by heating at about 70 ° C, and then cooled under stirring to obtain a semicrystalline amorphous solid. It dried under reduced pressure and obtained 5.8g of Form II crystal | crystallization of mesylic acid napamosat. The powder X-ray diffraction figure shown in FIG. 2 was obtained from this crystal.

Reference Example 2

30 ml of purified water was added to 10 g of mesyl acid napamostat to dissolve it at about 50 to 60 캜, and then 300 ml of acetone was added at 20 캜 or lower and crystallized under stirring. The precipitated crystals were filtered off and dried under reduced pressure to obtain 7.4 g of III-form crystals of mesylic acid napamosat. The powder X-ray diffraction figure shown in FIG. 3 was obtained from this crystal.

Example 1

200 ml of isopropyl alcohol was added to 5 g of type II crystal | crystallization of the mesylic acid napamostat obtained by the method of the reference example 1, and it suspended and stirred for 2 hours. The resulting crystals were filtered and dried under reduced pressure at 45 ° C. to obtain 4.8 g of the desired Form I crystal. The powder X-ray diffraction figure shown in FIG. 1 was obtained from this crystal.

Example 2

30 ml of purified water was added to 10 g of mesyl acid napamostat to dissolve it in warm form, and then 300 g of acetone was added at 25 to 45 ° C and crystallized under stirring. The precipitated crystals were filtered off and dried under reduced pressure to obtain 8.1 g of the desired Form I crystal. From this crystal, powder X-ray diffraction diagrams similar to those shown in FIG. 1 were obtained.

Example 3

200 ml of isopropyl alcohol was added to 5 g of type III crystal | crystallization of the mesylic acid napamostat obtained by the method of the reference example 2, and it suspended and stirred. The resulting crystals were filtered and dried under reduced pressure at 45 ° C. to obtain 4.7 g of the desired Type I crystals. From this crystal, powder X-ray diffraction diagrams similar to those shown in FIG. 1 were obtained.

Example 4

100 ml of anhydrous ethanol was added to 5 g of the solid obtained by freeze-drying an aqueous solution of mesylic acid napamostat, suspended at room temperature, filtered, and the obtained crystals were dried at 45 ° C. under reduced pressure to obtain 4.8 g of the desired Form I crystal. . From this crystal, powder X-ray diffraction diagrams similar to those shown in FIG. 1 were obtained.

Test Example 1

The crystalline polymorph (form I) of the present invention obtained in Examples 1 and 4 was subjected to an accelerated stability test for 6 months at a temperature of 40 ° C. and a humidity of 75%. At the same time, the stability test of the amorphous freeze-dried product obtained by lyophilization as a comparative control was conducted.

Table 1 shows the contents of the mesylic acid napamostat over time, and Table 2 shows the amount of byproduct decomposition products. In Table 1 and Table 2, the content of each component of mesylic acid napamostat, 6-amidino-2-naphthol and p-guanidinobenzoic acid was determined from the chart obtained using HPLC for the crystal polymorph. Marked as.

Trend of Content of Mesyl Acid Napamosat over Time (Unit: Area Percentage (%)) Retention period Example 1 Example 4 Freeze dried products 0 months 99.96 99.96 99.88 2 months 99.96 99.96 99.53 4 months 99.95 99.95 99.26 6 months 99.95 99.96 99.06

Trend of byproduct decomposition products (unit: area percentage (%)) Retention period Example 1 Example 4 Freeze dried products 0 months 0.040.00 0.040.00 0.060.01 2 months 0.040.01 0.040.01 0.280.14 4 months 0.040.01 0.040.01 0.430.23 6 months 0.040.01 0.040.01 0.580.31   Top: 6-amidino-2-naphthol Bottom: p-guanidinobenzoic acid

As is clear from Tables 1 and 2, in a 6 month accelerated stability test at a temperature of 40 ° C. and a humidity of 75% of the crystalline polymorph (form I) of the present invention, the freeze-dried product conducted as a comparative control was obtained from the powder of nafamostat of mesylic acid. The production of seafood 6-amidino-2-naphthol and p-guanisinobenzoic acid increased over time, and the mesylic acid napamostat content after 6 months was about 1% lower than the initial value.

On the other hand, the crystalline polymorph (form I) of the present invention did not cause any decrease in content, and no formation of 6-amidino-2-naphthol and p-guanidinobenzoic acid as decomposition products was observed.

In the present invention, the crystal polymorph of the present invention can be obtained by phase-converting the crystal of Form II to the crystal polymorph of the present invention by suspending in an alcohol such as methanol, ethanol, isopropyl alcohol, preferably isopropyl alcohol.

Furthermore, amorphous methamic acid napamosat, which does not exhibit a diffraction angle in powder X-ray diffraction, is suspended in an alcohol such as methanol, ethanol, isopropyl alcohol, preferably ethanol, to be phase-converted to the crystalline polymorph of the present invention. Crystal polymorphs can also be obtained. Amorphous mesylic acid napamosat can be obtained by freeze-drying an aqueous solution of mesylic acid napamosat.

BRIEF DESCRIPTION OF THE DRAWINGS The powder X-ray diffraction data of the crystal polymorph (type I) of mesylic acid napamosat of this invention are shown. This data is measured using the Cu-Kα line by RINT 2500V by Rigaku Electric Co., Ltd .. The vertical axis represents the intensity of X-rays, and the horizontal axis represents the diffraction angle (2θ).

Fig. 2 shows powder X-ray diffraction data of crystalline polymorph (Type II) of mesylic acid napamosat. This data is measured using the Cu-Kα line by RINT 2500V by Rigaku Electric Co., Ltd .. The vertical axis represents the intensity of X-rays, and the horizontal axis represents the diffraction angle (2θ).

Fig. 3 shows powder X-ray diffraction data of crystal polymorph (Type III) of mesylic acid napamosat. This data is measured using the Cu-Kα line by RINT 2500V of Rigaku Electric Co., Ltd. product. The vertical axis represents the intensity of X-rays, and the horizontal axis represents the diffraction angle (2θ).

Claims (5)

Crystalline polymorph of mesylic acid napamosat showing strong diffraction peaks at 17.0, 18.4, 19.3, 19.9, 20.9, 24.3 and 26.3 degrees at diffraction angle (2θ ± 0.1 degrees) in powder X-ray diffraction diagram. The method for producing a crystal polymorph according to claim 1, wherein the aqueous solution of nafamostat of mesyl acid is crystallized at 25 to 45 ° C in acetone. 2. The strong diffraction peak according to claim 1, wherein in the powder X-ray diffraction plot, strong diffraction peaks at 9.0, 13.0, 16.3, 17.1, 18.1, 19.3, 19.8, 20.2, 21.4, 22.4, 23.4, and 23.7 at diffraction angles (2θ ± 0.1 degrees). Or mesylic acid napamostat, which exhibits a characteristic peak, is phase-converted in alcohol in a suspended state. A strong diffraction peak or characteristic peak according to claim 1, in the powder X-ray diffraction plot, at 16.6, 17.0, 18.4, 19.3, 19.8, 20.2, 22.6, 23.4, 24.2 and 25.8 degrees at diffraction angle (2θ ± 0.1 degrees) A method for producing a crystalline polymorph, characterized in that mesylic acid napamostat showing a phase conversion in a suspended state in alcohol. The method for producing a crystalline polymorph according to claim 1, wherein in the powder X-ray diffraction graph, amorphous mesylic acid napamostat, which shows no diffraction peak, is phase-converted in the suspended state in alcohol.