KR101653816B1 - Crystalline Form of Sarpogrelate Oxalate Monohydrate or Sarpogrelate Oxalate Anhydride - Google Patents

Abstract

The present invention relates to crystalline sapoglylate oxalate monohydrate or an anhydride thereof, which is excellent in the solubility, stability and non-hygroscopicity for solvents, and which is useful for preparing a sapogrylate-containing medicament.

Description

Crystalline Form of Sargogrelate Oxalate Monohydrate or Sarpogrelate Oxalate Anhydride < RTI ID = 0.0 >

The present invention relates to crystalline sapoglylate oxalate monohydrate or an anhydride thereof, which is excellent in the solubility, stability and non-hygroscopicity for solvents, and which is useful for preparing a sapogrylate-containing medicament.

Sarpogrelate is represented by the following general formula (1), and the compound is named as (±) -2- (dimethylamino) -1 - [[2- (3-methoxyphenethyl) phenoxy] methyl] ethyl hydrogensulfate It's Nate.

[Chemical Formula 1]

It is well known that Sarpogrelate exhibits a pharmacological action that enhances the antagonism of 5-HT2 receptors of platelets and vascular smooth muscle and the activity of prostaglandin 12 in blood. The present invention relates to a pharmaceutical composition containing sapoglylate hydrochloride as an active ingredient for improving and / or improving ischemic symptoms such as ulcer, pain and cold due to chronic arterial occlusion (Burger's disease, occlusive atherosclerosis, diabetic peripheral vasculopathy etc.) And is commercially available as a therapeutic agent.

A method for producing the saponyl nitrate hydrochloride is disclosed in Japanese Patent Application Laid-open No. 58-032847, US Patent No. 4,220,603, and US Patent No. 4,599,419. In the method disclosed in the above patent, the hydrochloride salt of 1- [2- (3-methoxyphenethyl) phenoxy]) - 3- (dimethylamino) propan-2-ol represented by the following formula (II) is dissolved in a tetrahydrofuran solvent , And a 20% ethyl acetate-hydrogen chloride (EtOAc-HCl) solution is added thereto to prepare a target saponyl nitrate hydrochloride represented by the following formula (I).

[Reaction Scheme 1]

In the case of using ethyl acetate-hydrogen chloride (EtOAc-HCl) solution for the production of the saponyl chloride hydrochloride (I) as shown in Scheme 1, hydrogen chloride gas (HCl) is generated during the process, Process is required.

On the other hand, Japanese Patent Registration No. 3,864,991 discloses that two different crystal forms, i.e., type I and type II crystals, exist in the sapphyrylate hydrochloride. In addition, the above-mentioned type I crystals are very unstable in the above-mentioned Type I and II type crystals, while II-type crystals are relatively stable and are more useful as pharmaceuticals. In addition, the sapphyrylate hydrochloride disclosed in JP-A-58-032847 discloses a polymorphous compound containing about 70 mol% of the Ⅰ type crystal and about 30 mol% of the Ⅱ type crystal.

Table 1 below shows a powder X-ray diffraction spectrum of Form I crystals and II crystals of the saponyl nitrate hydrochloride identified in Japanese Patent Registration No. 3,864,991.

XRD comparison of sapogyrylate hydrochloride Type I crystal Type II crystal Diffraction peaks were confirmed at 9.3 ± 0.2 °, 10.7 ± 0.2 ° and 16.5 ± 0.2 °. Diffraction peaks were confirmed at 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.15 ± 0.1 °. 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.15 ± 0.1 °, where no diffraction peaks were identified No diffraction peaks were observed at 9.3 ± 0.2 °, 10.7 ± 0.2 ° and 16.5 ± 0.2 °

As described above, saponyl chloride hydrochloride or its crystalline polymorphic compound is known as the acid addition salt of the sapogillilate, but its solubility in a water solvent is low and it is difficult to formulate it as a drug. Therefore, it is urgently required to develop a new substitute salt that can improve the low solubility of the saponyl nitrate hydrochloride in water.

Japanese Patent Application Laid-Open No. 58-032847 U.S. Patent No. 4,220,603 U.S. Patent No. 4,599,419 Japanese Patent No. 3,864,991

It is an object of the present invention to provide a crystalline sapogrylate oxalate monohydrate or a crystalline sapogyrylate oxalate anhydride, which replaces the saprolylate hydrochloride.

It is another object of the present invention to provide a method for producing a crystalline sapoglurate oxalate monohydrate or an anhydride thereof.

The present invention also provides a pharmaceutical composition for improving and treating ulcer, pain and cold symptoms due to chronic arterial occlusive disease or chronic arteriosclerosis comprising crystal form sapogrilate oxalate monohydrate and / or an anhydrous crystalline form thereof as an active ingredient For other purposes.

In order to accomplish the object of the present invention, the present invention is characterized in that in the powder X-ray diffraction analysis, the peaks of diffraction angle 2? Are 8.58 ± 0.2, 11.42 ± 0.2, 14.18 ± 0.2, 16.44 ± 0.2, 16.89 ± 0.2, 17.32 ± 0.2 , 17.94 ± 0.2, 19.02 ± 0.2, 20.52 ± 0.2, 21.62 ± 0.2, 22.53 ± 0.2, 23.09 ± 0.2, 23.72 ± 0.2, 24.56 ± 0.2, 26.20 ± 0.2, 27.31 ± 0.2 °. The crystalline samboglate oxalate monohydrate .

In the powder X-ray diffraction analysis, the diffraction angle 2? Peak values were 9.60 ± 0.2, 11.08 ± 0.2, 11.96 ± 0.2, 14.08 ± 0.2, 15.94 ± 0.2, 17.24 ± 0.2, 17.86 ± 0.2, 19.06 ± 0.2, 19.94 ± 0.2, 20.79 ± 0.2, 21.80 ± 0.2, 22.42 ± 0.2, 23.06 ± 0.2, 24.05 ± 0.2, 25.22 ± 0.2, 25.88 ± 0.2, 26.39 ± 0.2, 27.58 ± 0.2, 31.84 ± 0.2, 34.12 ± 0.2, 0.2, 36.38 +/- 0.2 DEG, characterized by a crystalline sapoglylate oxalate anhydride.

Further, the present invention is characterized by a pharmaceutical composition comprising the crystalline sapoglurate oxalate monohydrate as an active ingredient.

Further, the present invention is characterized by a pharmaceutical composition comprising the above-described crystalline sapoglurate oxalate anhydride as an active ingredient.

In addition,

a) 1- [2- (3-methoxyphenethyl) phenoxy] -3- (dimethylamino) propane, 2-ol free base and succinic acid dihydrate to produce a free base of the saponylate; And

b) a step of reacting a free base of saponylate with a dihydrate of oxalic acid in the above inert solvent to produce crystalline sapogrylate oxalate monohydrate; Characterized in that it comprises a process for producing a crystalline sapogenate oxalate monohydrate.

In addition,

a) 1- [2- (3-methoxyphenethyl) phenoxy] -3- (dimethylamino) propane, 2-ol free base and succinic acid dihydrate to produce a free base of the saponylate;

b) a step of reacting a free base of saponylate with a dihydrate of oxalic acid in the above inert solvent to produce crystalline sapogrylate oxalate monohydrate; And

c) Vacuum drying of crystalline sapoglylate oxalate monohydrate at a temperature of 60 ° C to 100 ° C to produce crystalline sapogrylate oxalate anhydride; Characterized in that it comprises a process for producing a crystalline samboglirate oxalate anhydride.

Since the crystalline sapogenate monohydrate or its anhydride characterized by the present invention is excellent in solubility, stability and non-hygroscopicity to a solvent, it is easy to prepare it as a drug by incorporating it as an active ingredient, The drug is excellent in stability, and the drug is stored for a long period of time beyond the distribution period, so that the active ingredient is not decomposed and stably preserved.

Therefore, the crystalline sapoglurate oxalate monohydrate or an anhydride thereof of the present invention is useful as an ischemic symptom such as ulcer, pain and cold due to chronic arterial occlusion (Burger's disease, occlusive atherosclerosis, diabetic peripheral vasculopathy, etc.) Lt; RTI ID = 0.0 > and / or < / RTI >

The oxalic acid used for producing the acid addition salt of the present invention is not corrosive, is not harmful to the human body, is not hygroscopic, and is easy to handle, so that it is suitable for industrial application .

1 is a ¹ H NMR spectrum of a crystalline sapogenate oxalate monohydrate.
2 is a < ¹³ > C NMR spectrum of crystalline sapoglylate oxalate monohydrate.
3 is an FT-IR spectrum of crystalline sapoglylate oxalate monohydrate.
4 is an X-ray powder diffraction diagram of crystalline sapoglylate oxalate monohydrate.
Figure 5 is a TGA spectrum of crystalline sapogenate oxalate monohydrate.
6 is an FT-IR spectrum of crystalline sodium silicate oxalate anhydride.
7 is an X-ray powder diffraction diagram of crystalline sapoglylate oxalate anhydride.
8 is a TGA spectrum of crystalline sapogrylate oxalate anhydride.

The present invention relates to crystalline sapoglylate oxalate monohydrate or an anhydride thereof.

The crystalline sapvirilate oxalate monohydrate according to the present invention will now be described in detail.

The crystalline sapoglurate oxalate monohydrate may be prepared by a process comprising the steps of: a) dissolving 1, 2, 3, 4, 5, 6, 7, 8, 9, - [2- (3-methoxyphenethyl) phenoxy] -3- (dimethylamino) propan-2-ol free base and succinic acid dihydrate represented by the following formula A process for preparing a free base of a saponylate represented by the general formula (4); And b) a free base of a sapphirlyrate represented by the following general formula (4) and an oxalic acid dihydrate represented by the following general formula (5) are reacted with each other in the above inert solvent, The process for preparing the late oxalate monohydrate; .

[Reaction Scheme 2]

In step a), the compound represented by formula 2 is reacted with succinic anhydride represented by formula 3 to prepare a free base of the saponylate represented by formula 3. The succinic anhydride represented by the formula (3) may be used in an amount of 1 to 1.5 equivalents, preferably 1.1 to 1.2 equivalents, based on 1 equivalent of the compound represented by the formula (2). The temperature of the reaction may be in the range of about 15 ° C to 25 ° C, preferably about 4 to 5 hours, and the reaction can be completed sufficiently.

In the conventional method, the hydrochloride of the compound represented by the formula (2) is reacted with the succinic anhydride to prepare the hydrochloride of the saponylate. In this process, the generation of the hydrogen chloride gas is effective for the working environment. However, in the present invention, in order to limit the toxic gas emission to a maximum extent during the synthesis process, the compound represented by Formula 2 is used in the form of a free base, and the use of ethyl acetate-hydrogen chloride (EtOAc-HCl) It is different in that the work environment is improved by suppressing the emission of toxic gas to the utmost during the process such as the like.

The process b) comprises reacting the free base of the saponylate represented by the formula 4 with the oxalic acid dihydrate represented by the formula 5 to obtain the oxalate salt of the saponylate represented by the formula 6 It is the process of making monohydrate.

The oxalic acid dihydrate represented by Formula 5 may be used in an amount of 1 to 1.5 equivalents, preferably 1.1 to 1.2 equivalents, based on the free base of the sapphirelate. The temperature of the reaction may be in the range of about 15 ° C to 25 ° C, and the reaction time may be about 1 to 24 hours. In this case, a conventional organic solvent can be used as a reaction solvent, but the selection of a reaction solvent is also very important considering the yield and purity of the product. As a result of repeated experiments, the present inventors confirmed that at least one inert solvent selected from the group consisting of acetone, acetonitrile, ethyl acetate, and isopropyl alcohol as the reaction solvent is most preferable. The amount of the reaction solvent to be used is generally about 3 to 10 parts by weight, preferably 3 to 10 parts by weight, based on 1 part by weight of free base of the saponylate, 5 parts by weight may be used.

The crystalline sapoglurate oxalate monohydrate prepared through the above production method can be obtained by filtration and drying by drying at 20 to 40 ° C, and can be obtained by a conventional method. The moisture measured by a Karl-Fisher Moisture Analyzer The content ranged from 3.2 to 3.5%. In addition, the purified crystalline sapogenate oxalate monohydrate can be analyzed by hydrogen nuclear magnetic resonance ( ¹ H NMR), carbon nuclear magnetic resonance ( ¹³ C NMR), Fourier Transform Infrared Spectroscopy, powder X- (XRD, light source wavelength 1.5406 Å), and thermogravimetric analysis (TGA) were attached to FIGS. 1 to 5.

The crystalline samboglirate oxalate anhydride according to the present invention will be described in detail as follows.

Crystalline sapoglurate oxalate anhydride can be prepared by reacting an oxalic acid anhydride represented by the following general formula (2) with an acid anhydride represented by the following general formula (2) in an inert solvent selected from the group consisting of a) acetone, acetonitrile, ethyl acetate, and isopropyl alcohol; The free base is reacted with a succinic acid dihydrate represented by the following formula (3) to obtain a compound represented by the following formula (3): < EMI ID = Preparing a free base of the sapogenate represented by the formula (4); b) In the inert solvent, a free base of the saponylate represented by the following general formula (4) is reacted with an oxalic acid dihydrate represented by the following general formula (5) to obtain a crystalline sapoglurate represented by the following general formula (6) A process for preparing oxalate monohydrate; And c) vacuum drying the crystalline sapoglylate oxalate monohydrate represented by the following formula (6) at a temperature of 60 ° C to 100 ° C to produce a crystalline sapogyrylate oxalate anhydride represented by the following formula (7); .

[Reaction Scheme 3]

That is, the crystalline samboglate oxalate anhydride can be prepared by vacuum drying the crystalline sapoglurate oxalate monohydrate prepared by the processes a) and b) according to the above-mentioned Scheme 2.

Vacuum drying in the step c) may be carried out at a temperature of 60 to 100 캜 for about 4 to 24 hours. At this time, if the vacuum drying temperature is less than 60 ° C, the monohydrate of the crystalline sapogenate oxalate coexists with an anhydride, so that a target of high purity can not be obtained. If the vacuum drying temperature exceeds 100 ° C, impurities may be generated.

The crystalline samboglirrate oxalate anhydride prepared through the above production method can be obtained by filtration and drying by drying at a temperature of 20 to 40 ° C and can be obtained by a conventional method. The moisture content measured by a Karl-Fisher Moisture Analyzer Was in the range of 0 to 0.3%. In addition, it was confirmed that the purified crystalline sapoglylate oxalate anhydride was analyzed by hydrogen nuclear magnetic resonance ( ¹ H NMR) and carbon nuclear magnetic resonance ( ¹³ C NMR) analysis. The results of FT-IR spectroscopy, powder X-ray diffraction analysis (XRD, light source wavelength 1.5406 Å) and thermogravimetric analysis (TGA) were attached to FIGS.

It has been confirmed that the crystalline sapoglyrate oxalate monohydrate or an anhydride thereof produced through the above-described preparation method is a separate compound having a clear difference in optical analysis as compared to the commercially available sapogyrylate hydrochloride as the present drug . In addition, the crystalline sapoglurate oxalate monohydrate or an anhydride thereof according to the present invention is excellent in solubility in solvent, non-hygroscopicity and stability, and is thus effective as an active ingredient of a pharmaceutical composition. In particular, the solubility in water solvent is much superior to that of the crystalline sapogenate oxalate monohydrate or an anhydride thereof in comparison with the sapphyrylate hydrochloride.

Accordingly, the crystalline sapoglurate oxalate monohydrate or an anhydride thereof according to the present invention is useful as an active ingredient in a pharmaceutical composition for improving and treating ulcer, pain and cold symptoms due to chronic arteriosclerosis or chronic arteriosclerosis, . ≪ / RTI >

Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

[Example]

Example 1 Synthesis of (±) -2- (dimethylamino) -1 - [[2- (3-methoxyphenethyl) phenoxy] methyl] ethylhydrogen succinate

7.3 g (72 mmol) of succinic anhydride was added to dissolve in 45 mL of acetone. 20 g (60 mmol) of 1- [2- (3-methoxyphenethyl) phenoxy] -3- (dimethylamino) propan-2-ol was added to and dissolved in 46 mL of acetone in a separate container. Was added dropwise to the succinic anhydride solution. Stir 5 h at 0 < 0 > C and concentrate to afford 23.5 g (55 mmol, 91% yield) of the title compound as an oil.

Example 2. Synthesis of crystalline sapoglylate oxalate monohydrate

20 g (47 mmol) of 2- (dimethylamino) -1 - [[2- (3-methoxyphenethyl) phenoxy] methyl] ethylhydrogensuccinate was added to 120 mL of ethyl acetate, and then an oxalic acid dihydrate 6.6 g (52 mmol), and the mixture was stirred at room temperature for 5 hours. The solid was filtered off and dried under reduced pressure at 40 DEG C to give 25.7 g (46 mmol, yield 98%, HPLC purity 99.8%) of the title compound as a solid.

Melting point 116 to 120 캜; Moisture content measured with a Karl-Fisher Moisture Analyzer: 3.3%; ^{1 H NMR (DMSO, 400 MHz} , ppm) δ 7.16 (m, 3H), 6.94 (d, 1H), 6.87 (t, 1H), 6.81 (d, 1H), 6.79 (d, 1H), 6.73 (dd 2H), 2.79 (s, 3H), 2.48 (s, 3H), 2.49 (d, 4H); ^{13 C NMR (DMSO, 400 MHz} , ppm) δ 173.41, 171.91, 164.70, 159.27, 155.85, 143.56, 129.98, 129.72, 129.27, 127.37, 120.89, 120.64, 113.98, 111.61, 111.25, 67.92, 67.46, 57.27, 54.89, 43.67, 35.71, 32.00, 28.95, 28.65; FT-IR (cm ^-1 ) 1736, 1695, 1599, 1590, 1454, 1381, 1348, 1217, 1159, 1039, 752, 700; XRD (2 [Theta] 0.2 [deg.]) 8.58, 11.42, 14.18, 16.44, 16.89, 17.32, 17.94, 19.02, 20.52, 21.62, 22.53, 23.09, 23.72, 24.56, 26.20, 27.31.

Examples 3-6. Synthesis of crystalline sapoglylate oxalate monohydrate

The title compound was synthesized by the method of Example 2, except that the solvent of Table 2 was used instead of ethyl acetate. The yield and purity of the prepared title compound were measured and are shown in Table 2 below.

Example menstruum yield(%) water 2 Ethyl acetate 98 99.8 3 Acetone 88 99.4 4 Isopropyl alcohol 95 99.7 5 Acetonitrile 88 99.4 6 Methanol 48 88.7

Example 7. Synthesis of Crystalline Sapphyrylate Oxalate Anhydride

20 g (37 mmol) of the crystalline sapoglurate oxalate monohydrate prepared in Example 2 was vacuum-dried at 65 DEG C for 8 hours to obtain 19.3 g (36 mmol) of the title compound.

Melting point 106-112 DEG C; Moisture content measured with a Karl-Fisher Moisture Analyzer 0.1%; FT-IR (cm ^-1 ) 1731, 1596, 1621, 1455, 1351, 1240, 1204, 1156, 1041, 958, 850, 785, 751, 699; XRD (2 [theta] + - 0.2) 9.60, 11.08, 11.96, 14.08, 15.94, 17.24, 17.86, 19.06, 19.94, 20.79, 21.80, 22.42, 23.06, 24.05, 25.22, 25.88, 26.39, 27.58, 31.84, 34.12, 35.23,

Comparative Examples 1 to 17 Synthesis of oil / inorganic acid salt of the sapogyrylate

2 g (4.7 mmol) of 2- (dimethylamino) -1 - [[2- (3-methoxyphenethyl) phenoxy] methyl] ethylhydrogensuccinate was placed in 12 mL of ethyl acetate, The indicated oil / mineral acid (5.2 mmol) was added and stirred at room temperature. It was then concentrated to give the oil / mineral acid salt of the sapoglyreate. The properties, yield and purity of each of the oil / inorganic acid salts of the obtained sapoglylate were measured and are summarized in Table 3 below.

division Oil / Mineral Reaction time
(time) Oil / inorganic acid salt of saporoglate Appearance yield(%) water(%) Comparative Example 1 Tartaric acid 8 oil 92 99.0 Comparative Example 2 4-hydroxybenzoic acid 5 oil 83 99.2 Comparative Example 3 Formic acid 12 oil 80 98.7 Comparative Example 4 Malian 14 oil 79 98.9 Comparative Example 5 Methanesulfonic acid 10 oil 77 98.9 Comparative Example 6 Fumaric acid 5 oil 94 99.1 Comparative Example 7 Sulfuric acid 3 oil 81 99.2 Comparative Example 8 Maleic acid 10 oil 90 99.0 Comparative Example 9 Nicotinic acid 12 oil 89 98.9 Comparative Example 10 Camphorsulfonic acid 8 oil 90 98.7 Comparative Example 11 Benzenesulfonic acid 3 oil 82 98.9 Comparative Example 12 Para toluenesulfonic acid 4 oil 83 99.3 Comparative Example 13 L-Aspartic acid 24 oil 78 99.2 Comparative Example 14 Dibenzoyl-d-tartaric acid 18 oil 79 98.9 Comparative Example 15 Glyoxylic acid 4 oil 70 98.7 Comparative Example 16 Citric acid 12 oil 67 99.1 Comparative Example 17 Acetic acid 4 oil 93 99.1

[Experimental Example]

Experimental Example 1. Comparative Test for Stability against Heat and Moisture

The crystalline sapoglurate oxalate monohydrate (Example 2) or the crystalline sapoglurate oxalate anhydride (Example 7) according to the present invention was tested for stability against heat and moisture under the following conditions, Lt; / RTI > hydrochloride (amorphous).

The sapogyrylate hydrochloride used in this experiment was prepared and used according to the method of U.S. Patent No. 4,220,603.

<Experimental Conditions>

1) Storage device: Constant Temp & Humid Chamber SH-201S (Manufacturer: ACT)

2) Storage conditions: Acceleration test - Temperature 40 ± 1 ℃, relative humidity 75%

              Long term storage test - Temperature 20 ± 1 ℃, relative humidity 60%

3) Analytical instrument: HPLC

3) Preparation of standard and test solutions

① Standard solution: Each sample was dissolved in water to prepare a 0.4 mg / mL (100%) solution to prepare a calibration curve.

② Test solution: Accelerated and long-term preservation test samples were prepared and analyzed at a concentration of 1 mg / mL.

③ Calculation of residual ratio: The area value of each sample shown in the HPLC graph was compared with the standard solution and the content was calculated.

sample Test method Remaining rate (%) 1 day 6 days 28th 58 days 200 days Crystalline oxalate monohydrate Accelerated test 99.93 99.92 99.91 99.88 99.60 Long term storage test 99.93 99.92 99.91 99.90 99.85 Crystalline oxalate anhydride Accelerated test 99.93 99.93 99.92 99.92 99.88 Long term storage test 99.93 99.93 99.93 99.93 99.92 Amorphous hydrochloride Accelerated test 99.92 99.92 99.91 99.85 99.58 Long term storage test 99.92 99.92 99.91 99.86 99.72

As shown in Table 4 above, the crystalline sapoglurate oxalate monohydrate and the crystalline sapoglurate oxalate anhydride exhibited stability equal to or higher than that of sapoglylate hydrochloride under various humidity conditions. In addition, the crystalline sapoglurate oxalate monohydrate and the crystalline sapoglurate oxalate anhydride exhibit stability of 0.5% or less under the accelerated test conditions (relative humidity 75%), and thus they can be used for various formulations such as tablets, capsules, It can be seen that the work is advantageous.

Experimental Example 2: Solubility comparative test

The crystalline sapoglurate oxalate monohydrate (Example 2) or the crystalline sapogrylate oxalate anhydride (Example 7) according to the present invention was tested for solubility in solvents to obtain a conventional sapphyrylate hydrochloride (amorphous ).

menstruum Solubility (mg / mL) Crystalline oxalate
Monohydrate Crystalline oxalate
anhydride Amorphous hydrochloride water 21 35 7 Methanol 68 77 53 Ethyl acetate 0.2 0.2 0.3 Glacial acetic acid 28 29 31 ethanol 27 29 21

According to Table 5, it can be confirmed that the crystalline sapoglurate oxalate monohydrate and the crystalline sapogrylate oxalate anhydride have excellent solubility in water and various organic solvents. In particular, it is confirmed that the solubility in water is remarkably superior to that of sapoglylate hydrochloride.

Claims (7)

And the diffraction angle 2? Peaks in powder X-ray diffraction analysis were 8.58 0.2, 11.42 0.2, 14.18 0.2, 16.44 0.2, 16.89 0.2, 17.32 0.2, 17.94 0.2, 19.02 0.2, 20.52 ± 0.2, 21.62 ± 0.2, 22.53 ± 0.2, 23.09 ± 0.2, 23.72 ± 0.2, 24.56 ± 0.2, 26.20 ± 0.2, 27.31 ± 0.2 °.
And the diffraction angle 2? Peaks in powder X-ray diffraction analysis were 9.60 0.2, 11.08 0.2, 11.96 0.2, 14.08 0.2, 15.94 0.2, 17.24 0.2, 17.86 0.2, 19.06 ± 0.2, 19.94 ± 0.2, 20.79 ± 0.2, 21.80 ± 0.2, 22.42 ± 0.2, 23.06 ± 0.2, 24.05 ± 0.2, 25.22 ± 0.2, 25.88 ± 0.2, 26.39 ± 0.2, 27.58 ± 0.2, 31.84 ± 0.2, 34.12 ± 0.2 , 35.23 ± 0.2, 36.38 ± 0.2 °.
An agent for improving and treating ischemic symptoms of ulcer, pain and cold sensation caused by chronic arterial occlusive disease or chronic arteriolar obstruction, comprising the crystalline sapogenate oxalate monohydrate of claim 1 as an active ingredient.
A medicament for improving and treating ischemic symptoms of ulcers, pain and cold sensation due to chronic arterial occlusion or chronic arteriolar obstruction, comprising the crystalline sapogrylate oxalate anhydride of claim 2 as an active ingredient.
a) 1- [2- (3-methoxyphenethyl) phenoxy] -3- (dimethylamino) propane, 2-ol free base and succinic acid dihydrate to produce a free base of the saponylate; And
b) In an inert solvent selected from the group consisting of ethyl acetate and isopropyl alcohol, one equivalent of the free base of saponylate and 1 to 1.5 equivalents of oxalic acid dihydrate is reacted with stirring to obtain crystalline sapomil The process for preparing the late oxalate monohydrate;
Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;
a) 1- [2- (3-methoxyphenethyl) phenoxy] -3- (dimethylamino) propane, 2-ol free base and succinic acid dihydrate to produce a free base of the saponylate;
b) In an inert solvent selected from the group consisting of ethyl acetate and isopropyl alcohol, one equivalent of the free base of saponylate and 1 to 1.5 equivalents of oxalic acid dihydrate is reacted with stirring to obtain crystalline sapomil The process for preparing the late oxalate monohydrate; And
c) Vacuum drying of crystalline sapoglylate oxalate monohydrate at a temperature of 60 ° C to 100 ° C to produce crystalline sapogrylate oxalate anhydride;
Lt; RTI ID = 0.0 &gt; 2, &lt; / RTI &gt;
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