KR101019201B1 - Manufacturing method of dexibuprofen arginate - Google Patents

Abstract

The present invention relates to a method for preparing dexibuprofen arginine salt. The present invention provides a method for preparing a stable dexibuprofen alginine salt in crystalline form without using a crystallization solvent and a crystalline dexibuprofen arginine salt produced thereby.

Ibuprofen, dexibuprofen, dexibuprofen arginine, analgesic agents, crystalline

Description

Manufacturing method of dexibuprofen arginine salt {Manufacturing method of dexibuprofen arginate}

The present invention relates to a technique for preparing dexibuprofen arginate. More particularly, the present invention relates to a process for preparing a stable crystalline dexibuprofen alginine salt without using a crystallization solvent, and to a crystalline dexibuprofen alginine salt produced thereby.

Ibuprofen is a racemic compound as a representative analgesic anti-inflammatory antipyretic.

Dexibuprofen is the S-form isomer of ibuprofen and has the structure of formula (I)

[Formula I]

To date, no method of preparing dexibuprofen arginine salt (Formula II), a crystal form, or the like is specifically known.

≪ RTI ID = 0.0 &

ㆍNH2CNHNH(CH2)3CH(NH2)COOH

NH2CNHNH (CH2) 3CH (NH2) COOH

U.S. Patent 4,994,604 discloses dexibuprofen lysine salt, one of the dexibuprofen salts. This patent document describes a method for resolution and preparation of (S) -Ibuprofen- (S) -lysine (dexibuprofen lysine) from racemic ibuprofen. In the separation and preparation method disclosed in the above patent document, first, racemic ibuprofen and (S) -lysine are added to water / ethanol, and then the resulting slurry is stirred and aged at 30 ° C. for 24 hours, and filtered to obtain a supersaturated filtrate. Seeding the prepared 99.4% (S)-ibuprofen- (S)-lysine slurry to obtain the product is a very complicated process. The solvent used here is crystallization of dexibuprofen lysine with ethanol / water, methanol / water, isopropanol / water, or acetone / water, in particular with ethanol / water.

In the present invention, unlike the dexibuprofen lysine of US Pat. No. 4,994,604, crystalline dexibuprofen arginine salt can be prepared without using a crystallization solvent.

The crystalline dexibuprofen arginine salt of the present invention has a high solubility in water and has an excellent dissolution rate in water, and thus may have pharmacologically advantageous properties over dexibuprofen. In addition, the crystalline dexibuprofen arginine salt of the present invention is not hygroscopic has a characteristic of excellent stability without a change in moisture and no change in color.

Accordingly, the present inventors have completed the present invention by developing a method for preparing crystalline dexibuprofen alginine salt which is stable and has excellent dissolution rate.

It is therefore an object of the present invention to provide a process for the preparation of crystalline dexibuprofen dexibuprofen arginine salts without using a crystallization solvent.

Still another object of the present invention is to provide a stable and excellent dissolution rate of the crystalline dexibuprofen arginine salt prepared using the above method.

The present invention relates to a process for preparing crystalline dexibuprofen alginine salts without the use of crystallization solvents and to crystalline dexibuprofen alginine salts produced thereby.

Hereinafter, the present invention will be described in detail.

Method for producing crystalline dexibuprofen arginine salt according to the present invention

1) dissolving dexibuprofen in the reaction solvent to prepare a solution;

2) adding water to the obtained solution;

3) adding L-arginine to produce a crystal; And

4) filtering, washing and drying the obtained crystals

It includes.

In addition, the production method of the present invention may add a solvent in which the crystals do not melt in order to facilitate filtration in step 4). In addition, in order to make the particle size of the dried crystals uniform, a sieve treatment step may be further included after step 4) [step 5)].

The manufacturing method will be described in more detail by step as follows:

One) Dexibuprofen  Dissolving in a reaction solvent to prepare a solution

The reaction solvent may be one or more selected from the group consisting of isopropanol, ethanol, methanol, and water as a solvent for dissolving dexibuprofen, and isopropanol or a mixture of isopropanol and water is particularly preferable. The amount of the reaction solvent used is not particularly limited, and an amount sufficient to dissolve dexibuprofen is sufficient. For example, in the case of the isopropanol, solubility in dexibuprofen is used as the main reaction solvent, and the amount of the reaction solvent such as isopropanol is 1 (v / w) to 30 times (v) based on the weight of dexibuprofen. / w), more specifically 1 times (v / w) or less than 20 times (v / w), preferably 1.5 times (v / w) to 10 times (v /) by weight of dexibuprofen. w).

2) adding water to the obtained solution

The amount of water used may be appropriately determined to increase the solubility of L-arginine added to the next step, but too much may be an atherosclerosis that does not completely crystallize the final product, dexibuprofen arginine salt. . Therefore, the amount of water used may be 0.001 times to 1 times, preferably 0.01 times to 0.8 times, and more preferably 0.03 times to 0.08 times the amount of the reaction solvent of step 1), preferably isopropanol, based on volume. It is not limited to this.

3) L- Arginine  In addition Crystals  Generating step

The L-arginine may be used in an amount of 0.1 to 1.5 equivalents, more preferably 0.8 or more and less than 1 equivalent to 1 equivalent of dexibuprofen. The amount of L-arginine is used to maximize the reaction efficiency of the reaction between L-arginine and dexibuprofen in an equivalent ratio of 1: 1. When the reaction is performed with ethyl acetate and the like, excess L-arginine is washed. Excess dexibuprofen is easily washed, while the amount of L-arginine used is less than 1 equivalent to 1 equivalent of dexibuprofen as described above. It can manufacture. The L-arginine may be added in the form of 100% (w / v) L-arginine or in the form of a water bath by adding water to 100% (w / v) L-arginine, to prepare an aqueous solution. In case a large amount of water is added, such excess water may interfere with the crystallization of the final product dexibuprofen alginine salt, so 100% (w / v) L-arginine or 80 to 99.9% (w / v) Preference is given to using an aqueous L-arginine solution.

4) Crystals  Filtration, washing and Desiccant  step

The obtained dexibuprofen arginine salt may be filtered as it is, or may be filtered by adding a solvent for convenience of filtration. As the solvent added for the filtration, a solvent which does not dissolve dexibuprofen arginine salt, preferably ethyl acetate may be used.

  In this case, the amount of the solvent, preferably ethyl acetate, may be about 0.01 times (v / v) to 10 times (v / v) in volume ratio with respect to the volume of the reaction solvent, preferably isopropanol of step 1). . Preferably, it may be 0.1 to 5 times (v / v).

The washing and drying steps of the obtained crystals are not particularly limited, and any method commonly used in the art to which the present invention pertains may be used. For example, the mixture may be washed with ethyl acetate and dried at 20 to 100 ° C., preferably at 30 to 80 ° C., for 2 to 30 hours. There is no particular limitation on the drying method, and vacuum drying, ventilation drying, infrared drying, and the like, which are commonly used, may be used.

5) sieve treatment step

The particles can be made uniform by sieving the dried crystals.

The sieve used in the sieve treatment can be used that the lake is 4 mesh to 50 mesh, preferably 12 mesh to 30 mesh can be used to uniform the particles.

The crystalline dexibuprofen arginine salt prepared according to the present invention has the structure of formula II below.

≪ RTI ID = 0.0 &

ㆍNH2CNHNH(CH2)3CH(NH2)COOH

NH2CNHNH (CH2) 3CH (NH2) COOH

Crystalline dexibuprofen arginine salts produced by the preparation method of the present invention are crystalline and have, for example, crystallinity as shown in FIGS. 1 to 2 (diffraction angle (2θ, deg) 6.120, 14.920, 16.900 Peaks at, 19.140, 20.040, 21.482, 24.160, 26.380, 32.440, and 34.020 (FIG. 1), or 5.821, 14.602, 16.600, 18.861, 19.741, 20.899, 21.320, 24.079, 26.080, 32.280, and 33.759 (FIG. 2). ). The crystalline dexibuprofen arginine salt in the case of the present invention has good solubility in water, resulting in an excellent dissolution rate (elution rate of about 70% or more within 20 minutes). In addition, dexibuprofen arginine salt prepared by the production method of the present invention is also excellent in solubility at a pH similar to the gastric environment, has the advantage of excellent bioavailability. In addition, the crystalline dexibuprofen arginine salt prepared by the production method of the present invention has a characteristic that stability is excellent because there is little moisture change without moisture absorption under the condition of 40 ± 5% relative humidity.

The present invention provides a method for preparing the crystalline dexibuprofen arginine salt. The present invention provides a method for preparing dexibuprofen arginine salt without using a crystallization solvent, the prepared dexibuprofen arginine salt exhibits crystallinity, color and also stably maintained in white, solubility Also, it can be usefully used in various pharmaceutical fields.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples.

≪ Example 1 >

20.628 g (0.1 mol) of dexibuprofen was dissolved in 100 ml of isopropanol and 5 ml of water was added thereto. 17.4 g (0.0999 mol) of L-arginine was added thereto, followed by stirring for about 1 hour to form a crystal. 100 ml of ethyl acetate was added thereto, stirred for about 1 hour, filtered, and washed with ethyl acetate. It dried under vacuum at 60 degreeC for 5 hours, and obtained 37g (yield: 97.4%) of dexibuprofen arginine salts.

Infrared absorption spectrum: 1570cm ^-1 (carbonyl group)

<Example 2>

20.628 g (0.1 mol) of dexibuprofen was dissolved by adding 100 ml of isopropanol and 5 ml of water. 17.4 g (0.0999 mol) of L-arginine was added thereto, followed by stirring for about 1 hour to form a crystal. 100 ml of ethyl acetate was added thereto, stirred for about 1 hour, filtered, and washed with ethyl acetate. It vacuum-dried at 60 degreeC for 5 hours, and obtained 37.2 g of dexibuprofen arginine salts (yield: 97.9%).

Infrared absorption spectrum: 1570cm ^-1 (carbonyl group)

Experimental Example 1: Color Change Test and Hygroscopicity Test

Approximately 3 g of the dexibuprofen arginine salts prepared in Examples 1 and 2 were evenly spread over a petri dish, covered with an aluminum foil, and made a hole therein to store 40 ° C / RH 75% (RH: relative humidity). After leaving for 60 days at and observed the color change is shown in Table 1 the results.

TABLE 1

ingredient Initial color 60 days after color Example 1 White White Example 2 White White

As shown in Table 1, it can be seen that the dexibuprofen arginine salt prepared according to the present invention remains white not only at the beginning but also after a considerable period of time.

In addition, in order to test the hygroscopicity of the prepared dexibuprofen arginine salt, Karl Fischer (manufacturer: METTLER TOLEDO, model name: METTLER TOLEDO DL31) for the dexibuprofen arginine salt prepared in Examples 1 and 2 By measuring the amount of water after the initial and 60 days as shown in Table 2 below.

TABLE 2

ingredient Initial Moisture (%) % After 60 days Example 1 0.1979 0.2057 Example 2 0.1724 0.1884

As shown in Table 2, the dexibuprofen arginine salt prepared according to the present invention was found to be unchanged in water content even after a significant period of about 60 days.

As a result, it can be seen that the dexibuprofen arginine salt prepared according to the present invention is a stable compound which does not change color for a long time and does not absorb moisture.

Experimental Example 2 X-ray Diffraction Analysis

Dexibuprofen arginine salts prepared in Examples 1 and 2 by X-ray diffraction analysis using an X-ray diffractometer (manufacturer: RIGAKU, model name: D / MAX-IIIB), FIGS. 1 and 2 Shown in As can be seen from the X-ray diffraction analysis results shown in FIGS. 1 and 2, it can be seen that the dexibuprofen arginine salts prepared by the preparation method of the present invention all show distinct crystal forms.

Experimental Example 3: Solubility Test

The solubility of the dexibuprofen alginine salt of Example 1 in a pH = 1.2 solution (a solution prepared by adding 2 g of sodium chloride + 7 mL of concentrated hydrochloric acid to water to a total of 1 L) similar to water and the gastrointestinal environment was measured. SUZHOU NO. 4, PHARMCEUTICAL FACTORY, China). Specifically, this experiment was performed by dissolving each compound in distilled water (water) and pH = 1.2 solution according to the method introduced by the Korean Pharmacopoeia, and then analyzing the solution by liquid chromatography to measure the amount dissolved. The results are shown in Table 3.

 [Table 3]

ingredient Solubility (water) Solubility (pH = 1.2) Dexibuprofen 0.102mg / mL 0.076 mg / mL Example 1 1,000 mg / mL or more 1,000 mg / mL or more Example 2 1,000 mg / mL or more 1,000 mg / mL or more

As can be seen in Table 3, dexibuprofen arginine salt prepared according to the production method of the present invention shows a superior solubility in water and pH = 1.2 compared to dexibuprofen shows a high absorption in the body Can be.

Experimental Example 4: Measurement of Dissolution Rate

553 mg of dexibuprofen arginine salt of Example 1 (300 mg with dexibuprofen) was combined with 3 mL of ethanol and dried at 50 ° C. for 3 hours. The dried associations were filtered through an 18 mesh sieve, and then 60 mg of sodium starch glycolate, 10 mg of hard silicic anhydride, 10 mg of magnesium stearate, and 10 mg of talc were mixed, compressed, and then compressed into tablets.

The dissolution rate in water was measured according to the dissolution test method of the tablets prepared by the above method and commercially available dexibuprofen 300mg tablets in the eight general test methods. The elution rate of the sample collected at each elution time was measured under the following liquid chromatography operating conditions.

Detector: UV absorbance photometer (wavelength: 254 nm)

Column: A column packed with octadecylsilylated silica gel for liquid chromatograph of 5 µm in a stainless tube with a diameter of about 4 mm and a length of 25 cm.

Mobile phase: 4.0 g of chloroacetic acid, 400 mL of water and 600 mL of acetonitrile were adjusted to pH = 3 with ammonia water.

Column temperature: 40 ℃

Flow rate: 2.0 mL / min

Injection volume: 50 μl

The result eluted by the liquid chromatography conditions is shown in FIG. 3.

As can be seen in Figure 3 in the dissolution rate of the pharmacological aspect of the tablets prepared with dexibuprofen arginine salt (Example 1) of the present invention shows a higher dissolution rate than commercial dexibuprofen It is said to be excellent in analgesic, anti-inflammatory and antipyretic effects.

Figure 1 shows the X-ray diffraction analysis of the dexibuprofen arginine salt prepared in Example 1,

Figure 2 shows the X-ray diffraction analysis of the dexibuprofen arginine salt prepared in Example 2,

3 is a result of comparing the dissolution rate of the dexibuprofen arginine tablets prepared in Experimental Example 4 and commercially available dexibuprofen tablets in water.

Claims (5)

1) dissolving dexibuprofen in at least one reaction solvent selected from the group consisting of isopropanol, ethanol, methanol and water; 2) adding water to the solution obtained in step 1); And 3) adding L-arginine to the solution obtained in step 2) to form a crystal; And 4) adding ethyl acetate to the crystals, stirring and filtering, washing with ethyl acetate and drying Including, Process for the preparation of crystalline dexibuprofen arginine salt. The method of claim 1, The reaction solvent used in step 1) is isopropanol or a mixed solvent of isopropanol and water. The method of claim 1, The amount of the reaction solvent used is 1 times (v / w) to 30 times (v / w) based on the weight of dexibuprofen. The method of claim 1, The amount of water used in step 2) is 0.001 times to 1 times the amount of the reaction solvent based on the volume, the production method. It is prepared by the manufacturing method according to any one of claims 1 to 4, and has a structure of formula (II) X-ray diffraction pattern shows diffraction angle (2θ, deg) 6.120, 14.920, 16.900, 19.140, 20.040, 21.482, 24.160, 26.380, 32.440, and 34.020, or 5.821, 14.602, 16.600, 18.861, 19.741, 20.899, 21.320, 24.079, 26.080, 32.280, and 33.759 Characterized by having a peak in, Crystalline dexibuprofen arginine salt. &Lt; RTI ID = 0.0 &

NH2CNHNH (CH2) 3CH (NH2) COOH

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