KR100917593B1 - Manufacturing method of dexibuprofen salt - Google Patents

Abstract

The present invention relates to a method for preparing dexibuprofen lysine salt. Provided are a process for preparing crystalline stable dexibuprofen lysine anhydride and dexibuprofen lysine monohydrate using a water-insoluble organic solvent as the crystallization solvent, and the crystalline dexibuprofen lysine salt prepared thereby.

Ibuprofen, dexibuprofen, dexibuprofen lysine anhydride, dexibuprofen lysine monohydrate, analgesic anti-inflammatory

Description

Manufacturing method of dexibuprofen salt {Manufacturing method of dexibuprofen salt}

The present invention relates to a method for preparing dexibuprofen lysinate. More specifically, the present invention relates to a process for preparing stable crystalline dexibuprofen lysine monohydrate or dexibuprofen lysine anhydride using a water-insoluble organic solvent as the crystallization solvent.

Ibuprofen is a racemic compound as a representative analgesic anti-inflammatory antipyretic. Ibuprofen lysinate, a type of ibuprofen salt, is now commercialized and marketed worldwide.

Ibuprofen lysine has several pharmaceutical advantages over ibuprofen: The first is that ibuprofen lysine has better water solubility compared to ibuprofen, and the absorption rate is high. Second, lysine can be taken safely by reducing side effects such as gastrointestinal disorders that most analgesic anti-inflammatory drugs are.

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

[Formula I]

Dexibuprofen lysine, like ibuprofen lysine, has a high solubility in water, and thus may have pharmacologically advantageous properties over dexibuprofen.

US Pat. No. 4,994,604 describes a method for resolution and preparation of (S) -ibuprofen- (S) -lysine using (S) -lysine (L-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 ethanol / water, methanol / water, isopropanol / water, or acetone / water, in particular an aqueous organic solvent such as ethanol / water (97/3 v / v) is used. In addition, when the concentration of water in the ethanol / water mixture is 5% or more, it is crystallized to the (S, S) salt of monohydrate (Formula II), and the concentration of water is relatively 5% or less, preferably 97/3 and 92/8. On the other hand, it is merely described that it is crystallized in the (S, S) form of anhydrous dexibuprofen lysinate (III), but there is no specific disclosure about the crystal form and the preparation method.

[Formula II]

ㆍNH₂(CH₂)₄CH(NH₂)COOHㆍH₂O

NH ₂ (CH ₂ ) ₄ CH (NH ₂ ) COOHH ₂ O

[Formula III]

ㆍNH₂(CH₂)₄CH(NH₂)COOH

NH ₂ (CH ₂ ) ₄ CH (NH ₂ ) COOH

As mentioned above, the representative crystalline dexibuprofen lysine salts include crystalline dexibuprofen lysine monohydrate and crystalline dexibuprofen lysine anhydride, which are distinguished according to water content. Therefore, the water content in the crystal form is an important factor in determining the pharmacological properties of the drug. If the moisture content is affected by the surrounding environment during the storage period of the drug, it is undesirable to affect the pharmacological properties of the drug. Therefore, improvement of stability such as maintenance of water content of dexibuprofen salt is very important for improvement of pharmacological properties.

Existing dexibuprofen salt manufacturing method has not proposed a method for improving the stability, such as maintaining the water content of the prepared drug.

Accordingly, the present inventors have completed the present invention by developing a method for preparing crystalline dexibuprofen lysine monohydrate and crystalline dexibuprofen lysine anhydride with improved stability.

It is therefore an object of the present invention to provide a process for the preparation of crystalline dexibuprofen lysine anhydride with improved stability using a water-insoluble organic solvent.

It is another object of the present invention to provide a process for preparing crystalline dexibuprofen lysine monohydrate with improved stability using a water-insoluble organic solvent.

 The present invention relates to a process for preparing the crystalline dexibuprofen lysine salt using a water-insoluble organic solvent as the crystallization solvent. More specifically, the non-aqueous organic solvent may be used as a reaction solvent, a crystallization solvent, or both, and may be one or more selected from the group consisting of ethyl acetate and isopropanol.

Hereinafter, the present invention will be described in detail.

Method for preparing crystalline dexibuprofen lysine salt according to the present invention

1) mixing dexibuprofen and L-lysine with the reaction solvent to prepare a mixed solution;

2) adding a crystallization solvent to the obtained mixed solution to produce a crystal; And

3) filtering, washing and drying the obtained crystals

It includes.

In addition, the manufacturing method of the present invention may further comprise a sieve treatment step after step 3) to uniformize the particle size of the dried crystals [step 4)].

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

Dexibuprofen and L-Lysine Mixed Solution Preparation Step

The reaction solvent is a solvent for dissolving dexibuprofen and / or L-lysine, and may be a mixture of isopropanol and water, or a mixture of isopropanol, ethyl acetate and water. The amount of the reaction solvent used is not particularly limited, and an amount capable of dissolving dexibuprofen and / or L-lysine is sufficient.

For example, in the case of isopropanol, the solubility in dexibuprofen is used as a main reaction solvent, and the amount of monohydrate and anhydride in which the water penetrates into the reactant of dexibuprofen and lysine varies depending on the amount of isopropanol. Can be an important factor in determining. Therefore, while being able to dissolve the dexibuprofen of isopropanol sufficiently, it can be suitably adjusted according to the kind of salt which is desired, ie, it is made with a monohydrate or an anhydride. In consideration of this point, the amount of isopropanol used may be 1 (v / w) to 30 times (v / w) based on the weight of dexibuprofen, and more specifically, when preparing dexibuprofen lysine monohydrate, It may be 1 times (v / w) or more than 10 times (v / w), preferably 1.5 times (v / w) to 5 times (v / w) with respect to sibuprofen weight, dexibuprofen When preparing lysine anhydride, it can be 10 times (v / w) to 30 times (v / w), preferably 10 times (v / w) to 25 times (v / w) with respect to the weight of dexibuprofen. have.

The amount of the reaction solvent other than isopropanol may be appropriately determined to complete the dissolution of dexibuprofen or to control the moisture according to the amount of isopropanol used. For example, 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 0.5 times the amount of isopropanol on a volume basis. More specifically, the amount of water used when preparing dexibuprofen lysine monohydrate may be 0.001 times to 0.15 times the amount of isopropanol used on a volume basis, and the amount of water used isopropanol on a volume basis. It may be more than 0.15 times and 0.5 times or less of the amount used. The amount of ethyl acetate used may be 0.1 times to 2 times, preferably 0.5 times to 1.5 times, the volume of isopropanol.

The L-lysine 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-lysine is used to maximize the reaction efficiency of the L- lysine and dexibuprofen in an equivalent ratio of 1: 1. When the reaction is performed with ethyl acetate and the like, the excess L-lysine is not washed. On the other hand, since excess dexibuprofen is easily washed, the amount of L-lysine used in less than 1 equivalent to 1 equivalent of dexibuprofen can be prepared more precise 1: 1 salt as described above. . The L-lysine may be added in the form of 100% L-lysine, or may be added in a state of more than 10% to 90% aqueous solution, preferably 50% L-lysine aqueous solution. Since 100% L-lysine is very expensive and hardly soluble in organic solvents, it is more advantageous in terms of economic and reaction efficiency to use it in an aqueous solution, especially in a 50% aqueous solution.

Crystallization stage

When a crystallization solvent is added to the mixture of dexibuprofen and L-lysine obtained above, crystals of dexibuprofen lysine salt are generated and grown to obtain a crystalline dexibuprofen lysine salt. As the crystallization solvent, a water-insoluble solvent, preferably ethyl acetate or a mixture of ethyl acetate and isopropanol can be used.

  In this case, the amount of the crystalline solvent may be about 1 times (v / w) to 60 times (v / w) in volume ratio with respect to the weight of dexibuprofen. It may be more than 1 times (v / w) or less than 15 times (v / w), preferably 2 times (v / w) to 10 times (v / w) when preparing monohydrate, and 15 times when preparing anhydride. To 60 times (v / w), preferably 15 times to 50 times (v / w).

In the case of using a mixture of ethyl acetate and isopropanol, ethyl acetate insoluble to dexibuprofenlysin salt acts as the main crystallization solvent, and isopropanol is monohydrate or anhydride of dexibuprofenlysin salt in liquid phase with ethyl acetate. By blending well, it helps to make decisions. Therefore, when a small amount of isopropanol is mixed with ethyl acetate as a crystallization solvent, the ethyl acetate may be easily penetrated into the monohydrate or anhydride of dexibuprofenlysin salt in the liquid phase, which may be more advantageous for crystal formation. At this time, the mixing ratio of ethyl acetate and isopropanol is 1: 0.05 to 1: 1, preferably 1: 0.1 to 1: 0.7, more preferably 1: 0.18 to 1: 0.5 (ethyl acetate volume: isopropanol volume) May be).

Isopropanol, which helps the penetration of ethyl acetate in the crystallization step, may be used by mixing with ethyl acetate as a crystallization solvent as described above, and isopropanol used as a reaction solvent may be used. Therefore, the reaction solvent and the crystallization solvent may be used separately in different steps, or may be simultaneously used to prepare the dexibuprofen and L-lysine mixed solution and the crystallization step.

As can be seen in the comparative examples below, crystals are not produced when a substance other than the ethyl acetate and / or isopropanol is used, such as toluene or heptane, even in a non-aqueous solvent. In addition, when using acetone, which is a water-soluble solvent, a pale yellow precipitate is formed. When methanol is used, crystals are hardly generated due to high solubility of dexibuprofenlysin. In the case of ibuprofen or dexibuprofen, it is mainly dissolved in a polar organic solvent and then crystallized by adding water. However, in case of dexibuprofenlysin, it is highly soluble in water and is completely dissolved when water is added, so that crystals are not formed. .

Accordingly, the present invention is characterized in that the crystallization efficiency of dexibuprofenlysin is increased by using ethyl acetate or a mixture of ethyl acetate and isopropanol, which are non-aqueous solvents, as the crystallization solvent.

Filtration, Washing and Drying Steps

Filtration, 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, it may be carried out by washing with ethyl acetate and drying for 2 to 30 hours at 20 to 80 ℃, preferably 30 to 70 ℃. There is no particular limitation on the drying method, and vacuum drying, ventilation drying, infrared drying, etc. which are commonly used may be used.

Sieve treatment step

The sieve treatment of the dried crystals may make the particles uniform.

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.

Crystalline dexibuprofen lysine monohydrate prepared according to the present invention has a structure of formula (II) below, and crystalline dexibuprofen lysine anhydride has structure of formula (III) below.

[Formula II]

ㆍNH₂(CH₂)₄CH(NH₂)COOHㆍH₂O

NH ₂ (CH ₂ ) ₄ CH (NH ₂ ) COOHH ₂ O

[Formula III]

ㆍNH₂(CH₂)₄CH(NH₂)COOH

NH ₂ (CH ₂ ) ₄ CH (NH ₂ ) COOH

All of the dexibuprofenlysin monohydrates or anhydrides produced by the production method of the present invention are crystalline, for example, as shown in Figs. 1 to 5. If the crystallinity is excellent, the fluidity is good at the time of formulation, and even if a small amount of excipient or the like is added, the formulation is possible. On the other hand, there is a disadvantage in that the dissolution of the active ingredient is delayed due to the crystallinity, dexibuprofenlysin salt in the case of the present invention has a good solubility in water rarely causes such a problem of delayed dissolution. That is, the crystalline dexibuprofenlysin monohydrate or anhydride prepared according to the present invention has the advantage of having excellent processability and no problem of elution delay due to crystallinity.

In addition, the crystalline dexibuprofenlysin monohydrate or anhydride prepared by the production method of the present invention is characterized by excellent stability because there is almost no change in moisture content even in vacuum drying at a high temperature of 70 ℃ or more.

The present invention provides a new method for preparing crystalline dexibuprofen lysine anhydride and dexibuprofen lysine monohydrate. The present invention provides a method for preparing anhydrous and dexibuprofen lysine monohydrate using a non-aqueous solvent, wherein the prepared dexibuprofen lysine salt exhibits crystallinity, color also stably remains white and 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

<Example 1>

2.0715 g (0.01004 mol) of dexibuprofen was dissolved in 10 ml of isopropanol, 2.8828 g (0.00986 mol) of 50% L-lysine was added thereto, stirred for about 10 minutes, and then 1 ml of water was added thereto. 20 ml of ethyl acetate was added thereto and crystallized. The mixture was stirred for 30 minutes, filtered, and washed with ethyl acetate. Vacuum drying at 40 ° C. for 10 hours yielded 3.56 g (yield: 97.5%) of dexibuprofen lysine monohydrate.

Infrared absorption spectrum: 1544cm ^-1 (carbonyl group)

<Example 2>

2.0714 g of dexibuprofen was dissolved in 5 ml of isopropanol, 2.8828 g of 50% L-lysine was added thereto, stirred for about 10 minutes, and 0.5 ml of water was added thereto. 10 ml of ethyl acetate was added thereto, crystallized, stirred for 30 minutes, filtered, and washed with ethyl acetate. Vacuum drying at 40 ° C. for 10 hours yielded 3.55 g of dexibuprofen lysine monohydrate (yield: 97.2%).

Infrared absorption spectrum: 1544cm ^-1 (carbonyl group)

<Example 3>

2.0714 g of dexibuprofen was dissolved in 10 ml of ethyl acetate, 2.8828 g of 50% L-lysine was added thereto, stirred for about 10 minutes, and 0.5 ml of water was added thereto. 5 ml of isopropanol was added thereto, followed by crystallization by adding 10 ml of ethyl acetate, stirring for 30 minutes, filtering, and washing with ethyl acetate. It was vacuum-dried at 40 degreeC for 10 hours, and 3.47 g (yield: 95%) of dexibuprofen lysine monohydrate was obtained.

Infrared absorption spectrum: 1544cm ^-1 (carbonyl group)

<Example 4>

3 ml of isopropanol was mixed with 2.8828 g of 50% L-lysine, a solution of 2.0714 g of dexibuprofen in 16 ml of ethyl acetate was added thereto, stirred for about 10 minutes, and the resulting crystals were stirred for 30 minutes, filtered, and washed with ethyl acetate. Vacuum drying at 40 ° C. for 10 hours yielded 3.57 g of dexibuprofen lysine monohydrate (yield: 97.8%).

Infrared absorption spectrum: 1543cm ^-1 (carbonyl group)

<Example 5>

2.0714 g of dexibuprofen was dissolved in 50 ml of isopropanol, 2.8828 g (0.00986 mol) of 50% L-lysine was added thereto, stirred for about 10 minutes, and then 2 ml of water was added thereto. 100 ml of ethyl acetate was added thereto, crystallized, stirred for 30 minutes, filtered, and washed with ethyl acetate. It vacuum-dried at 40 degreeC for 10 hours, and obtained 3.37 g (yield: 97%) of dexibuprofen lysine anhydride.

Infrared absorption spectrum: 1500cm ^-1 (carbonyl group)

<Example 6>

2.0714 g of dexibuprofen was dissolved in 20 ml of isopropanol, 2.8828 g of 50% L-lysine was added thereto, stirred for about 10 minutes, and 2 ml of water was added to prepare a clear solution. 30 ml of ethyl acetate was added thereto, crystallized, stirred for 30 minutes, filtered, and washed with ethyl acetate. It vacuum-dried at 40 degreeC for 10 hours, and obtained 3.34 g (yield: 96%) of dexibuprofen lysine anhydride.

Infrared Absorption Spectrum: 1501cm ^-1 (carbonyl group)

Comparative Example 1 When Normal-heptane is Used as the Crystallization Solvent

2.0715 g (0.01004 mol) of dexibuprofen was dissolved in 10 ml of isopropanol, 2.8828 g (0.00986 mol) of 50% L-lysine was added thereto, stirred for about 10 minutes, and then 1 ml of water was added thereto. 20 ml of normal-heptane was added thereto, followed by stirring for 18 hours, but no crystals were formed.

Comparative Example 2: When Toluene is Used as the Crystallization Solvent

2.0715 g (0.01004 mol) of dexibuprofen was dissolved in 10 ml of isopropanol, 2.8828 g (0.00986 mol) of 50% L-lysine was added thereto, stirred for about 10 minutes, and then 1 ml of water was added thereto. 20 ml of toluene was added thereto and stirred for 18 hours, but no crystals were formed.

Comparative Example 3 Using Acetone as a Crystallization Solvent

 2.0715 g (0.01004 mol) of dexibuprofen was dissolved in 20 ml of acetone, 2.8828 g (0.00986 mol) of 50% L-lysine was added thereto, stirred for about 10 minutes, and then 1 ml of water was added thereto. 20 ml of acetone was added thereto to obtain a pale yellow precipitate of atherosclerosis.

Experimental Example 1 Measurement of Water Content

Table 1 shows the results of water measurement using Karl Fischer (manufacturer: METTLER TOLEDO, model name: METTLER TOLEDO DL31) using the dexibuprofen lysine salts prepared in Examples 1, 3, 4, 5, and 6. .

TABLE 1

Example Example 1 Example 3 Example 4 Example 5 Example 6 Moisture (% by weight) 4.7902 4.7724 4.8040 0.3984 0.4011

As can be seen from the results of Table 1, the dexibuprofen lysine salts prepared in Examples 1, 3 and 4 can be seen that the water content was prepared in the monohydrate form as 4.7902%, 4.7724% and 4.8040%, respectively. Dexibuprofen lysine salts prepared in Examples 5 and 6 can be confirmed that the water content of 0.3984% and 0.4011%, respectively, in anhydrous form.

Experimental Example 2 Measurement of Change in Water Content at High Temperature

After dexibuprofen lysine salts prepared in Examples 1, 3, 4, 5 and 6 were vacuum dried at 70 ° C. for 24 hours, about 200 mg of the solution was extracted with Karl Fischer (manufacturer: METTLER TOLEDO, model name: METTLER TOLEDO DL31). The change was analyzed and the results are shown in Table 2 below.

TABLE 2

Example Example 1 Example 3 Example 4 Example 5 Example 6 Moisture (% by weight) 4.7813 4.7657 4.7901 0.3872 0.4008

As can be seen in Table 2, the dexibuprofen lysine salt prepared according to the present invention appears to maintain the moisture content even after a long time (24 hours) vacuum drying treatment at high temperature (70 ℃), stability You can see the improvement.

Experimental Example 3: Differential Thermal Analysis

Differential thermal analysis (10 ° C./min) of dexibuprofen lysine salts prepared in Examples 3, 4, 5 and 6 was performed. Using a differential thermal analysis machine (Universal V4 2E TA Instruments), the sample was taken to about 4 mg and analyzed to 230 ° C. with an initial temperature set to 50 ° C. and an increase of 10 ° C. per minute. The results thus obtained are shown in FIGS. 6, 7, 8 and 9.

As can be seen in FIGS. 6, 7, 8, and 9, it can be seen that dexibuprofen lysine monohydrate and anhydride show different aspects. In particular, in Figure 7 showing the differential thermal analysis results of the dexibuprofen lysine monohydrate prepared in Example 4, the endothermic peak by the crystal water at 105.43 ℃ is shown, the deximbu prepared in Examples 5 and 6 8 and 9 showing the differential thermal analysis of the propene lysate anhydride, showing that there is no crystal water, it can be seen that dexibuprofen lysine monohydrate and dexibuprofen lysine anhydride were prepared, respectively.

Experimental Example 4: Color Change

0.7 g of each white dexibuprofen lysine monohydrate and dexibuprofen lysine anhydride obtained in Examples 1, 3, 5 and 6 were spread out on a watch plate and visually changed color at 40 ° C. and 75% RH for 2 months. Observation of the result is shown in Table 3.

TABLE 3

Example Example 1 Example 3 Example 5 Example 6 color White White White White

As can be seen in Table 3, the monohydrate and the anhydride prepared according to the production method of the present invention were all white without color change under 40 ℃, 75% RH storage conditions for 2 months, most of the lysine salt compound There was no general pattern of yellowing observed at. Therefore, it can be seen that the dexibuprofen lysine salt prepared by the production method of the present invention significantly increases the stability compared to the conventional lysine salt compound.

Experimental Example 5: X-ray Diffraction Analysis

Dexibuprofen lysine salts prepared in Examples 1, 3, 4, 5 and 6 were obtained by X-ray diffraction analysis using an X-ray diffractometer (manufacturer: RIGAKU, model name: D / MAX-IIIB). Are shown in Figures 1, 2, 3, 4 and 5. As can be seen from the X-ray diffraction analysis results, it was confirmed that both dexibuprofen lysine monohydrate and dexibuprofen lysine anhydride prepared by the production method of the present invention showed a crystalline form.

Experimental Example 6: Solubility Test

The dexibuprofen lysine monohydrate of Example 1 and the dexibu of Example 5 in a pH = 1.2 solution similar to water and gastric environment (a solution prepared by adding 1 g of water in 2 g of sodium chloride + 7 mL of concentrated hydrochloric acid). Solubility of propene lysine anhydride was compared with dexibuprofen (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 4.

 TABLE 4

ingredient Solubility (water) Solubility (pH = 1.2) Dexibuprofen 0.102mg / mL 0.076 mg / mL Dexibuprofenlysin Monohydrate (Example 1) 1,000 mg / mL or more 1,000 mg / mL or more Dexibuprofenlysin Anhydride (Example 5) 1,000 mg / mL or more 1,000 mg / mL or more

As can be seen in Table 4, the monohydrate and the anhydride prepared according to the production method of the present invention shows superior solubility in water and pH = 1.2 compared to dexibuprofen, showing a high absorption rate in the body.

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

Figure 2 shows the X-ray diffraction analysis of the dexibuprofen lysine prepared in Example 3,

Figure 3 shows the X-ray diffraction analysis of the dexibuprofen lysine prepared in Example 4,

Figure 4 shows the X-ray diffraction analysis of the dexibuprofen lysine prepared in Example 5,

5 shows the results of X-ray diffraction analysis of dexibuprofen lysine prepared in Example 6,

Figure 6 shows the differential thermal analysis of the dexibuprofen lysine prepared in Example 3,

Figure 7 shows the differential thermal analysis of the dexibuprofen lysine prepared in Example 4,

Figure 8 shows the differential thermal analysis of the dexibuprofen lysine prepared in Example 5,

Figure 9 shows the differential thermal analysis of the dexibuprofen lysine prepared in Example 6.

Claims (9)

1) mixing dexibuprofen and L-lysine with the reaction solvent to prepare a mixed solution; 2) adding a crystallization solvent to the obtained mixed solution to produce a crystal; And 3) filtering, washing and drying the obtained crystals, The crystallization solvent is characterized in that the ethyl acetate, or a mixture of ethyl acetate and isopropanol, Method for preparing crystalline dexibuprofen lysine salt. The method of claim 1, The reaction solvent is a mixture of isopropanol and water, or isopropanol, ethyl acetate and water mixture. The method of claim 2, The isopropanol is used in an amount of 1 times (v / w) to 30 times (v / w) based on the weight of dexibuprofen. The method of claim 3, The isopropanol is used in an amount of 1 times (v / w) or more than 10 times (v / w) with respect to the weight of dexibuprofen, and the dexibuprofen lysine salt to be produced is a monohydrate. The method of claim 3, The isopropanol is used in an amount of 10 times (v / w) or more than 30 times (v / w) with respect to the weight of dexibuprofen, and the prepared dexibuprofen lysine salt is an anhydride. The method of claim 1, The amount of the crystallization solvent used is 1 times (v / w) to 60 times (v / w) of dexibuprofen. The method of claim 6, The amount of the crystallization solvent used is 1 times (v / w) or more than 15 times (v / w) of dexibuprofen, and the crystalline dexibuprofen lysine salt to be prepared is crystalline dexibuprofen lysine monohydrate. Way. The method of claim 6, The use amount of the crystallization solvent is 15 to 60 times (v / w) of dexibuprofen, and the crystalline dexibuprofen lysine salt to be prepared is crystalline dexibuprofen lysine anhydride. delete

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