Crystal compound of dexibuprofen arginine, preparation method of crystal compound and composition containing crystal compound

Abstract

The invention relates to a crystal form compound of dexibuprofen arginine, which has diffraction peaks at diffraction angles 2 theta of 6.0 + / -0.2 degrees, 16.8 + / -0.2 degrees, 17.9 + / -0.2 degrees, 19.1 + / -0.2 degrees, 21.5 + / -0.2 degrees, 23.4 + / -0.2 degrees and 24.1 + / -0.2 degrees in an X-ray powder diffraction pattern measured under Cu-K alpha radiation. The invention also relates to a preparation method of the crystal-form compound and a pharmaceutical composition containing the crystal-form compound.

Description

TECHNICAL FIELD

[0001] The present application relates to a new crystal form compound of arginine dexibuprofen and a preparation method thereof, and a pharmaceutical composition comprising the new crystal form compound. BACKGROUND

[0002] Two crystal forms of arginine dexibuprofen are disclosed in Korean Patent KR101019201B, which have characteristic peaks at the following diffraction angles 2θ, respectively:

[0003] Form 1: 6.120, 14.920, 16.900, 19.140, 20.040, 21.482, 24.160, 26.380, 32.440 and 34.020;

[0004] Form 2: 5.821, 14.602, 16.600, 18.861, 19.741, 20.899, 21.320, 24.079, 26.080, 32.280 and 33.759.

[0005] Chinese Patent CN102344360B mentions obtaining arginine dexibuprofen in the form of white crystals with melting points of 175-178℃, 175.2-177.6℃, 175.8-178.2℃, respectively, but the document does not record data characterizing these crystals. SUMMARY

[0006] The present application provides, in one aspect, a new crystal form compound of arginine dexibuprofen, which has better stability, faster dissolution rate and lower hygroscopicity than existing crystal form compounds of arginine dexibuprofen, and better dissolution performance when formulated.

[0007] The present application provides, in another aspect, a method for preparing the new crystal form compound of arginine dexibuprofen.

[0008] Specifically, the present application relates to:

[0009] (1) a crystal form compound of arginine dexibuprofen, which has diffraction peaks at diffraction angles 2θ of 6.0±0.2, 16.8±0.2, 17.9±0.2, 19.1±0.2, 21.5±0.2, 23.4±0.2, 24.1±0.2 degrees in an X-ray powder diffraction pattern measured at 25℃ and Cu-Kα radiation.

[0010] (2) The crystalline compound according to the above (1), which has diffraction peaks at diffraction angles 2Θ of 6.0±0.2, 16.8±0.2, 17.9±0.2, 19.1±0.2, 20.0±0.2, 21.0±0.2, 21.5±0.2, 23.4±0.2, 24.1±0.2, 26.3±0.2 degrees.

[0011] (3) The crystalline compound according to the above (1) or (2), which has a melting point of 176 to 178°C.

[0012] (4) A pharmaceutical composition containing the crystalline compound of dexibuprofen arginine according to any one of the above (1) to (3).

[0013] (5) The pharmaceutical composition according to the above (3), which further contains one or two or more pharmaceutically acceptable excipients selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, povidone, sucrose, colloidal silicon dioxide, and a coating agent.

[0014] (6) The pharmaceutical composition according to the above (5), which contains microcrystalline cellulose, sodium carboxymethyl starch, povidone, sucrose, colloidal silicon dioxide, and a coating agent as excipients.

[0015] (7) Dexibuprofen arginine containing 0.01 to 100% by weight of the crystalline compound of dexibuprofen arginine according to any one of the above (1) to (3).

[0016] (8) A method for producing the crystalline compound of dexibuprofen arginine according to any one of the above (1) to (3), which comprises the steps of dissolving dexibuprofen in a solvent at 55 to 75°C, followed by adding arginine, and, after completion of the reaction, cooling to 40 to 45°C and maintaining for 3 to 5 hours, and then further cooling to 0 to 5°C and maintaining for 2 hours or more at 0 to 5°C to crystallize, and isolating the crystalline compound.

[0017] (9) The method according to the above (8), wherein dexibuprofen is dissolved in a solvent at 60 to 70°C.

[0018] (10) The method according to the above (8) or (9), wherein the solvent is acetone, methanol, ethanol, or isopropanol.

[0019] (11) The method according to any one of the above (8) to (10), wherein the solvent is ethanol.

[0020] (12) The method according to the above (11), wherein the concentration of ethanol is 85% (V / V) to 95% (V / V). BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 XRD pattern of the new crystal of arginine dexibuprofen (A00455) obtained in Example 1.

[0022] Figure 2 XRD pattern of the new crystal of arginine dexibuprofen (A00454) obtained in Example 2.

[0023] Figure 3 XRD pattern of the new crystal of arginine dexibuprofen (A00456) obtained in Example 3.

[0024] Figure 4 XRD pattern of the new crystal of arginine dexibuprofen (241001) obtained in Example 4.

[0025] Figure 5 XRD pattern of the new crystal of arginine dexibuprofen (241002) obtained in Example 5.

[0026] Figure 6 XRD pattern of the crystal of arginine dexibuprofen obtained in Comparative Example 1 (the method of Example 1 in KR101019201B).

[0027] Figure 7 XRD pattern of the crystal of arginine dexibuprofen obtained in Comparative Example 2 (the method of Example 1 in CN102344360B).

[0028] Figure 8 XRD pattern of the crystal of arginine dexibuprofen obtained in Comparative Example 3 (the method of Example 2 in CN102344360B).

[0029] Figure 9 XRD pattern of the crystal of arginine dexibuprofen obtained in Comparative Example 4 (the method of Example 3 in CN102344360B). DETAILED DESCRIPTION

[0030] Example

[0031] In the examples of the present application, the XRD pattern of the crystal was determined under the following conditions:

[0032] Cu-K α radiation;

[0033] Detection conditions: tube voltage 40 KV, tube current 30 mA, emission slit 1°, divergence slit 1°, acceptance slit 0.30 mm, scanning mode θ-2θ linkage continuous scanning, scanning rate 0.2° / min, scanning range 5°-70°.

[0034] In the examples of the present application, the melting point of the crystal was determined under the following conditions:

[0035] Detection condition: Chinese Pharmacopoeia General 0612 Melting Point Determination Method First Method, heating rate 1.0-1.5°C / min.

[0036] Example 1 Preparation of Arginine D-buprofen New Crystal (A00455)

[0037] D-buprofen 1000 g was dissolved in 90% (V / V) ethanol solution 4505 g at 65°C, then arginine 845 g was added, after the reaction was completed (free D-buprofen ≤1.0%), the temperature was lowered to 40-45°C for 3-5 h, then the temperature was continuously lowered to 0-5°C, and maintained at 0-5°C for 2 h or more for crystallization, and centrifuged to obtain a white crystalline powder with a yield of 91.2% and a melting point of 176-178°C. The XRD pattern of the obtained crystal is shown in Figure 1

[0038] Example 2 Preparation of Arginine D-buprofen New Crystal (A00454)

[0039] D-buprofen 1000 g was dissolved in 90% (V / V) ethanol solution 4505 g at 60°C, then arginine 845 g was added, after the reaction was completed (free D-buprofen ≤1.0%), the temperature was lowered to 40-45°C for 3-5 h, then the temperature was continuously lowered to 0-5°C, and maintained at 0-5°C for 2 h or more for crystallization, and centrifuged to obtain a white crystalline powder with a yield of 90.2% and a melting point of 177-178°C. The XRD pattern of the obtained crystal is shown in Figure 2

[0040] Example 3 Preparation of Arginine D-buprofen New Crystal (A00456)

[0041] D-buprofen 1000 g was dissolved in 90% (V / V) ethanol solution 4505 g at 70°C, then arginine 845 g was added, after the reaction was completed (free D-buprofen ≤1.0%), the temperature was lowered to 40-45°C for 3-5 h, then the temperature was continuously lowered to 0-5°C, and maintained at 0-5°C for 2 h or more for crystallization, and centrifuged to obtain a white crystalline powder with a yield of 90.4% and a melting point of 177-178°C. The XRD pattern of the obtained crystal is shown in Figure 3

[0042] The characteristic peaks of the XRD patterns of the arginine D-buprofen new crystals obtained in Examples 1 to 3 and the XRD patterns of the crystals of KR101019201B Example 1 and Example 2 are compared as shown in Table 1 below.

[0043] Table 1

[0044]

[0045] ​​​From the above table, the characteristic peaks of the crystal XRD patterns prepared in Examples 1 to 3 are substantially identical, unlike the crystal of KR101019201B.

[0046] Preparation of Example 4, a new crystal of dexibuprofen arginine (241001)

[0047] Dissolve dexibuprofen 1000 g in 95% (V / V) ethanol solution 4505 g at 65°C, then add arginine 845 g, and after the reaction is completed (free dexibuprofen ≤ 1.0%), cool to 40-45°C for 3-5 hours, then continue to cool to 0-5°C, and maintain 0-5°C for crystallization for 2 hours or more, and centrifuge to obtain a white crystalline powder with a yield of 93.5% and a melting point of 176-178°C. The XRD pattern of the obtained crystal is shown in FIG. 1. Figure 4

[0048] Preparation of Example 5, a new crystal of dexibuprofen arginine (241002)

[0049] Dissolve dexibuprofen 1000 g in 85% (V / V) ethanol solution 4505 g at 65°C, then add arginine 845 g, and after the reaction is completed (free dexibuprofen ≤ 1.0%), cool to 40-45°C for 3-5 hours, then continue to cool to 0-5°C, and maintain 0-5°C for crystallization for 2 hours or more, and centrifuge to obtain a white crystalline powder with a yield of 91.2% and a melting point of 176-178°C. The XRD pattern of the obtained crystal is shown in FIG. 2. Figure 5

[0050] Comparison of the characteristic peaks of the crystal XRD patterns of Example 1 and Examples 4 and 5 is shown in Table 2 below.

[0051] Table 2

[0052]

[0053]

[0054] Comparative Example 1

[0055] Prepare a crystal of dexibuprofen arginine according to the method of Example 1 of Korean Patent KR101019201B, with the following specific operations:

[0056] Dissolve dexibuprofen 1000 g in isopropyl alcohol solution 4847 ml, then add water 242 g. Add 845 g of arginine thereto, and then stir for about 1 hour to form a crystal. Add 4847 ml of ethyl acetate thereto, stir for about 1 hour, filter, and wash with ethyl acetate. Dry at 60°C under vacuum for 5 hours to obtain a white crystalline powder with a yield of 89.3%.

[0057] ​​The melting point of the obtained crystal is 160-163°C, and the actual XRD pattern is as shown in Figure 6

[0058] Analysis Figure 6 The characteristic peaks of the obtained XRD pattern are shown in Table 3.

[0059] Table 3

[0060]

[0061] Comparative Example 2

[0062] The arginine-drofenin crystal was prepared according to the method of Example 1 of Chinese patent CN102344360B, and the specific operation was as follows:

[0063] Drofenin 208.3 g (1.01 mol) was dissolved in 720 ml of 95% (V / V) ethanol aqueous solution, heated to 55°C, and L-arginine 174.2 g (1.0 mol) was slowly and continuously added dropwise under stirring. The addition was completed in 10 min, and the reaction was continued to stir at 55°C for 3 hours. After standing for 30 min, the temperature was cooled to room temperature, and the crystal was obtained by suction filtration. The crystal was washed with 50 ml of 95% (volume percent concentration) ethanol aqueous solution for 3 times, and dried at 65°C for 6 hours to obtain 353.1 g of white crystal with a yield of 92.3%, and a melting point of 175-178°C.

[0064] The XRD pattern of the obtained crystal is as shown in Figure 7

[0065] Comparative Example 3

[0066] The arginine-drofenin crystal was prepared according to the method of Example 2 of Chinese patent CN102344360B, and the specific operation was as follows:

[0067] Drofenin 221.2 g (1.07 mol) was dissolved in 720 ml of 95% (V / V) ethanol aqueous solution, heated to 50°C, and L-arginine 174.2 g (1.0 mol) was slowly and continuously added dropwise under stirring. The addition was completed in 15 min, and the reaction was continued to stir at 50°C for 2 hours. After standing for 25 min, the temperature was cooled to room temperature, and the crystal was obtained by suction filtration. The crystal was washed with 50 ml of 95% (volume percent concentration) ethanol aqueous solution for 3 times, and dried at 70°C for 4 hours to obtain 347.6 g of white crystal with a yield of 87.9%, and a melting point of 175-178°C.

[0068] The XRD pattern of the obtained crystal is as shown in Figure 8

[0069] Comparative Example 4

[0070] ​​​The arginine-dexibuprofen crystal was prepared according to the method of Example 3 of Chinese patent CN102344360B, and the specific operation was as follows:

[0071] Dexibuprofen 219.4 g (1.06 mol) was dissolved in 720 ml of 95% (V / V) ethanol aqueous solution, heated to 60°C, and L-arginine 174.2 g (0.1 mol) was slowly and continuously added dropwise under stirring. The dropwise addition was completed in 20 min, and the reaction was continued to stir at 60°C for 3.5 h. After standing for 35 min, the solution was cooled to room temperature, and then filtered. The obtained crystal was washed with 50 ml of 95% (volume percent concentration) ethanol aqueous solution for 3 times, and dried at 68°C for 5 h to obtain 350.8 g of white crystal with a yield of 89.1% and a melting point of 175-178°C.

[0072] The XRD pattern of the obtained crystal is shown in Figure 9 .

[0073] Analysis Figures 7-9 The characteristic peaks of the obtained XRD pattern are shown in Table 4.

[0074] Table 4

[0075]

[0076] Example 5: Comparison of dissolution rate

[0077] The dissolution rate of the crystal obtained in Example 1 and Comparative Examples 1 and 2 was determined by the shake flask method (equilibrium solubility method) at 25°C±0.5°C, and the results are shown in Table 5.

[0078] Table 5

[0079]

[0080] From the above table, it can be seen that the crystal obtained in Example 1 has a significantly faster dissolution rate than the crystals in Comparative Examples 1 and 2, and can reach the saturated dissolution state more quickly.

[0081] Example 6: Evaluation of hygroscopicity

[0082] The hygroscopicity of the crystal obtained in Example 1 and Comparative Examples 1 and 2 was determined according to the drying loss test method of Chinese Pharmacopoeia 0831 at a drying temperature of 105°C, and the results are shown in Table 6.

[0083] Table 6

[0084] Wet-gain Example 1 Comparative Example 1 Comparative Example 2 0 days 0.1％ 0.2％ 0.1％ Accelerated 6 months 0.1％ 1.2％ 1.5％ Long-term 6 months 0.1％ 0.3％ 0.5％

[0085] From the above table, it can be seen that the crystal obtained in Example 1 has a lower hygroscopicity than the crystals in Comparative Examples 1 and 2.

[0086] Evaluation of dissolution rate of the preparation of Example 7.

[0087]

[0088] The dissolution rate of the preparation in 0.1 mol / L hydrochloric acid solution was determined under the following conditions, and the results are shown in Table 7 below.

[0089] Detection conditions: Dissolution medium: 0.1 mol / L hydrochloric acid solution (take hydrochloric acid 9.0 ml, dilute with water to 1000 ml, shake well, and it is ready), paddle method, 50 revolutions / minute.

[0090] Table 7 Dissolution rate in 0.1 mol / L hydrochloric acid solution

[0091]

Claims

1. Arginine dexibuprofen crystalline compound having an X-ray powder diffraction pattern, measured at Cu-K α peaks at diffraction angles 2 theta of 6.0 ± 0.2, 16.8 ± 0.2, 17.9 ± 0.2, 19.1 ± 0.2, 21.5 ± 0.2, 23.4 ± 0.2, 24.1 ± 0.2 degrees.

2. The crystalline compound of claim 1, which has diffraction peaks at diffraction angles 2Θ of 6.0±0.2, 16.8±0.2, 17.9±0.2, 19.1±0.2, 20.0±0.2, 21.0±0.2, 21.5±0.2, 23.4±0.2, 24.1±0.2, 26.3±0.2 degrees.

3. The crystalline compound of claim 1 or 2, which has a melting point of 176-178 °C.

4. A pharmaceutical composition comprising the crystalline compound of dexibuprofen arginine of any one of claims 1 to 3.

5. The pharmaceutical composition of claim 3, which further comprises one or more than two pharmaceutically acceptable excipients selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, povidone, sucrose, colloidal silicon dioxide, and coating agent.

6. The pharmaceutical composition of claim 5, which comprises microcrystalline cellulose, sodium carboxymethyl starch, povidone, sucrose, colloidal silicon dioxide, and coating agent as excipients.

7. Dexibuprofen arginine comprising 0.01 wt% to 100 wt% of the crystalline compound of dexibuprofen arginine of any one of claims 1 to 3.

8. A method for preparing the crystalline compound of dexibuprofen arginine of claim 1 or 2, which comprises the steps of dissolving dexibuprofen in a solvent at 55-75 °C, preferably 60-70 °C, followed by adding arginine, and after the reaction is completed, cooling to 40-45 °C for 3-5 h, and then continuing to cool to 0-5 °C, and maintaining at 0-5 °C for crystallization for 2 h or more, and isolating the crystalline compound.

9. The method of claim 8, wherein the solvent is acetone, methanol, ethanol, or isopropanol.

10. The method of claim 9, wherein the solvent is ethanol, preferably at a concentration of 85% (V / V) to 95% (V / V).

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