NOVEL CRYSTALLINE FORM OF ATORVASTATIN HEMI-CALCIUM SALT, HYDRATE THEREOF, AND METHOD OF PRODUCING THE SAME

Abstract

The present invention provides a novel crystalline form of [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptanoic acid hemi-calcium salt (atorvastatin hemi-calcium salt) of the following formula 1, which is known to be useful as a drug, a hydrate thereof and a preparation method thereof:

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Claims

1. A crystalline Form α atorvastatin hemi-calcium salt or a hydrate thereof, characterized by having peaks at 2θ values of 8.8, 9.6, 11.9, 16.9, 19.6, 21.7, 23.5, 26.9 and 29.7±0.5° in an X-ray powder diffraction.

2. The crystalline Form α atorvastatin hemi-calcium salt or hydrate thereof of claim 1, characterized by having peaks having a relative intensity greater than 10% at 2θ values of 8.8, 9.6, 11.9, 16.9, 19.6, 21.7, 23.5 and 29.7±0.5° in the X-ray powder diffraction.

3. The crystalline Form α atorvastatin hemi-calcium salt or hydrate thereof of claim 1, characterized by having broad peaks at 2θ values of 8.8, 9.6, 16.9, 21.7 and 23.5±0.5° in the X-ray powder diffraction.

4. The crystalline Form α atorvastatin hemi-calcium salt or hydrate thereof of claim 1, characterized by showing the X-ray powder diffraction spectrum as shown in FIG. 2.

5. The crystalline Form α atorvastatin hemi-calcium salt or hydrate thereof of claim 1, characterized by showing the solid-state .sup.13C NMR spectrum as shown in FIG. 3.

6. A method for preparing a crystalline Form α atorvastatin hemi-calcium salt or a hydrate thereof, comprising the steps of: suspending a crude atorvastatin hemi-calcium salt in a mixed solvent of methanol and water; and stirring the suspension at a reaction temperature of 5˜25° C. for 1-10 hours.

7. The method of claim 6, wherein the volume ratio of methanol:water in the mixed solvent is 1:10 (v/v)˜1:15 (v/v), and the ratio of volume of the mixed solvent:weight of the crude atorvastatin hemi-calcium salt is 1:60˜65 (v/wt).

8. The method of claim 6, wherein the reaction temperature is 10˜20° C.

9. The method of claim 6, wherein the stirring is carried out for 1-5 hours.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0035] FIG. 1 shows the results of high-performance liquid chromatography (HPLC) of an amorphous atorvastatin hemi-calcium salt prepared according to the method of Example 10 of U.S. Pat. No. 5,273,995.

[0036] FIG. 2 shows the powder X-ray diffraction spectrum of a crystalline atorvastatin hemi-calcium salt prepared according to the method of Example 1 of present invention.

[0037] FIG. 3 shows the solid-state .sup.13C nuclear magnetic resonance (NMR) spectrum of the crystalline atorvastatin hemi-calcium salt prepared according to the method of Example 1 of present invention.

[0038] FIG. 4 shows the results of HPLC of a reaction product obtained before filtration of the mixture in the method of Example 1 of the present invention.

[0039] FIG. 5 shows the results of HPLC of a crystalline atorvastatin hemi-calcium salt obtained by filtering, water washing and drying the reaction product in the method of Example 1 of the present invention.

[0040] FIG. 6 shows the results of HPLC of a reaction product obtained before filtration of the mixture in the method of Comparative Example 1.

[0041] FIG. 7 shows the results of HPLC of a crystalline form I atorvastatin hemi-calcium salt obtained by filtering, water washing and drying the reaction product in the method of Comparative Example 1.

[0042] FIG. 8 shows the powder X-ray diffraction spectrum of a crystalline atorvastatin hemi-calcium salt prepared according to the method of Example 2 of present invention.

[0043] FIG. 9 shows the solid-state .sup.13C nuclear magnetic resonance (NMR) spectrum of the crystalline atorvastatin hemi-calcium salt prepared according to the method of Example 2 of present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

[0044] Hereinafter, the present invention will be described in further detail with reference to examples. It is to be understood, however, that these examples are for illustrative purposes only and the scope of the present invention is not limited thereto.

Example 1

[0045] As crude atorvastatin, an amorphous atorvastatin hemi-calcium salt prepared according to the method of Example 10 of U.S. Pat. No. 5,273,995 was used. The HPLC graph and peak results of the amorphous atorvastatin hemi-calcium salt are shown in FIG. 1 and Table 1 below.

TABLE-US-00003 TABLE 1 Classification RT Area % area 1 Peak 1 15.296 2.48858 0.006 2 Peak 2 16.333 1.71720 0.004 3 des-fluoro 23.616 21.17357 0.055 4 trans-isomer 24.143 30.46073 0.079 5 Atorvastatin 25.723 38294.5 99.457 6 di-fluoro 27.293 7.37744 0.019 7 Peak 7 32.645 0.00000 0.000 8 Lactone 34.209 63.30801 0.164 9 Peak 9 39.358 12.00771 0.031 10 Pak 10 40.697 26.27836 0.068 11 Peak 11 47.803 21.32455 0.055 12 Peak 12 49.506 18.76946 0.049 13 Peak 13 51.266 4.14277 0.011

[0046] Subsequently, 10 g of the prepared amorphous atorvastatin hemi-calcium salt was added to a mixture of 50 ml of methanol and 600 ml of water and stirred at room temperature for 1 hour. The stirred mixture was filtrated, and the resulting solid was washed with water. The washed solid was dried under reduced pressure at 40° C. for 5 hours, thus obtained 9.6 g of a crystalline Form α atorvastatin hemi-calcium salt.

[0047] The X-ray powder diffraction spectrum of the obtained crystalline Form α atorvastatin hemi-calcium salt is shown in FIG. 2, and the numerical values of the X-ray powder diffraction spectrum are shown in Table 2 below.

TABLE-US-00004 TABLE 2 2θ d Relative intensity (>10%) 8.820 10.0175 31.1 9.642 9.1652 24.4 11.860 7.4562 13.1 16.900 5.242 100.0 19.583 4.5294 16.9 21.679 4.0960 44.1 23.480 3.7858 26.6 29.702 3.0054 15.9

[0048] The .sup.13C nuclear magnetic resonance (NMR) spectrum of the obtained crystalline Form α atorvastatin hemi-calcium salt is shown in FIG. 3, and the numerical values of the .sup.13C NMR spectrum are shown in Table 3.

TABLE-US-00005 TABLE 3 Chemical shift 224.37 224.15 221.60 217.76 216.11 214.64 214.43 210.16 181.68 180.17 179.27 177.60 165.92 161.45 159.48 136.75 134.15 130.25 128.63 127.02 122.68 120.73 120.03 117.34 113.94 112.90 74.01 72.13 70.83 69.46 68.32 67.12 66.41 64.88 64.01 49.26 47.69 46.45 45.84 45.28 44.57 42.32 40.72 39.38 36.84 35.16 25.43 23.85 20.24 18.52

[0049] After the mixture of methanol, water and atorvastatin has been stirred, the resulting reaction product was taken with a pipette before filtration and subjected to HPLC. The HPLC results of the reaction product are shown in FIG. 4 and Table 4 below. The HPLC graph and peak results of the crystalline Form α atorvastatin hemi-calcium salt that has been filtered, washed with water and dried are shown in FIG. 5 and Table 5 below.

TABLE-US-00006 TABLE 4 Classification RT Area % area 1 Peak 1 15.472 17.91986 0.061 2 Peak 2 16.336 9.32039 0.032 3 des-fluoro 23.552 16.81358 0.057 4 trans-isomer 24.094 23.46393 0.080 5 Atorvastatin 25.655 29329.1 99.52 6 di-fluoro 27.177 3.40998 0.012 7 Peak 7 32.564 2.16635 0.007 8 lactone 33.596 48.39322 0.165 9 Peak 9 39.160 3.17732 0.011 10 Peak 10 41.657 4.58379 0.016 11 Peak 11 47.817 8.68831 0.029 12 Peak 12 49.015 4.54222 0.015

TABLE-US-00007 TABLE 5 Classification RT Area % area 1 Peak 1 15.398 1.47642 0.004 2 Peak 2 17.078 3.99462 0.010 3 des-fluoro 23.764 22.21842 0.055 4 trans-isomer 24.331 20.21887 0.050 5 Atorvastatin 25.881 40320.8 99.65 6 di-fluoro 27.461 3.47598 0.009 7 Peak 7 32.614 14.46725 0.036 8 lactone 33.868 44.04422 0.109 9 Peak 9 39.574 7.35996 0.018 10 Peak 10 40.879 9.01929 0.022 11 Peak 11 47.552 8.38994 0.021 12 Peak 12 49.894 7.57033 0.019

[0050] As can be seen in Tables above, the % area of the impurity of lactone form was 0.164% in the crude atorvastatin hemi-calcium salt (Table 1), was maintained at 0.165% before filtration of the mixture (Table 4), and was 0.109% after filtration of the mixture (Table 5). This suggests that the reaction mixture shows a stable state which does not increase the impurity.

Comparative Example 1

[0051] For comparison with the present invention, a crystalline form I was prepared in the following manner according to method B of Example 1 of U.S. Pat. No. 5,969,156, and the HPLC area ratio of the crystalline form I atorvastatin trihydrate was examined. 10 g of amorphous atorvastatin was stirred in a mixture of 170 ml of water and 30 ml of methanol at 40° C. for 17 hours. The mixture was filtered and washed with water. Then, the resulting solid was dried under reduced pressure, thus obtaining 9.6 g of a crystalline form I atorvastatin hemi-calcium salt.

[0052] After the mixture of methanol, water and atorvastatin has been stirred, the resulting reaction product was taken with a pipette before filtration and subjected to HPLC. The results of HPLC of the reaction product are shown in FIG. 6 and Table 6 below. The HPLC graph and peak results of the crystalline form I atorvastatin hemi-calcium salt that has been filtered, washed with water and dried are shown in FIG. 7 and Table 7 below.

TABLE-US-00008 TABLE 6 Classification RT Area % area 1 Peak 1 15.408 2.04671 0.005 2 Peak 2 16.381 2.16140 0.006 3 des-fluoro 23.666 21.93967 0.057 4 trans-isomer 24.192 34.10612 0.089 5 Atorvastatin 25.777 38190.7 99.28 6 di-fluoro 27.344 6.60240 0.017 7 Peak 7 32.594 1.27799 0.003 8 lactone 34.277 124.41223 0.323 9 Peak 9 39.421 13.85361 0.036 10 Peak 10 40.771 31.64594 0.082 11 Peak 11 47.517 20.25181 0.053 12 Peak 12 49.321 18.38314 0.048

TABLE-US-00009 TABLE 7 Classification RT Area % area 1 Peak 1 15.591 17.33613 0.044 2 Peak 2 16.637 2.97883 0.007 3 des-fluoro 23.978 21.56549 0.055 4 trans-isomer 24.841 22.55341 0.057 5 Atorvastatin 26.114 39301.8 99.40 6 di-fluoro 27.725 9.04092 0.023 7 Peak 7 32.645 10.38568 0.026 8 lactone 34.238 52.05996 0.132 9 Peak 9 39.857 16.09881 0.041 10 Peak 10 41.204 33.47954 0.085 11 Peak 11 47.687 32.49892 0.082 12 Peak 12 49.440 18.34163 0.046

[0053] As can be seen in Tables above, the % area of the lactone impurity was 0.164% in the crude atorvastatin hemi-calcium salt (Table 1), but increased to 0.323% before filtration of the mixture (Table 6) and was shown to be 0.132% even after the mixture was filtered and then dried so that the impurity was removed to the parent liquor (Table 7).

[0054] This suggests that the impurity increases because the mixture is allowed to react at high temperature for 17 hours.

Example 2

[0055] 10 g of a mixture of amorphous and crystalline forms of atorvastatin hemi-calcium salt was added to a mixture of 50 ml of methanol and 500 ml of water and stirred at 5˜15° C. for 5 hours. The stirred mixture was filtered and the resulting solid was washed with water. The washed solid was dried under reduced pressure at 40° C. for 5 hours, thus obtaining 9.8 g of a crystalline Form α atorvastatin hemi-calcium salt.

[0056] The X-ray powder diffraction spectrum of the obtained crystalline Form α atorvastatin hemi-calcium salt is shown in FIG. 8, and the numerical values of the X-ray powder diffraction spectrum are shown in Table 8 below.

[0057] The .sup.13C NMR (nuclear magnetic resonance) of the obtained crystalline Form α atorvastatin hemi-calcium salt are shown in FIG. 9, and the numerical values thereof are shown in Table 9 below.

TABLE-US-00010 TABLE 8 Relative intensity 2θ d (>10%) 8.960 9.8611 34.0 9.499 9.3029 19.5 11.939 7.4065 16.2 16.899 5.2422 100.0 19.322 4.5900 21.4 21.701 4.0920 49.0 23.339 3.8083 22.4 29.258 3.0500 13.5

TABLE-US-00011 TABLE 9 Chemical shift 224.37 221.58 217.72 217.22 216.09 214.86 210.11 181.75 179.45 177.56 165.98 161.43 159.47 136.73 134.12 130.22 129.71 128.64 127.34 122.65 120.67 120.02 117.32 112.90 74.00 72.81 72.68 72.21 70.81 70.37 69.51 67.17 65.32 64.99 63.96 49.23 48.39 47.54 46.44 45.77 45.03 44.21 42.34 40.82 39.38 38.03 37.01 35.26 25.43 24.00 20.29

Comparative Example 2

[0058] In order to examine whether the crystalline Form α atorvastatin hemi-calcium salt prepared according to the method of Example of the present invention is stable under storage conditions for three batches, a stability test was performed under accelerated conditions of a temperature of 40° C. and a relative humidity of 75%. The storage stability of the crystalline Form α atorvastatin hemi-calcium salt was determined using the HPLC area ratio. The test results are shown in Table 10 below.

TABLE-US-00012 TABLE 10 Test Period conditions Initial 1 month 2 months 3 months 4 months 5 months 6 months Batch 1 40° C. and 99.64 99.60 99.56 99.53 99.50 99.48 99.45 No. 75% RH 2 40° C. and 99.65 99.60 99.58 99.55 99.52 99.50 99.48 75% RH 3 40° C. and 99.70 99.66 99.60 99.57 99.54 99.51 99.48 75% RH

[0059] As can be seen in Table 10 above, the purity of the crystalline Form α atorvastatin hemi-calcium salt was maintained without a significant change under accelerated conditions. Thus, it could be seen that the crystalline Form α atorvastatin hemi-calcium salt showed excellent stability.