CRYSTALLINE SALT OF ERIBULIN
20230234961 · 2023-07-27
Assignee
Inventors
- Areum BAEK (Suwon-si, Gyeonggi-do, KR)
- Hyunik SHIN (Suwon-si, Gyeonggi-do, KR)
- Yongseo PARK (Suwon-si, Gyeonggi-do, KR)
- Seongtaek KIM (Suwon-si, Gyeonggi-do, KR)
- Seunghui SIN (Suwon-si, Gyeonggi-do, KR)
Cpc classification
C07D493/22
CHEMISTRY; METALLURGY
International classification
Abstract
An eribulin salt formed by combining an eribulin free base with a low molecular weight amine compound through a diacid compound is disclosed. As the diacid compound, edisylic acid, 1,5-naphthalenedisulfonic acid, trans-2-butene-1,4-dicarboxylic acid, pyrophosphoric acid, and combination thereof may be employed. As the amine, ammonia, cyclohexylamine, dicyclohexylamine, and a combination thereof may be employed. The eribulin salt can be crystallized by recrystallization to produce a crystalline eribulin salt with increased purity.
Claims
1. An eribulin salt represented by the following formula (I): ##STR00005## wherein, Y represents a diacid compound, and Z represents an amine compound.
2. The eribulin salt according to claim 1, wherein the diacid compound is represented by the following formula (II):
X—R—X (I) wherein, R represents a C.sub.1-C.sub.6 alkylene group, a C.sub.2-C.sub.6 alkenylene group, an arylene group, or an oxygen atom, and X represents a sulfonic acid group, a carboxylic acid group, or a phosphonic acid group.
3. The eribulin salt according to claim 1, wherein the amine compound is represented by the following formula (III): ##STR00006## wherein, R.sup.1, R.sup.2 and R.sup.3 each independently represent a hydrogen atom, a C.sub.1-C.sub.6 alkyl group, or a C.sub.3-C.sub.10 cycloalkyl group.
4. The eribulin salt according to claim 1, wherein the diacid compound is selected from the group consisting of edisylic acid, 1,5-naphthalenedisulfonic acid, trans-2-butene-1,4-dicarboxylic acid and pyrophosphoric acid.
5. The eribulin salt according to claim 1, wherein the amine compound is selected from the group consisting of ammonia, cyclohexylamine and dicyclohexylamine.
6. The eribulin salt according to claim 1, wherein the diacid compound is edisylic acid and the amine compound is ammonia.
7. The eribulin salt according to claim 6, wherein the salt shows an X-ray powder diffraction pattern characterized by peaks having I/I.sub.0 values of at least 10% (I is the intensity of each peak; I.sub.0 is the intensity of the highest peak) at diffraction angles (2θ) of 6.7±0.2, 7.3±0.2, 9.8±0.2, 10.3±0.2, 10.8±0.2, 11.8±0.2, 13.0±0.2, 13.7±0.2, 14.4±0.2, 14.8±0.2, 15.6±0.2, 16.1±0.2, 16.4±0.2, 16.8±0.2, 17.2±0.2, 17.7±0.2, 18.4±0.2, 18.9±0.2, 19.3±0.2, 20.3±0.2, 20.6±0.2, 21.2±0.2, 22.1±0.2, 22.6±0.2, 23.1±0.2, 23.7±0.2, 26.4±0.2, 26.9±0.2, 27.8±0.2, and 37.8±0.2.
8. The eribulin salt according to claim 6, wherein the salt shows an X-ray powder diffraction pattern characterized by peaks having I/I.sub.0 values of at least 10% (I is the intensity of each peak; I.sub.0 is the intensity of the highest peak) at diffraction angles (2θ) of 14.8±0.2, 17.7±0.2, 19.3±0.2, 22.0±0.2, 23.1±0.2, 23.7±0.2, 26.4±0.2, 26.8±0.2, 28.9±0.2, 31.0±0.2, 32.8±0.2, 34.5±0.2 and 37.8±0.2.
9. The eribulin salt according to claim 1, wherein the diacid compound is edisylic acid and the amine compound is cyclohexylamine.
10. The eribulin salt according to claim 9, wherein the salt shows an X-ray powder diffraction pattern characterized by peaks having I/I.sub.0 values of at least 10% (I is the intensity of each peak; I.sub.0 is the intensity of the highest peak) at diffraction angles (2θ) of 8.6±0.2, 10.0±0.2, 11.3±0.2, 17.4±0.2, 17.8±0.2, 18.2±0.2, 18.9±0.2, 19.4±0.2, 20.2±0.2, 21.2±0.2, 22.1±0.2 and 22.9±0.2.
11. The eribulin salt according to claim 1, wherein the diacid compound is edisylic acid and the amine compound is dicyclohexylamine.
12. The eribulin salt according to claim 11, wherein the salt shows an X-ray powder diffraction pattern characterized by peaks having I/I.sub.0 values of at least 10% (I is the intensity of each peak; I.sub.0 is the intensity of the highest peak) at diffraction angles (2θ) of 10.0±0.2, 11.2±0.2, 18.3±0.2, 18.7±0.2, 19.3±0.2, 20.1±0.2, 20.8±0.2, 21.2±0.2, 21.8±0.2, 22.5±0.2, 23.0±0.2 and 27.1±0.2.
13. The eribulin salt according to claim 1, wherein the diacid compound is 1,5-naphthalenedisulfonic acid, and the amine compound is ammonia.
14. The eribulin salt according to claim 13, wherein the salt shows an X-ray powder diffraction pattern characterized by peaks having I/I.sub.0 values of at least 10% (I is the intensity of each peak; I.sub.0 is the intensity of the highest peak) at diffraction angles (2θ) of 16.7±0.2, 21.3±0.2, 23.0±0.2, 24.3±0.2, 25.0±0.2, 25.7±0.2 and 29.4±0.2.
15. The eribulin salt according to claim 1, wherein the diacid compound is trans-2-butene-1,4-dicarboxylic acid, and the amine compound is ammonia.
16. The eribulin salt according to claim 15, wherein the salt shows an X-ray powder diffraction pattern characterized by peaks at diffraction angles (2θ) of 17.2±0.2, 19.0±0.2, 22.1±0.2, 24.0±0.2, 26.0±0.2, 31.7±0.2, 32.8±0.2 and 38.5±0.2.
17. The eribulin salt according to claim 1, wherein the diacid compound is pyrophosphoric acid, and the amine compound is ammonia.
18. The eribulin salt according to claim 17, wherein the salt shows an X-ray powder diffraction pattern characterized by peaks having I/I.sub.0 values of at least 10% (I is the intensity of each peak; I.sub.0 is the intensity of the highest peak) at diffraction angles (2θ) of 13.5±0.2, 15.8±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 19.5±0.2, 22.1±0.2, 23.2±0.2, 24.1±0.2, 27.1±0.2, 27.7±0.2, 28.4±0.2, 29.6±0.2 and 33.1±0.2.
Description
BRIEF DESCRIPTION OF FIGURES
[0048]
[0049]
[0050]
[0051]
[0052]
[0053]
[0054]
[0055]
[0056]
[0057]
[0058]
[0059]
[0060]
[0061]
[0062]
[0063]
BEST MODE
[0064] The present invention is further illustrated by the following examples, which are not to be construed to limit the scope of the invention.
[0065] The crystalline form of the eribulin salt prepared in Examples below was confirmed by X-ray powder diffraction analysis (XRPD) and differential scanning calorimetry (DSC), and the specific measurement method is as follows.
[0066] (1) X-Ray Powder Diffraction Analysis
[0067] Diffraction patterns were obtained in the range of 3 to 40° 2θ using a X-ray powder diffractometer, and the X-ray powder diffraction analysis conditions were as follows. [0068] Instrument: BrukerA26X1 D2 Phaser [0069] Time per step: 0.5 s [0070] Scanning method: Continuous PSD fast [0071] Detector: Lynxeye (1D mode)
[0072] (2) Differential Scanning Calorimetry (DSC)
[0073] Analysis was performed using the Q2000 model of TA instrument. Approximately 2-3 mg of a sample was placed in an aluminum pan and covered with lid having a hole to prepare a sample required for the DSC experiment. After recording the exact weight, it was heated to 25-210° C. under nitrogen at a rate of 10° C./min.
Example 1: Preparation of Eribulin Edisylate Ammonium Salt
[0074] Eribulin free base (1 g) was stirred in acetonitrile (12.5 mL) at room temperature, and ethane-1,2-disulfonic acid (0.3 g) was dissolved in 30% aqueous ammonia (4.1 mL) and water (13.5 mL) and added dropwise to the mixture. After stirring for 30 minutes, the resulting solution was distilled under reduced pressure and then azeotroped using acetonitrile to obtain an eribulin edisylate ammonium salt.
Example 2: Recrystallization of Eribulin Edisylate Ammonium Salt
[0075] Eribulin edisylate ammonium salt (1 g, purity: 96.3%) obtained in Example 1 was suspended in acetonitrile/water=9:1 (10 mL) and thoroughly dissolved by heating to about 50-60° C. Thereafter, acetonitrile (30 mL) was slowly added dropwise, and upon completion of the addition, the mixture was cooled to room temperature. After cooling, the solid obtained by stirring was washed with acetonitrile. The washed solid was vacuum-dried to obtain an eribulin edisylate ammonium salt (purity: 98.0%) with increased purity. X-ray powder diffraction analysis and differential scanning calorimetry were performed, and the results are shown in
[0076] Endothermic point (Differential scanning calorimetry, DSC): 169.0, 187.2, 191.3° C.
TABLE-US-00001 TABLE 1 No. 2θ Relative strength (%) 1 6.668 14.9 2 7.254 42.5 3 8.044 9.3 4 8.701 8.4 5 9.202 9.9 6 9.826 100.0 7 10.273 65.1 8 10.786 64.9 9 11.808 25.0 10 13.006 28.3 11 13.738 31.5 12 14.379 15.2 13 14.770 24.1 14 15.646 33.3 15 16.065 29.1 16 16.443 53.7 17 16.828 51.2 18 17.239 40.4 19 17.735 78.8 20 18.430 16.7 21 18.897 12.0 22 19.348 33.0 23 20.277 19.7 24 20.622 40.0 25 21.235 16.5 26 22.081 14.8 27 22.551 13.2 28 23.127 39.2 29 23.725 56.8 30 26.424 28.2 31 26.872 42.3 32 27.825 14.1 33 28.881 6.6 34 32.881 6.9 35 34.462 6.8 36 35.107 8.4 37 36.537 6.9 38 37.549 9.9 39 37.829 11.2 40 38.986 8.8
Example 3: Preparation of Eribulin Edisylate Ammonium Salt Crystalline Form I
[0077] Eribulin edisylate ammonium salt (1 g) obtained in Example 2 was suspended in isopropyl alcohol (20 mL) and then heated and stirred. The resulting solution was cooled to room temperature, filtered, and washed with isopropyl alcohol. The thus-obtained crystals were vacuum-dried and subjected to X-ray powder diffraction analysis and differential scanning calorimetry. The results are shown in Table 2 and
[0078] Endothermic point (Differential scanning calorimetry, DSC): 182.5° C.
TABLE-US-00002 TABLE 2 No. 2θ Relative strength (%) 1 14.775 18.2 2 17.724 100 3 18.749 6.6 4 19.261 29.3 5 20.521 8.4 6 20.640 9.0 7 21.358 3.0 8 22.045 36.4 9 23.115 93.9 10 23.709 65.9 11 26.409 67.0 12 26.810 44.5 13 27.860 4.7 14 28.879 20.0 15 31.030 10.6 16 32.840 10.2 17 33.374 2.7 18 34.499 13.4 19 37.459 9.7 20 37.819 19.0 21 39.012 6.8
Example 4: Preparation of Eribulin Edisylate Cyclohexylamine Salt
[0079] Eribulin free base (1 g) was dissolved in acetonitrile (10 mL) at room temperature. Thereafter, cyclohexylamine (0.16 mL) and ethane-1,2-disulfonic acid (0.3 g) were dissolved in water (13.3 mL), added dropwise to the mixture, and stirred for 30 minutes. The resulting solution was distilled under reduced pressure and then azeotroped with acetonitrile to obtain eribulin edisylate cyclohexylamine salt.
Example 5: Recrystallization of Eribulin Edisylate Cyclohexylamine Salt
[0080] Eribulin edisylate cyclohexylamine salt (1 g, purity: 97.18%) obtained in Example 4 was suspended in acetonitrile/water=9:1 (6.7 mL) and thoroughly dissolved by heating to about 50-60° C. Thereafter, acetonitrile (40 mL) was slowly added dropwise, and upon completion of the addition, the mixture was cooled to room temperature. After cooling, the solid obtained by stirring was washed with acetonitrile. The washed solid was vacuum-dried to obtain an eribulin edisylate cyclohexylamine salt (purity: 98.99%) with increased purity. X-ray powder diffraction analysis and differential scanning calorimetry were performed, and the results are shown in Table 3, and
[0081] Endothermic point (Differential scanning calorimetry, DSC): 167.4° C.
TABLE-US-00003 TABLE 3 No. 2θ Relative strength (%) 1 8.587 37.0 2 9.551 7.9 3 9.997 10.9 4 11.273 13.6 5 12.217 4.5 6 12.855 4.6 7 13.952 4.1 8 14.435 5.8 9 14.893 7.6 10 15.967 6.3 11 16.391 7.5 12 16.874 8.6 13 17.112 8.1 14 17.410 13.1 15 17.516 9.0 16 17.785 10.0 17 18.232 26.0 18 18.898 21.5 19 19.370 12.9 20 20.187 14.1 21 20.431 9.4 22 21.179 100.0 23 22.085 29.9 24 22.919 20.0 25 24.838 5.4 26 25.591 3.3 27 27.555 2.9 28 28.051 6.1 29 29.382 6.2 30 31.331 4.1 31 32.283 3.2 32 32.709 3.0 33 33.658 3.0 34 33.890 3.3
Example 6: Preparation of Eribulin Edisylate Dicyclohexylamine Salt
[0082] Eribulin free base (1 g) was dissolved in acetonitrile (10 mL) at room temperature. Thereafter, dicyclohexylamine (0.28 mL) and ethane-1,2-disulfonic acid (0.3 g) were dissolved in water (13.3 mL), added dropwise to the mixture, and stirred for 30 minutes. The resulting solution was distilled under reduced pressure and then azeotroped with acetonitrile to obtain eribulin edisylate dicyclohexylamine salt.
Example 7: Recrystallization of Eribulin Edisylate Dicyclohexylamine Salt
[0083] Eribulin edisylate dicyclohexylamine salt (1 g, purity: 97.21%) obtained in Example 6 was suspended in acetonitrile/water=9:1 (6.7 mL) and thoroughly dissolved by heating to about 50-60° C. Thereafter, acetonitrile (40 mL) was slowly added dropwise, and upon completion of the addition, the mixture was cooled to room temperature. After cooling, the solid obtained by stirring was washed with acetonitrile. The washed solid was vacuum-dried to obtain an eribulin edisylate dicyclohexylamine salt (purity: 98.47%) with increased purity. X-ray powder diffraction analysis and differential scanning calorimetry were performed, and the results are shown in Table 4, and
[0084] Endothermic point (Differential scanning calorimetry, DSC): 198.5° C.
TABLE-US-00004 TABLE 4 No. 2θ Relative strength (%) 1 9.997 100.0 2 11.234 15.9 3 18.114 7.5 4 18.340 11.0 5 18.712 69.6 6 19.331 32.4 7 20.110 69.3 8 20.751 23.1 9 21.197 25.0 10 21.788 27.3 11 22.473 20.1 12 23.003 29.2 13 27.067 11.9 14 27.975 4.1 15 30.297 8.6 16 35.549 3.5 17 38.420 5.7
Example 8: Preparation of Eribulin 1,5-naphthalenedisulfonate Ammonium Salt
[0085] Eribulin free base (1 g) was dissolved in acetonitrile (12.5 mL) at room temperature. Thereafter, 1,5-naphthalenedisulfonic acid tetrahydrate (0.47 g) was dissolved in 30% aqueous ammonia (4.1 mL) and water (13.5 mL), added dropwise to the mixture, and stirred for 30 minutes. The resulting solution was distilled under reduced pressure and then azeotroped with acetonitrile to obtain eribulin 1,5-naphthalenedisulfonate ammonium salt.
Example 9: Recrystallization of Eribulin 1,5-naphthalenedisulfonate Ammonium Salt
[0086] Eribulin 1,5-naphthalenedisulfonate ammonium salt (1 g) obtained in Example 8 was dissolved in acetonitrile (3.64 mL) and heated to 40° C. Thereafter, water (1.38 mL) was added dropwise. When the mixture became clear, acetonitrile (13 mL) was added dropwise, and the mixture was cooled to room temperature. After cooling, the solid obtained by stirring was washed with acetonitrile. The washed solid was vacuum-dried to obtain an eribulin 1,5-naphthalenedisulfonate ammonium salt with increased purity. X-ray powder diffraction analysis and differential scanning calorimetry were performed, and the results are shown in Table 5 and
[0087] Endothermic point (Differential scanning calorimetry, DSC): at least 325° C.
TABLE-US-00005 TABLE 5 No. 2θ Relative strength (%) 1 15.587 5.6 2 16.172 3.5 3 16.725 100.0 4 17.373 7.6 5 19.703 3.4 6 21.334 17.5 7 22.535 7.1 8 22.997 30.7 9 24.270 30.9 10 25.004 12.3 11 25.674 32.7 12 26.032 6.9 13 27.122 5.6 14 27.235 6.5 15 27.729 2.8 16 29.358 10.3 17 30.174 1.8 18 31.748 7.5 19 32.489 6.6 20 33.466 7.6 21 34.610 5.6 22 36.896 7.6 23 39.046 3.1
Example 10: Preparation of Eribulin trans-2-butene-1,4-dicarboxylate Ammonium Salt
[0088] Eribulin free base (1 g) was dissolved in acetonitrile (12.5 mL) at room temperature. Thereafter, trans-2-butene-1,4-dicarboxylic acid (0.19 g) was dissolved in 30% aqueous ammonia (4.1 mL) and water (13.5 mL), added dropwise to the mixture, and stirred for 30 minutes. The resulting solution was distilled under reduced pressure and then azeotroped with acetonitrile to obtain eribulin trans-2-butene-1,4-dicarboxylate ammonium salt.
Example 11: Recrystallization of Eribulin trans-2-butene-1,4-dicarboxylate Ammonium Salt
[0089] Eribulin trans-2-butene-1,4-dicarboxylate ammonium salt (1 g) obtained in Example 10 was suspended in isopropanol (3.81 mL) and heated to 40° C. Thereafter, water (0.91 mL) was added dropwise. When the mixture became clear, acetonitrile (13.7 mL) was added dropwise, and the mixture was cooled to room temperature. After cooling, the solid obtained by stirring was washed with acetonitrile. The washed solid was vacuum-dried to obtain an eribulin trans-2-butene-1,4-dicarboxylate ammonium salt with increased purity. X-ray powder diffraction analysis and differential scanning calorimetry were performed, and the results are shown in Table 6 and
[0090] Endothermic point (Differential scanning calorimetry, DSC): 168.0 and 182.7° C.
TABLE-US-00006 TABLE 6 No. 2θ Relative strength (%) 1 17.189 2.5 2 19.026 1.4 3 22.058 6.3 4 24.013 100.0 5 25.980 3.9 6 31.725 1.1 7 32.819 1.8 8 38.502 0.9
Example 12: Preparation of Eribulin Pyrophosphate Ammonium Salt
[0091] Eribulin free base (1 g) was dissolved in acetonitrile (12.5 mL) at room temperature. Thereafter, pyrophosphoric acid (0.24 g) was dissolved in 30% aqueous ammonia (4.1 mL) and water (13.5 mL), added dropwise to the mixture, and stirred for 30 minutes. The resulting solution was distilled under reduced pressure and then azeotroped with acetonitrile to obtain eribulin pyrophosphate ammonium salt.
Example 13: Recrystallization of Eribulin Pyrophosphate Ammonium Salt
[0092] Eribulin pyrophosphate ammonium salt (1 g, purity: 98.16%) obtained in Example 12 was suspended in isopropyl alcohol (20 mL) and heated and stirred. Thereafter, the mixture was cooled to room temperature, washed with isopropyl alcohol, and then vacuum-dried to obtain an eribulin pyrophosphate ammonium salt (purity: 98.48%) with increased purity. X-ray powder diffraction analysis was performed, and the results are shown in Table 7 and
TABLE-US-00007 TABLE 7 No. 2θ Relative strength (%) 1 13.456 32.6 2 15.800 75.3 3 16.356 100.0 4 17.601 39.6 5 17.893 63.9 6 19.457 53.0 7 22.056 16.2 8 23.162 28.9 9 24.069 26.5 10 27.066 79.5 11 27.688 89.6 12 28.381 20.6 13 29.579 38.4 14 33.112 17.7
Experimental Example 1: Stability Test
[0093] In order to evaluate the moisture and thermal stability of the eribulin edisylate ammonium salt obtained in Example 2 and amorphous eribulin mesylate, the active component of commercially available Halaven, 20 mg each was placed in a screwcap amber vial and sealed, and stored at 40±2° C., 75±5% RH. After 2 weeks and 4 weeks of storage, the occurrence and increase of related substances in each sample were evaluated by high-performance liquid chromatography, and changes were confirmed by X-ray powder diffraction analysis and differential scanning calorimetry to evaluate stability.
[0094] No change in properties of the eribulin edisylate ammonium salt was observed during the stability test period. However, in the case of eribulin mesylate, the solid deliquesced and the color changed to yellow in the 2nd week, and the deliquescent state was maintained and the color changed from yellow to brown in the 4th week.
[0095] In addition, as a result of high-performance liquid chromatography analysis for confirming related substances, the eribulin edisylate ammonium salt obtained in Example 2 showed a small increase in related substances resulting in a decrease in purity within about 0.5% during 4 weeks of the stability test period as shown in Table 8 below. On the other hand, the purity of eribulin mesylate decreased to 7% in the 4th week due to the increase in related substances. Therefore, it was confirmed that the eribulin edisylate ammonium salt of Example 2 exhibited excellent stability to heat and humidity up to 4 weeks compared to the stability of the amorphous eribulin mesylate.
TABLE-US-00008 TABLE 8 Time (week) Eribulin edisylate ammonium salt Eribulin mesylate 0 99.73% 99.66% 2 99.50% 88.00% 4 99.35% 7.30%
[0096] In addition, the X-ray powder diffraction analysis results are shown in Table 9 below. As shown in Table 9 below, eribulin mesylate was initially an amorphous solid, but deliquescence was observed over time in the stability test.
TABLE-US-00009 TABLE 9 Time (week) Eribulin edisylate ammonium salt Eribulin mesylate 0 crystalline amorphous 2 maintain deliquescence 4 maintain deliquescence
[0097] The stability test results showed that the crystalline form of eribulin edisylate ammonium salt was more stable to heat and humidity than eribulin mesylate, which is the active component of commercially available Halaven.
Experimental Example 2: Hygroscopicity Test
[0098] Eribulin edisylate obtained in Examples 2, 5, and 7 and the amorphous eribulin mesylate, which is the active component of commercially available Halaven, were subjected to hygroscopicity test by repeating moisture adsorption and desorption once at an interval of 5% RH in an isothermal condition of 25° C. and a relative humidity of 2 to 98% using dynamic vapor adsorption and desorption (DVS) (dynamic vapor adsorption, VTI SGA-100, TA Instruments). The results are shown in Table 10 and
[0099] As a result of the hygroscopicity test, it was confirmed that the amorphous eribulin mesylate showed a rapid weight increase pattern during the hygroscopicity test and its stability to moisture was lowered by adsorption of moisture up to 11.8%. In addition, deliquescence was observed during the test. On the other hand, eribulin edisylate obtained in Examples 2, 5, and 7 showed lower hygroscopicity at 25° C. and 80% RH than the amorphous eribulin mesylate. In addition, it was confirmed that the initial crystalline form was maintained after the test was completed and the eribulin edisylate of Examples 2, 5, and 7 had superior stability to moisture than the amorphous eribulin mesylate.
TABLE-US-00010 TABLE 10 Hygroscopicity Eribulin salt (EP standard (25° C., 80% RH)) amorphous eribulin mesylate 11.8% Example 2 5.4% Example 5 5.2% Example 7 5.6%