CN1915978A - Crystal form of lonidamine, preparation method, and composition of containing the crystal form - Google Patents

Crystal form of lonidamine, preparation method, and composition of containing the crystal form Download PDF

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CN1915978A
CN1915978A CN 200510028846 CN200510028846A CN1915978A CN 1915978 A CN1915978 A CN 1915978A CN 200510028846 CN200510028846 CN 200510028846 CN 200510028846 A CN200510028846 A CN 200510028846A CN 1915978 A CN1915978 A CN 1915978A
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lonidamine
crystal
crystalline
acid
iii
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CN1915978B (en
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邬晓琪
郭殿武
钟伟勤
姜新民
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Hangzhou Minsheng Pharmaceutical Co Ltd
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Hangzhou Minsheng Pharmaceutical Co Ltd
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Abstract

This invention provides a method for preparing lonidamine crystals with the forms of I, II and III, as well as a composition containing lonidamine crystals. The lonidamine crystals have good release performance.

Description

The crystallized form of lonidamine, its preparation method and contain the composition of described crystallized form
Technical field
The present invention relates to lonidamine crystal, their preparation method of form I, II and III and contain described crystalline composition.
Background technology
The lonidamine chemistry is by name: 1-(2,4-dichlorobenzene methyl)-1H-indazole-3-carboxylic acid, at first by German Angelopharm exploitation, went on the market in Italy in 1986, nineteen ninety Portugal's listing, it is clinical that the U.S., Canada etc. are in the III phase, and it is clinical that France, Japan etc. are in the II phase, before several countries such as Australia are in registration.This is to belong to indazole lopps substitutive derivative, finds that the earliest it has the smart effect of killing.Find its anti-tumor activity in the exploration of the further pharmacological research and the mechanism of action, by inside and outside a series of studies show that of body, it is a kind of tumour temperature-sensitive medicine that is different from traditional antineoplastic.It does not influence proliferation of cells, mainly acts on the energy metabolism of cell.By changing the mitochondria ultrastructure of tumour cell, suppress the oxygen consumption of malignant cell, reach and press down tumoricidal purpose.Clinical study shows that it can act on the tumorigenesis of various attributes, particularly mammary cancer, lung cancer, prostate cancer and the cancer of the brain, can unite use with radiotherapy and other treatment means.
German Patent 2310031 (1972) and United States Patent (USP) 3.895.026 (1975) have disclosed the method for synthetic lonidamine: by 3-carboxylic acid-indazole and 2, the 4-dichlorobenzyl chloride takes off HCl and is condensed into the product lonidamine under alkaline condition.
Compound experiment finds that lonidamine has amorphous and form crystal formation, and the solubleness of crystal formation lonidamine is significantly better than amorphous, so affiliated technical field is sought after good stability, be easy to the new crystal of lonidamine making and prepare.
Summary of the invention
An object of the present invention is to provide be easy to make and prepare, to light, wet, good thermal stability, be suitable for the new lonidamine crystal of suitability for industrialized production and storage.
A further object of the present invention provides and contains described crystalline composition.
Another object of the present invention provides described crystalline preparation method.
These purposes of the present invention reach by following design:
The invention provides the lonidamine crystal of form I, using 35kv, under the Cu-k α radiation source irradiates of 30mA, following X-ray powder diffraction spectrum with 2 θ angles and spacing d value representation is arranged:
2 θ d values
11.7 7.5
12.7 7.0
14.5 6.1
15.0 5.9
17.7 5.0
17.9 4.9
24.1 3.7
25.2 3.5
25.6 3.5
26.4 3.4
27.1 3.3
28.3 3.2
28.9 3.1
29.4 3.0
30.0 3.0
31.9 2.8。
This crystalline DSC endothermic transition is at 211.0 ℃.
Another aspect of the present invention provides the lonidamine crystalline method of preparation form I, comprising:
A): the mixture that will form by the dilute alkaline aqueous solution of amorphous lonidamine of 10-45% and 55-90%, control pH8-10, be heated to more than 80 ℃ until backflow, slowly reduce the temperature to 80 ℃-50 ℃ after the dissolving, dropping inorganic acid is to pH3-5 in solution, cool to room temperature is separated out the lonidamine crystal of required form I; Perhaps
B) amorphous lonidamine is dissolved in recrystallisation solvent, is heated to backflow, dissolving, cooling fast then, crystallization obtains the lonidamine crystal of required form I; Wherein said recrystallisation solvent is selected from the doubly ethanol of (w/v) of (1) 8-15, (2) Glacial acetic acid of 6-12 times (w/v), (3) Glacial acetic acid of 6-12 times (w/v) adds methyl alcohol or the alcoholic acid mixed solution of 1%-30% (v/v), (4) ethanol of 8-15 times (w/v) adds the mixed solution of 1%-30% acetone (v/v), and the ethanol of (5) 8-15 times (w/v) adds the mixed solution of 1%-30% (v/v) ethyl acetate.
Described mineral acid preferably is selected from hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid; Described dilute alkaline aqueous solution preferably is selected from aqueous sodium hydroxide solution, potassium hydroxide aqueous solution.
The present invention also provides the lonidamine crystal of form II, is using 35kv, under the Cu-k α radiation source irradiates of 30mA, following X-ray powder diffraction spectrum with 2 θ angles and spacing d value representation is arranged:
2 θ d values
11.3 7.8
11.7 7.6
15.3 5.8
20.1 4.4
22.9 3.9
26.0 3.4
27.1 3.3
32.2 2.8。
This form II lonidamine crystal belongs to triclinic(crystalline)system, the P-1 spacer, and unit cell parameters is: a=7.7117  b=8.1384  c=11.987  α=106.17 ° of β=93.05 ° γ=96.96 ° of R values are 0.0450.
The lonidamine crystalline CSC endothermic transition of described form II is at 211.2 ℃.
The present invention also provides the lonidamine crystalline method of preparation form II, amorphous lonidamine is dissolved in recrystallisation solvent, it is clear to add thermosol, leave standstill then, slowly reduce to 15-25 ℃ of static crystallization, the lonidamine form II that filters requiredly, wherein said recrystallisation solvent are selected from doubly (w/v) Glacial acetic acid of (1) 15.5-25, and (2) 15.5-25 times of (w/v) Glacial acetic acid adds methyl alcohol or the alcoholic acid mixed solution of 1%-80% (v/v).
The present invention further provides the lonidamine crystal of form III, used 40kv, under the Cu-k α radiation source irradiates of 300mA, following X-ray powder diffraction spectrum with 2 θ angles and spacing d value representation has been arranged:
2 θ d values
5.3 16.6
11.1 7.9
11.5 7.7
13.2 6.7
14.0 6.28
16.8 5.3
21.5 4.1
22.2 4.0
22.5 3.9
23.2 3.8
27.5 3.2。
The lonidamine crystal of this form III belongs to triclinic(crystalline)system, the P-1 spacer, and unit cell parameters is: a=5.2879  b=8.1754  c=16.768  α=80.09 ° of β=89.89 ° γ=80.65 ° of R values are 0.0477.
The DSC endothermic transition of the lonidamine crystalline substance of described form III is at 211.3 ℃.
Described DSC data record on DSC Q100 V7.3 Build 249 instruments.
The invention still further relates to the lonidamine crystalline method of preparation form III, comprising:
Amorphous lonidamine is dissolved in the solvent of 15.5-18 times (w/v), is heated to backflow, molten clear, leave standstill then, slowly be cooled to 35-45 ℃, static crystallization gets required crystalline lonidamine form III, and wherein said solvent is a Glacial acetic acid.
In addition, the present invention also provides a kind of pharmaceutical composition, and it comprises in the lonidamine crystal of above-mentioned form I, II or III one or more and pharmaceutically acceptable carrier.
Description of drawings
The X-powder diagram of Fig. 1: form I;
The DSC differential scanning figure of Fig. 2: form I;
The infrared spectra of Fig. 3: form I (IR);
The X-powder diagram of Fig. 4: form II;
The space multistory structure of the molecule of Fig. 5: form II;
Fig. 6 a: form II is at the structure cell accumulation graph of A direction;
The stretch-out view of a pile in the structure cell accumulation graph of Fig. 6 b: form II;
The situation of the intermolecular formation hydrogen bond of Fig. 7: form II;
The differential scanning figure of Fig. 8: form II;
The infared spectrum of Fig. 9: form II;
The X-powder diagram of Figure 10: form III;
The space multistory structure of the molecule of Figure 11: form III;
Figure 12 a: form III is at the structure cell accumulation graph of A direction;
Figure 12 b: form III is at the structure cell accumulation graph of B direction;
The stretch-out view of a pile in the structure cell accumulation graph of Figure 13: form III;
The situation of the intermolecular formation hydrogen bond of Figure 14: form III;
The differential scanning figure of Figure 15: form III;
The infared spectrum of Figure 16: form III;
The weightless scintigram of the differential thermal of Figure 17: form III;
Figure 18: the stripping curve of lonidamine crystal habit I sheet;
Figure 19: the stripping curve that contains lonidamine crystal habit II sheet;
Figure 20: the stripping curve that contains the tablet of lonidamine crystal habit I and amorphous lonidamine mixture;
Embodiment
With reference to Ger.2310031 1972, the embodiment of these two pieces of patents of US.3.895.026.1975.Promptly by 3-carboxylic acid-indazole and 2, the 4-dichlorobenzyl chloride takes off the HCl condensation under alkaline condition, be refined into the product lonidamine.3-carboxylic acid-indazole is then by the istain open loop, and diazotization is reduced, and closed loop forms.
Except as otherwise noted, in this article, temperature be meant centigradetemperature (℃), room temperature is meant 15-25 ℃.
Already with being selected from the X-ray powder diffraction, X-ray single crystal diffraction, the DSC differential thermogram, analysis means such as infrared spectrogram characterize lonidamine crystalline feature of the present invention.Generally mark and levy that crystalline is formed or it is identified with XRD, the diffractogram that is obtained by crystalline compounds is distinctive often for a given crystal habit, though weak or very weak diffraction peak may always not occur in the same diffractogram that the crystallization by continuous lot number obtains, when other crystal habit of significant quantity is especially arranged in sample.The relative intensity of bands of a spectrum may change because of the advantage orientation effect that is produced by the difference of for example crystal habit, particle diameter and other condition.Therefore, the relative intensity of diffraction peak be not at last at crystal habit be distinctive, on the contrary, more should note the relative position at peak rather than their amplitude, to determine whether the lonidamine crystallization is described a kind of herein.
The differential scanning of three kinds of crystalline lonidamine forms (DSC) endothermic transition peak and heat absorption beginning temperature value are approaching, also the have an appointment difference of 0.5-0.7 of the differential scanning figure (DSC) that obtains by the same crystallization of continuous lot number, may with degree of crystallinity, different sub-samplings, factors such as experimental error are relevant, illustrate also in identical crystallisation process simultaneously and also can separate out simultaneously that the difficult difference of their relative thermostability is so DSC can be used as reference.The synthetic crystalline polamer also just conforms to.
The infared spectrum of three kinds of crystalline lonidamine forms also can be seen difference each other in their fingerprint region.
Crystalline lonidamine form I
Fig. 1 has shown that this form using Cu-k α source of radiation, 35kv, and 30mA, the X-ray powder diffraction spectroscopic data that records under (DMAX-IIID) is as follows:
Sequence number 2θ Intensity Width The d value I
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 11.720 12.680 14.560 14.980 17.660 17.940 18.880 19.680 19.960 21.320 21.880 22.300 22.480 22.840 23.720 24.060 24.340 25.220 316 135 294 114 137 477 54 38 42 45 58 40 41 50 88 99 110 165 .240 .240 .270 .270 .210 .240 .240 .300 .180 .270 .270 7.5447 6.9755 6.0788 5.9093 5.0181 4.9404 4.6965 4.5073 4.4447 4.1642 4.0588 3.9833 3.9518 3.8904 3.7480 3.6958 3.6539 3.5284 66 28 62 24 29 100 11 8 9 9 12 8 9 10 18 21 23 35
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 25.660 26.400 26.620 27.140 28.300 28.860 29.360 30.040 31.860 32.960 33.460 36.560 37.040 39.360 41.600 42.580 46.300 47.720 58.040 115 103 111 77 120 102 133 100 99 34 37 63 49 41 32 29 32 36 29 .300 .210 .270 .210 .240 .270 .390 .300 .360 .240 3.4688 3.3733 3.3459 3.2829 3.1510 3.0911 3.0396 2.9723 2.8065 2.7153 2.6759 2.4558 2.4251 2.2873 2.1692 2.1215 1.9593 1.9043 1.5878 24 22 23 16 25 21 28 21 21 7 8 13 10 9 7 6 7 8 6
The differential scanning figure (DSC) of crystalline lonidamine form I has endothermic transition at about 211.0 ℃, and heat absorption beginning temperature is at about 210.1 ℃ (referring to Fig. 2), and has basically infrared spectra as shown in Figure 3.
Lonidamine form II
Second kind of new crystalline state of lonidamine---crystalline lonidamine form II is characterized in that, it uses Cu-k α source of radiation, 35kv, and 30mA, the X-ray powder diffraction spectroscopic data with 2 θ angles and spacing (d value) expression that (DMAX-IIID) records is as follows:
Sequence number 2θ Intensity Width The d value I
1 2 3 4 11.300 11.660 13.160 14.380 487 197 46 63 .240 .270 7.8241 7.5833 6.7222 6.1545 90 36 9 12
5 6 7 S 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 15.320 16.240 17.080 20.120 20.640 21.680 22.860 23.620 24.380 24.940 25.360 26.020 26.720 27.140 28.780 29.740 30.360 31.040 32.200 33.640 34.660 35.180 37.360 38.240 38.760 42.180 45.300 46.280 47.780 49.960 54.240 391 47 89 131 46 34 368 122 125 85 60 440 98 540 45 44 76 33 88 46 41 37 38 43 35 47 34 36 40 54 30 .270 .210 .270 .240 .240 .270 .360 .270 .240 .270 .240 .270 5.7789 5.4535 5.1872 4.4097 4.2998 4.0958 3.8870 3.7636 3.6480 3.5673 3.5092 3.4217 3.3336 3.2829 3.0995 3.0016 2.9417 2.8788 2.7777 2.6620 2.5859 2.5489 2.4050 2.3517 2.3213 2.1407 2.0002 1.9601 1.9020 1.8240 1.6897 72 9 16 24 9 6 68 23 23 16 11 81 18 100 8 8 14 6 16 9 8 7 7 8 6 9 6 7 7 10 6
36 37 56.060 59.140 29 25 1.6391 1.5609 5 5
With Mo-k α source of radiation, (RAXS-IV type of science), the monocrystalline X-ray diffraction data of form II are as follows: this crystalline molecular formula is C 15H 10Cl 2N 2O, molecular weight are 321.15, and this crystal belongs to triclinic(crystalline)system, and P-1 spacer, unit cell parameters are a=7.7117
Figure A20051002884600132
α=106.17 ° β=93.05 ° γ=96.96 °, the R value is 0.0450
Fig. 5, Fig. 6 and Fig. 7 have shown the situation of stretch-out view and intermolecular formation hydrogen bond in the space multistory structure, its structure cell accumulation graph of this molecule respectively.
Among Fig. 6 b, intermolecular by hydrogen bond and π-π reactive force combination, the distance of plane C1i C2i C3i C4i C5iC6i and C1f C2f C3f C4f C5f C6f is
Figure A20051002884600133
The distance of plane C1i C2i C3i C4i C5iC6i and C1d C2d C3d C4d C5d C6d is
The atomic coordinate (* 10 of table 1 p-1 4) and equivalent isotropy alternate parameter
(equivalent isotropic displacement parameters) ( 2* 10 3) U (eq) be defined as orthogonal Uij tensor trace 1/3
x y z U(eq)
Cl(1) Cl(2) O(1) O(2) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) 3351(1) 514(1) 9034(2) 8323(2) 4733(3) 6225(3) 2774(3) 1956(3) 1507(3) 1821(4) 2642(4) 3153(3) 4081(4) 4027(3) 2508(3) 2174(4) 3287(3) 4777(3) 5164(3) 6497(3) 8045(3) 7874(1) 1198(1) 5480(3) 5970(2) 7498(3) 6797(3) 6026(4) 4540(4) 3101(4) 3102(4) 4604(4) 6099(3) 7732(4) 7875(3) 8588(3) 8814(4) 8348(4) 7645(3) 7395(3) 6729(3) 6019(3) 4597(1) 3537(1) 8777(2) 10626(2) 8147(2) 8183(2) 5033(2) 4213(2) 4568(2) 5702(3) 6512(2) 6197(2) 7049(2) 9194(2) 9531(2) 10667(2) 11461(2) 11133(2) 9972(2) 9274(2) 9607(2) 77(1) 79(1) 53(1) 52(1) 45(1) 45(1) 49(1) 54(1) 56(1) 61(1) 56(1) 45(1) 51(1) 40(1) 49(1) 56(1) 54(1) 49(1) 40(1) 40(1) 43(1)
The key length of table 2 p-1 [A] and angle (degree)
Cl(1)-C(1) Cl(2)-C(3) O(1)-C(15) O(1)-HIE O(2)-C(15) N(1)-N(2) N(1)-C(8) N(1)-C(7) N(2)-C(14) C(1)-C(2) C(1)-C(6) C(2)-C(3) C(2)-H(2A) C(3)-C(4) C(4)-C(5) C(4)-H(4A) C(5)-C(6) C(5)-H(5A) C(6)-C(7) C(7)-H(7A) C(7)-H(7B) C(8)-C(9) C(8)-C(13) C(9)-C(10) C(9)-H(9A) C(10)-C(11) C(10)-H(10A) C(11)-C(12) 1.742(3) 1.749(3) 1.298(3) 0.91(4) 1.241(3) 1.348(3) 1.366(3) 1.454(3) 1.330(3) 1.384(4) 1.393(3) 1.367(4) 0.9300 1.368(4) 1.387(4) 0.9300 1.391(4) 0.9300 1.503(4) 0.9700 0.9700 1.399(3) 1.410(3) 1.365(4) 0.9300 1.407(4) 0.9300 1.372(4)
C(11)-H(11A) C(12)-C(13) C(12)-H(12A) C(13)-C(14) C(14)-C(15) C(15)-O(1)-HIE N(2)-N(1)-C(8) N(2)-N(1)-C(7) C(8)-N(1)-C(7) C(14)-N(2)-N(1) C(2)-C(1)-C(6) C(2)-C(1)-Cl(1) C(6)-C(1)-Cl(1) C(3)-C(2)-C(1) C(3)-C(2)-H(2A) C(1)-C(2)-H(2A) C(2)-C(3)-C(4) C(2)-C(3)-Cl(2) C(4)-C(3)-Cl(2) C(3)-C(4)-C(5) C(3)-C(4)-H(4A) C(5)-C(4)-H(4A) C(4)-C(5)-C(6) C(4)-C(5)-H(5A) C(6)-C(5)-H(5A) C(5)-C(6)-C(1) C(5)-C(6)-C(7) C(1)-C(6)-C(7) N(1)-C(7)-C(6) N(1)-C(7)-H(7A) 0.9300 1.403(3) 0.9300 1.423(3) 1.471(3) 114(3) 112.56(19) 118.5(2) 128.9(2) 105.53(19) 122.4(3) 118.9(2) 118.7(2) 118.2(2) 120.9 120.9 122.0(3) 118.9(2) 119.1(3) 118.9(3) 120.5 120.5 121.6(2) 119.2 119.2 116.8(3) 122.8(2) 120.4(2) 113.7(2) 108.8
C(6)-C(7)-H(7A) N(1)-C(7)-H(7B) C(6)-C(7)-H(7B) H(7A)-C(7)-H(7B) N(1)-C(8)-C(9) N(1)-C(8)-C(13) C(9)-C(8)-C(13) C(10)-C(9)-C(8) C(10)-C(9)-H(9A) C(8)-C(9)-H(9A) C(9)-C(10)-C(11) C(9)-C(10)-H(10A) C(11)-C(10)-H(10A) C(12)-C(11)-C(10) C(12)-C(11)-H(11A) C(10)-C(11)-H(11A) C(11)-C(12)-C(13) C(11)-C(12)-H(12A) C(13)-C(12)-H(12A) C(12)-C(13)-C(8) C(12)-C(13)-C(14) C(8)-C(13)-C(14) N(2)-C(14)-C(13) N(2)-C(14)-C(15) C(13)-C(14)-C(15) O(2)-C(15)-O(1) O(2)-C(15)-C(14) O(1)-C(15)-C(14) 108.8 108.8 108.8 107.7 131.1(2) 106.3(2) 122.6(2) 116.5(2) 121. 8 121.8 122.1(2) 119.0 119.0 121.6(3) 119.2 119.2 117.9(2) 121.0 121.0 119.3(2) 137.0(2) 103.71(19) 111.89(19) 119.3(2) 128.8(2) 124.8(2) 119.8(2) 115.4(2)
Be used for the symmetry conversion of homoatomics such as producing:
Table 3: for the isotropy alternate parameter ( of p-1 2* 10 3).Isotropy substitutes factor index such form :-2pi 2[h 2A* 2U11+ ... + 2hka*b*U12]
U11 U22 U33 U23 U13 U12
Cl(1) Cl(2) O(1) O(2) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) 102(1) 79(1) 46(1) 49(1) 45(1) 44(1) 48(1) 52(2) 47(1) 65(2) 66(2) 42(1) 57(2) 43(1) 44(1) 52(1) 60(2) 56(2) 42(1) 41(1) 41(1) 87(1) 74(1) 71(1) 72(1) 53(1) 52(1) 65(2) 77(2) 66(2) 58(2) 61(2) 57(2) 59(2) 40(1) 48(2) 56(2) 59(2) 48(2) 38(1) 42(1) 43(1) 54(1) 67(1) 47(1) 42(1) 39(1) 41(1) 40(1) 35(1) 50(2) 61(2) 47(1) 42(1) 43(1) 39(1) 57(2) 61(2) 45(1) 42(1) 38(1) 39(1) 46(1) 40(1) -6(1) 21(1) 22(1) 16(1) 15(1) 21(1) 13(1) 5(1) 22(1) 24(1) 17(1) 21(1) 12(1) 16(1) 12(1) 13(1) 15(1) 12(1) 13(1) 15(1) 5(1) 1(1) 6(1) 1(1) -1(1) 3(1) 10(1) 7(1) 5(1) -4(2) -6(1) 4(1) -1(1) 3(1) 3(1) 17(1) 13(1) 1(1) 0(1) 1(1) 0(1) 8(1) 14(1) 19(1) 20(1) 15(1) 13(1) 19(1) 22(1) 19(1) 7(1) 10(1) 18(1) 15(1) 8(1) 10(1) 14(1) 8(1) 5(1) 5(1) 7(1) 5(1)
The hydrogen coordinate of table 4 p-1 (hydrogen coordinates) (* 10 4) and isotropy alternate parameter (A 2* 10 3)
x y z U9eq)
H(2A) H(4A) H(5A) H(7A) H(7B) H(9A) H(10A) H(11A) H(12A) HIE 1719 1489 2857 5059 3279 1764 1179 3006 5507 9990(60) 4521 2112 4611 8187 8583 8891 9290 8520 7343 5060(60) 3440 5927 7284 6694 7208 9008 10924 12226 11664 9010(40) 65 73 68 62 62 59 68 65 58 133(17)
The torsion(al)angle (degree) of table 6:p-1
C(8)-N(1)-N(2)-C(14) C(7)-N(1)-N(2)-C(14) C(6)-C(1)-C(2)-C(3) Cl(1)-C(1)-C(2)-C(3) C(1)-C(2)-C(3)-C(4) C(1)-C(2)-C(3)-Cl(2) C(2)-C(3)-C(4)-C(5) Cl(2)-C(3)-C(4)-C(5) C(3)-C(4)-C(5)-C(6) C(4)-C(5)-C(6)-C(1) C(4)-C(5)-C(6)-C(7) C(2)-C(1)-C(6)-C(5) Cl(1)-C(1)-C(6)-C(5) C(2)-C(1)-C(6)-C(7) Cl(1)-C(1)-C(6)-C(7) -0.4(3) -179.6(2) 0.1(4) -179.84(19) 0.9(4) -178.68(18) -0.9(4) 178.6(2) -0.1(4) 1.0(4) -178.6(2) -1.1(4) 178.89(19) 178.6(2) -1.5(3)
N(2)-N(1)-C(7)-C(6) C(8)-N(1)-C(7)-C(6) C(5)-C(6)-C(7)-N(1) C(1)-C(6)-C(7)-N(1) N(2)-N(1)-C(8)-C(9) C(7)-N(1)-C(8)-C(9) N(2)-N(1)-C(8)-C(13) C(7)-N(1)-C(8)-C(13) N(1)-C(8)-C(9)-C(10) C(13)-C(8)-C(9)-C(10) C(8)-C(9)-C(10)-C(11) C(9)-C(10)-C(11)-C(12) C(10)-C(11)-C(12)-C(13) C(11)-C(12)-C(13)-C(8) C(11)-C(12)-C(13)-C(14) N(1)-C(8)-C(13)-C(12) C(9)-C(8)-C(13)-C(12) N(1)-C(8)-C(13)-C(14) C(9)-C(8)-C(13)-C(14) N(1)-N(2)-C(14)-C(13) N(1)-N(2)-C(14)-C(15) C(12)-C(13)-C(14)-N(2) C(8)-C(13)-C(14)-N(2) C(12)-C(13)-C(14)-C(15) C(8)-C(13)-C(14)-C(15) N(2)-C(14)-C(15)-O(2) C(13)-C(14)-C(15)-O(2) N(2)-C(14)-C(15)-O(1) C(13)-C(14)-C(15)-O(1) 78.3(3) -100.8(3) 12.9(4) -166.8(2) -179.4(2) -0.2(5) 0.6(3) 179.7(2) -179.6(3) 0.5(4) -0.4(4) 0.3(4) -0.2(4) 0.2(4) -179.5(3) 179.6(2) -0.4(4) -0.5(2) 179.4(2) 0.0(3) -180.0(2) -179.9(3) 0.3(3) 0.2(5) -179.7(2) 179.1(2) -0.9(4) -0.9(3) 179.1(2)
Be used for the symmetry conversion of homoatomics such as producing
The hydrogen bond (A and degree) of table 6:p-1
D-H...A O(1)-HIE...0(2)#1 d(D-H) 0.91(4) d(H…A) 1.73(4) d(D…A) 2.638(2) ＜(DHA) 174(4)
Be used for the symmetry conversion of homoatomics such as producing:
#1-x+2，-y+1，-z+2
mpln c1i c2i c3i c4i c5i c6i
c1f c2f c3f c4f c5f c6f 3.4638
c1i c2i c3i c4i c5i c6i
c1d c2d c3d c4d c5d c6d 3.8582
As shown in Figure 8, crystalline lonidamine form II has endothermic transition at about 211.2 ℃, and heat absorption beginning temperature is at about 208.8 ℃; Fig. 9 has shown the infrared spectra of this crystalline.
Crystallization lonidamine form III
The new crystalline state of the third lonidamine---crystalline lonidamine form III is characterized in that, it uses Cu-k α source of radiation, and the X-ray powder diffraction spectroscopic data with 2 θ angles and spacing (d value) expression that 40kv, 300mA record is as follows:
Sequence number 2θ d(A) BG Highly 1％ Area 1％ FWHM
1 2 3 4 5 6 7 8 9 10 11 12 5.302 10.758 11.182 11.520 11.918 12.960 13.218 14.081 14.757 16.817 17.704 17.978 16.6525 8.2169 7.9062 7.6752 7.4193 6.8253 6.6924 6.2845 5.9980 5.2676 5.0057 4.9301 134 68 80 84 78 100 111 97 82 68 71 70 569 123 1674 2637 137 162 1302 1184 87 1084 129 402 21.6 4.7 63.5 100.0 5.2 6.1 49.4 44.9 3.3 41.1 4.9 15.2 6281 3034 18919 17474 2063 1791 10707 9391 799 7194 3129 5594 33.2 16.0 100.0 92.4 10.9 9.5 56.6 49.6 4.2 38.0 16.5 29.6 0.188 0.419 0.192 0.113 0.256 0.177 0.140 0.135 0.156 0.113 0.412 0.237
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 19.097 20.864 21.498 22.181 22.497 23.198 23.760 24.525 25.340 25.881 26.758 26.999 27.180 27.520 28.420 28.758 29.421 30.061 31.061 31.637 32.461 33.039 33.882 35.100 35.440 36.420 36.796 37.145 37.541 38.821 40.381 4.6435 4.2542 4.1300 4.0043 3.9488 3.8311 3.7418 3.6268 3.5119 3.4396 3.3289 3.2997 3.2782 3.2384 3.1379 3.1017 3.0333 2.9702 2.8769 2.8258 2.7559 2.7090 2.6435 2.5545 2.5308 2.4649 2.4406 2.4184 2.3938 2.3178 2.2318 67 73 123 132 119 112 93 76 70 78 98 96 93 107 99 96 91 78 68 74 69 66 67 63 63 59 60 71 55 60 66 222 45 937 851 480 1043 205 82 205 153 246 367 426 1171 92 146 54 61 239 264 267 121 149 194 177 95 55 75 78 72 85 8.4 1.7 35.5 32.3 18.2 39.6 7.8 3.1 7.8 5.8 9.3 13.9 16.2 44.4 3.5 5.5 2.0 2.3 9.1 10.0 10.1 4.6 5.7 7.4 6.7 3.6 2.1 2.8 3.0 2.7 3.2 2107 567 7747 10635 8704 7107 2030 636 2101 2956 4130 9218 11359 10993 1287 2118 1520 1828 2806 3415 2934 1054 1782 2492 2146 1831 555 513 1490 1520 991 11.1 3.0 40.9 56.2 46.0 37.6 10.7 3.4 11.1 15.6 21.8 48.7 60.0 58.1 6.8 11.2 8.0 9.7 14.8 18.1 15.5 5.6 9.4 13.2 11.3 9.7 2.9 2.7 7.9 8.0 5.2 0.161 0.202 0.141 0.212 0.308 0.116 0.168 0.132 0.174 0.328 0.285 0.402 0.453 0.160 0.238 0.247 0.450 0.509 0.200 0.220 0.187 0.148 0.203 0.218 0.206 0.328 0.172 0.116 0.325 0.359 0.198
44 45 46 47 48 49 50 42.219 43.321 43.856 45.760 47.240 48.700 48.923 2.1388 2.0869 2.0626 1.9812 1.9225 1.8682 1.8602 54 60 67 65 60 58 53 68 119 85 63 71 57 68 2.6 4.5 3.2 2.4 2.7 2.2 2.6 566 2170 1663 1433 2617 1051 1946 3.0 11.5 8.8 7.6 13.8 5.6 10.3 0.141 0.310 0.333 0.387 0.627 0.313 0.486
Single crystal structure is resolved---form III
1. this crystalline molecular formula is C 15H 10Cl 2N 2O 2, molecular weight is 321.15;
2. this crystal belongs to triclinic(crystalline)system, and P-1 spacer, unit cell parameters are a=5.2879
Figure A20051002884600231
Figure A20051002884600232
α=80.09 ° β=89.89 ° γ=80.65 °, the R value is 0.0477
Figure 11 has shown the space multistory structure of the molecule of form III; Figure 12 a and Figure 12 b have shown the structure cell accumulation graph of form III in A, B direction respectively; Figure 13 be among Figure 12 a a pile stretch-out view, intermolecular by hydrogen bond and π-π reactive force combination, the distance of plane C1a C2a C3a C4a C5a C6a and C1b C2b C3bC4b C5b C6b is
The distance of plane C1b C2b C3b C4b C5b C6b and C1c C2c C3c C4c C5c C6c is
The distance of plane C8a C9a C10a C11a C12a C13a and C8b C9b C10b C11b C12b C13b is
The distance of plane C8b C9b C10b C11b C12b C13b and C8c C9c C10c C11c C12c C13c is
Figure 14 is the situation of the intermolecular formation hydrogen bond of form III, and the carboxyl of a molecule carboxyl and another molecule has formed intermolecular hydrogen bonding.
The atomic coordinate (atomic coordinates) (* 10 of table 7:p-1 4) and isotropy alternate parameter (A 2* 10 3)
U (eq) be defined as orthogonal Uij tensor trace 1/3
x y z U(eq)
Cl(1) Cl(2) O(1) O(2) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) 8859(2) 5539(2) 7296(5) 8923(5) 2599(5) 4695(5) 3059(7) 4710(7) 6664(7) 6916(7) 5210(7) 3253(6) 1405(7) 1611(6) -550(6) -1055(7) 536(8) 2659(7) 3206(6) 5102(6) 7258(6) -2573(1) 4113(1) 6399(3) 3842(3) 4635(4) 4044(4) 382(5) -1027(5) -827(4) 757(4) 2140(4) 1998(5) 3493(5) 6271(4) 7342(5) 8943(5) 9505(5) 8464(5) 6802(4) 5350(4) 5160(5) 4444(1) 3996(1) 169(2) 859(2) 2239(2) 1847(2) 3128(2) 3501(2) 3996(2) 4145(2) 3773(2) 3251(2) 2844(2) 1936(2) 2145(2) 1716(2) 1097(2) 882(2) 1306(2) 1287(2) 739(2) 72(1) 68(1) 58(1) 59(1) 50(1) 49(1) 57(1) 57(1) 50(1) 53(1) 48(1) 48(1) 62(1) 46(1) 55(1) 63(1) 63(1) 56(1) 45(1) 43(1) 44(1)
Bond distance (A) and the angle (degree) of table 8:p-1
Cl(1)-C(3) Cl(2)-C(5) O(1)-C(15) O(1)-H(1E) O(2)-C(15) N(1)-N(2) N(1)-C(8) N(1)-C(7) N(2)-C(14) C(1)-C(2) C(1)-C(6) C(1)-H(1A) C(2)-C(3) C(2)-H(2A) C(3)-C(4) C(4)-C(5) C(4)-H(4A) C(5)-C(6) C(6)-C(7) C(7)-H(7A) C(7)-H(7B) C(8)-C(13) C(8)-C(9) C(9)-C(10) C(9)-H(9A) C(10)-C(11) C(10)-H(10A) C(11)-C(12) C(11)-H(11A) C(12)-C(13) 1.745(4) 1.753(3) 1.270(4) 1.26(9) 1.263(4) 1.351(4) 1.364(4) 1.471(4) 1.341(4) 1.382(5) 1.391(5) 0.9300 1.374(5) 0.9300 1.387(5) 1.381(5) 0.9300 1.389(5) 1.498(5) 0.9700 0.9700 1.404(4) 1.405(5) 1.365(5) 0.9300 1.399(5) 0.9300 1.381(5) 0.9300 1.405(5)
C(12)-H(12A) C(13)-C(14) C(14)-C(15) C(15)-O(1)-H(1E) N(2)-N(1)-C(8) N(2)-N(1)-C(7) C(8)-N(1)-C(7) C(14)-N(2)-N(1) C(2)-C(1)-C(6) C(2)-C(1)-H(1A) C(6)-C(1)-H(1A) C(3)-C(2)-C(1) C(3)-C(2)-H(2A) C(1)-C(2)-H(2A) C(2)-C(3)-C(4) C(2)-C(3)-Cl(1) C(4)-C(3)-Cl(1) C(5)-C(4)-C(3) C(5)-C(4)-H(4A) C(3)-C(4)-H(4A) C(4)-C(5)-C(6) C(4)-C(5)-Cl(2) C(6)-C(5)-Cl(2) C(1)-C(6)-C(5) C(1)-C(6)-C(7) C(5)-C(6)-C(7) N(1)-C(7)-C(6) N(1)-C(7)-H(7A) C(6)-C(7)-H(7A) N(1)-C(7)-H(7B) C(6)-C(7)-H(7B) 0.9300 1.429(5) 1.468(4) 118(3) 113.0(3) 120.5(3) 125.9(3) 105.0(3) 122.5(4) 118.7 118.7 118.9(3) 120.5 120.5 120.6(4) 120.0(3) 119.4(3) 119.1(3) 120.4 120.4 122.1(3) 117.8(3) 120.1(3) 116.7(3) 121.0(3) 122.3(4) 113.3(3) 108.9 108.9 108.9 108.9
H(7A)-C(7)-H(7B) N(1)-C(8)-C(13) N(1)-C(8)-C(9) C(13)-C(8)-C(9) C(10)-C(9)-C(8) C(10)-C(9)-H(9A) C(8)-C(9)-H(9A) C(9)-C(10)-C(11) C(9)-C(10)-H(10A) C(11)-C(10)-H(10A) C(12)-C(11)-C(10) C(12)-C(11)-H(11A) C(10)-C(11)-H(11A) C(11)-C(12)-C(13) C(11)-C(12)-H(12A) C(13)-C(12)-H(12A) C(8)-C(13)-C(12) C(8)-C(13)-C(14) C(12)-C(13)-C(14) N(2)-C(14)-C(13) N(2)-C(14)-C(15) C(13)-C(14)-C(15) O(2)-C(15)-O(1) O(2)-C(15)-C(14) O(1)-C(15)-C(14) 107.7 106.5(3) 131.6(3) 121.9(3) 117.7(3) 121.2 121.2 121.2(4) 119.4 119.4 121.7(4) 119.1 119.1 118.2(3) 120.9 120.9 119.2(3) 103.9(3) 136.9(3) 111.6(3) 120.1(3) 128.3(3) 124.7(3) 120.0(3) 115.2(3)
Be used for the symmetry conversion of homoatomics such as producing:
Table 9: for the isotropy alternate parameter ( of p-1 2* 10 3).Isotropy substitutes factor index such form :-2pi 2[h 2A* 2U11+ ... + 2hka*b*U12]
U11 U22 U33 U23 U13 U12
Cl(1) Cl(2) O(1) O(2) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) 84(1) 86(1) 61(2) 55(2) 45(2) 41(2) 51(2) 61(2) 60(2) 66(2) 57(2) 43(2) 45(2) 44(2) 45(2) 52(2) 71(3) 57(2) 47(2) 41(2) 44(2) 48(1) 46(1) 57(2) 53(2) 56(2) 56(2) 73(3) 52(2) 45(2) 53(2) 43(2) 58(2) 75(3) 53(2) 67(3) 70(3) 49(2) 54(2) 48(2) 49(2) 45(2) 79(1) 76(1) 49(2) 61(2) 47(2) 46(2) 54(2) 65(3) 45(2) 45(2) 47(2) 43(2) 60(3) 41(2) 52(2) 67(3) 66(3) 54(2) 39(2) 38(2) 43(2) -3(1) -16(1) 3(1) -2(1) -2(2) -4(2) -18(2) -21(2) -7(2) -11(2) -9(2) -5(2) 4(2) -10(2) -17(2) -25(2) -6(2) -7(2) -9(2) -6(2) -9(2) 0(1) 6(1) 13(1) 17(1) 8(1) 7(1) 6(2) 13(2) 9(2) -2(2) 13(2) 14(2) 14(2) -4(2) 4(2) -7(2) -11(2) -3(2) -6(2) 5(2) 4(2) -8(1) -18(1) -5(1) 3(1) -3(1) -2(1) -24(2) -20(2) -8(2) -20(2) -15(2) -10(2) -9(2) -3(2) -2(2) 5(2) -3(2) -6(2) -7(2) -6(2) -10(2)
The hydrogen coordinate (hydrogen coordinates) (* 10 of table 10:p-1 4) and isotropy alternate parameter (A 2* 10 3)
x y z U(eq)
H(1A) H(2A) H(4A) H(7A) H(7B) H(9A) H(10A) H(11A) H(12A) H(1E) 1767 4502 8215 40 640 -1600 -2483 154 3699 9210(160) 246 -2094 887 3103 4113 6973 9673 10608 8852 6350(90) 2782 3419 4490 2581 3252 2560 1839 822 468 -280(60) 68 68 64 75 75 66 76 76 67 270(40)
The torsion(al)angle (degree) of table 11:p-1
C(8)-N(1)-N(2)-C(14) C(7)-N(1)-N(2)-C(14) C(6)-C(1)-C(2)-C(3) C(1)-C(2)-C(3)-C(4) C(1)-C(2)-C(3)-Cl(1) C(2)-C(3)-C(4)-C(5) Cl(1)-C(3)-C(4)-C(5) C(3)-C(4)-C(5)-C(6) C(3)-C(4)-C(5)-Cl(2) C(2)-C(1)-C(6)-C(5) C(2)-C(1)-C(6)-C(7) C(4)-C(5)-C(6)-C(1) Cl(2)-C(5)-C(6)-C(1) C(4)-C(5)-C(6)-C(7) Cl(2)-C(5)-C(6)-C(7) N(2)-N(1)-C(7)-C(6) C(8)-N(1)-C(7)-C(6) C(1)-C(6)-C(7)-N(1) C(5)-C(6)-C(7)-N(1) N(2)-N(1)-C(8)-C(13) C(7)-N(1)-C(8)-C(13) N(2)-N(1)-C(8)-C(9) C(7)-N(1)-C(8)-C(9) N(1)-C(8)-C(9)-C(10) C(13)-C(8)-C(9)-C(10) C(8)-C(9)-C(10)-C(11) C(9)-C(10)-C(11)-C(12) C(10)-C(11)-C(12)-C(13) N(1)-C(8)-C(13)-C(12) C(9)-C(8)-C(13)-C(12) 1.4(4) 173.4(3) -1.8(5) 2.5(5) -177.4(3) -1.5(5) 178.4(2) -0.3(5) 178.4(3) 0.0(5) -179.2(3) 1.0(5) -177.6(2) -179.8(3) 1.6(4) 27.7(5) -161.4(3) -112.9(4) 67.9(4) -1.0(4) -172.5(3) 178.1(4) 6.6(6) -179.5(4) -0.6(5) -0.6(6) 1.0(6) -0.2(6) -179.5(3) 1.3(5)
N(1)-C(8)-C(13)-C(14) C(9)-C(8)-C(13)-C(14) C(11)-C(12)-C(13)-C(8) C(11)-C(12)-C(13)-C(14) N(1)-N(2)-C(14)-C(13) N(1)-N(2)-C(14)-C(15) C(8)-C(13)-C(14)-N(2) C(12)-C(13)-C(14)-N(2) C(8)-C(13)-C(14)-C(15) C(12)-C(13)-C(14)-C(15) N(2)-C(14)-C(15)-O(2) C(13)-C(14)-C(15)-O(2) N(2)-C(14)-C(15)-O(1) C(13)-C(14)-C(15)-O(1) 0.2(4) -179.0(3) -0.9(5) 179.5(4) -1.2(4) -179.8(3) 0.6(4) -179.8(4) 179.1(3) -1.3(7) -9.1(5) 172.5(3) 171.7(3) -6.7(5)
Be used for the symmetry conversion of homoatomics such as producing
The hydrogen bond (A and degree) of table 12:p-1
D-H…A O(1)-H(1E)…O(2)#1 d(D-H) 1. 26(9) d(H…A) 1.39(9) d(D…A) 2.642(3) ＜(DHA) 170(8)
Be used for the symmetry conversion of homoatomics such as producing:
#1-x+2，-y+1，-z
Figure 15 has shown the differential scanning figure (DSC) of crystalline lonidamine form III, and it has little endotherm(ic)peak at about 183 ℃; There is heat release to change at about 196 ℃; At about 211.4 ℃ endothermic transition is arranged, heat absorption beginning temperature is at about 208.7 ℃.
Figure 16 has shown this crystalline infrared spectra.
Figure 17 has shown the weightless scintigram (DTG) of the differential thermal of crystalline lonidamine form III.
The present invention also provides a kind of pharmaceutical composition, and it comprises in the lonidamine crystal of above-mentioned form I, II or III one or more and pharmaceutically acceptable carrier.The composition that contains the lonidamine of novel crystalline form attitude has good dissolution degree, and the solubleness of crystal form lonidamine is with amorphous obviously different, and the former composition has a clear superiority in.
Figure 18-20 pair of crystal or unbodied tablet that contains the lonidamine different shape made dissolution rate relatively, and its stripping data separately are as follows:
Lonidamine sheet dissolution rate %
Lot number
10 minutes 20 minutes 30 minutes 45 minutes 75 minutes 90 minutes
1 28.15 54.73 78.06 99.51
2 28.23 54.85 78.46 99.99
3 2.78 14.41 28.40 45.48 53.11 53.55
Lot number 1 is for containing the tablet of lonidamine form I.
Lot number 2 is for containing the tablet of lonidamine form II.
Lot number 3 is for containing the tablet of lonidamine form I and unbodied mixture.
Can find out lot number 1 from last table, the lonidamine sheet dissolution rate of lot number 2 is good.
Can find out that from X-powdery diffractometry test the crystalline state lonidamine that lot number 3 contains is form I, not have other crystalline state to find, but degree of crystallinity obviously poor than in the lot number 1, its amorphous content height, corresponding tablet dissolution rate is also relatively poor.
Synthetic embodiment
With raw material 3-carboxylic acid indazole 38.0 grams (0.234 mole), sodium hydroxide 28.1 grams (0.702MOL) are in the there-necked flask that 650 milliliters of inputs of water are 1000 milliliters, stir, be heated to 100 degree, slowly drip 2,4-dichlorobenzyl chloride 60 grams (0.307 mole), dropwised in 30 minutes, reaction is 3-4 hour under 100 degree insulations, stops heating after reaction finishes, naturally cool to room temperature (25 ℃), filter, washing, product must wet: 135.0 grams.Wet product add the dilute hydrochloric acid acidifying, filter, and washing is drained, and get finished product after the drying: 61.5 grams.Finished product is the mixture of amorphous or other crystal formation.
Crystallization embodiment
Embodiment 1
With synthetic lonidamine 10 grams, be soaked in the 40 gram water, stir, be heated to more than 80 ℃, the hydro-oxidation sodium solution is transferred about pH9 simultaneously, and dissolving adds proper amount of active carbon, refluxed 20 minutes, heat filtering then, filtrate slowly cools to 80 ℃-50 ℃ naturally, drip 10% hydrochloric acid simultaneously, fully acidifying is after pH reaches 4-5, be cooled to room temperature, standing over night then, leach, an amount of washing, drain, dry that form I lonidamine crystal 9.2 restrains MP205.5-207.5 ℃.
Embodiment 2
With synthetic lonidamine 10 grams, be dissolved in 80 milliliters in Glacial acetic acid, heated and stirred, dissolving is fully, add proper amount of active carbon, refluxed about 30 minutes, heat filtering then, the quick crystallisation by cooling of filtrate, room temperature is placed and is spent the night, filtration next day, dry that form I lonidamine crystal 9.0 restrains MP208.5-210.0 ℃.
Embodiment 3
With synthetic lonidamine 10 grams, be dissolved in 200 milliliters of the mixed solutions of ethanol and Glacial acetic acid (V/V=1/1), heated and stirred, dissolving is fully, add proper amount of active carbon, refluxed about 30 minutes, heat filtering, filtrate slowly is cooled to room temperature, 15-25 ℃ static crystallization 1-3 days, leach, dry that form II lonidamine crystal 7.5 restrains MP207.5-210.5 ℃.。
Embodiment 4
With synthetic lonidamine 10 grams, be dissolved in 160 milliliters in Glacial acetic acid, heated and stirred, dissolving is fully, refluxed about 20 minutes, and left standstill then, slowly reduce to 35-45 ℃, static crystallization 1-3 days, leach, dry that form III lonidamine crystal 7.0 restrains MP210.5-211.0 ℃.

Claims (13)

1. the lonidamine crystal of a form I is characterized in that, is using 35kv, under the Cu-k α radiation source irradiates of 30mA, following X-ray powder diffraction spectrum with 2 θ angles and spacing d value representation is arranged:
2 θ d values
11.7 7.5
12.7 7.0
14.5 6.1
15.0 5.9
17.7 5.0
17.9 4.9
24.1 3.7
25.2 3.5
25.6 3.5
26.4 3.4
27.1 3.3
28.3 3.2
28.9 3.1
29.4 3.0
30.0 3.0
31.9 2.8。
2. the lonidamine crystal of form I as claimed in claim 1 is characterized in that, its DSC endothermic transition is at 211.0 ℃.
3. lonidamine crystalline method for preparing form I as claimed in claim 1 or 2 comprises:
A): the mixture that will form by the dilute alkaline aqueous solution of amorphous lonidamine of 10-45% and 55-90%, control pH 8-10, be heated to more than 80 ℃ until backflow, slowly reduce the temperature to 80 ℃-50 ℃ after the dissolving, dropping inorganic acid is to pH 3-5 in solution, cool to room temperature is separated out the lonidamine crystal of required form I; Perhaps
B) amorphous lonidamine is dissolved in recrystallisation solvent, is heated to backflow, dissolving, cooling fast then, crystallization obtains the lonidamine crystal of required form I; Wherein said recrystallisation solvent is selected from doubly (w/v) ethanol of (1) 8-15, (2) 6-12 times of (w/v) Glacial acetic acid, (3) Glacial acetic acid of 6-12 times (w/v) adds methyl alcohol or the alcoholic acid mixed solution of 1%-30% (v/v), (4) ethanol of 8-15 times (w/v) adds the mixed solution of 1%-30% acetone (v/v), and the ethanol of (5) 8-15 times (w/v) adds the mixed solution of 1%-30% (v/v) acetoacetic ester.
4. method according to claim 3, wherein said mineral acid is selected from hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid; Described dilute alkaline aqueous solution is selected from aqueous sodium hydroxide solution, potassium hydroxide aqueous solution.
5. the lonidamine crystal of a form II is characterized in that, is using 35kv, under the Cu-k α radiation source irradiates of 30mA, following X-ray powder diffraction spectrum with 2 θ angles and spacing d value representation is arranged:
2 θ d values
11.3 7.8
11.7 7.6
15.3 5.8
20.1 4.4
22.9 3.9
26.0 3.4
27.1 3.3
32.2 2.8。
6. the lonidamine crystal of a form II, it is characterized in that, this crystal belongs to triclinic(crystalline)system, the P-1 spacer, and unit cell parameters is: a=7.7117  b=8.1384  c=11.987  α=106.17 ° of β=93.05 ° γ=96.96 ° of R values are 0.0450.
7. according to the lonidamine crystal of claim 5 or 6 described form II, its DSC endothermic transition is at 211.2 ℃.
8. lonidamine crystalline method for preparing as claim 5 or 6 described form II, comprise the recrystallisation solvent that amorphous lonidamine is dissolved in, it is clear to add thermosol, leave standstill then, slowly reduce to 15-25 ℃ of static crystallization, the lonidamine form II that filters requiredly, wherein said recrystallisation solvent are selected from the doubly Glacial acetic acid of (w/v) of (1) 15.5-25, and the Glacial acetic acid of (2) 15.5-25 times (w/v) adds methyl alcohol or the alcoholic acid mixed solution of 1%-80% (v/v).
9. the lonidamine crystal of a form III is characterized in that, is using 40kv, under the Cu-k α radiation source irradiates of 300mA, following X-ray powder diffraction spectrum with 2 θ angles and spacing d value representation is arranged:
2 θ d values
5.31 6.6
11.1 7.9
11.5 7.7
13.2 6.7
14.0 6.28
16.8 5.3
21.5 4.1
22.2 4.0
22.5 3.9
23.2 3.8
27.5 3.2。
10. the lonidamine crystal of a form III, it is characterized in that, this crystal belongs to triclinic(crystalline)system, the P-1 spacer, and unit cell parameters is: a=5.2879  b=8.1754  c=16.768  α=80.09 ° of β=89.89 ° γ=80.65 ° of R values are 0.0477.
11. according to the lonidamine crystalline substance of claim 9 or 10 described form III, its DSC endothermic transition is at 211.3 ℃.
12. a lonidamine crystalline method for preparing as the arbitrary described form III of claim 9-11 comprises:
Amorphous lonidamine is dissolved in the solvent of 15.5-18 times (w/v), is heated to backflow, molten clear, leave standstill then, slowly be cooled to 35-45 ℃, static crystallization gets required crystalline lonidamine form III, and wherein said solvent is a Glacial acetic acid.
13. a pharmaceutical composition, it comprises in the lonidamine crystal that is selected from claim 1,5 and 9 described form I, II or III one or more and pharmaceutically acceptable carrier.
CN2005100288467A 2005-08-17 2005-08-17 Crystal form of lonidamine, preparation method, and composition of containing the crystal form Expired - Fee Related CN1915978B (en)

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CN103159679A (en) * 2013-04-17 2013-06-19 盐城格瑞茵化工有限公司 Synthetic method of anti-tumor medicament lonidamine

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CN103159679A (en) * 2013-04-17 2013-06-19 盐城格瑞茵化工有限公司 Synthetic method of anti-tumor medicament lonidamine

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