CN104557961B - SN38 crystal formation and preparation method thereof and application - Google Patents
SN38 crystal formation and preparation method thereof and application Download PDFInfo
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Abstract
The present invention relates to SN38 crystal formation and preparation method thereof and application, be designated as crystal form II and crystalline form III respectively. Crystal form II uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles the angle of diffraction be 5.64,10.80,12.55,13.48,17.09,17.65,18.21,18.79,24.52 and 26.84 degree of places have characteristic peak, 2 θ range of error are ± 0.2 degree. Crystalline form III uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles the angle of diffraction be 4.58,9.34,10.42,11.12,12.30,13.40,14.40,16.34,16.86,17.20,17.70,18.72,19.32,21.48,22.44,24.90,25.40,25.68,27.44 degree of places have characteristic peak, 2 θ range of error are ± 0.2 degree. Two kinds of crystal formation dissolubility of the SN38 of the present invention are high, have good stability.
Description
Technical field
The present invention relates to the two of SN38 kind novel crystal forms and preparation method thereof, belong to field of pharmaceutical chemistry technology.
Background technology
Irinotecan (mnotecan, CPT-11) is the semi-synthetic soluble derivative of camptothecine, and its anti-tumor activity is higher than camptothecine, and toxic and side effects is lower than camptothecine. The antitumor mechanism of irinotecan mainly suppresses the activity of topoisomerase-I, affects DNA replication dna thus causing cell death. CPT-11 is small cell lung cancer (small cellIungcancer, SCLC) important drugs treated, 2010 beautiful with National Cancer Comprehensive Treatment alliance (NationalComprehensiveCancerNetwork, NCCN) recommend CPT-11 as the first-line treatment medicine of SCLC in late period, it is also possible in second line treatment. Irinotecan is ester prodrug, is mainly played anti-tumor activity by carboxylesterase metabolism for activity better SN38 (SN-38) in vivo, and the chemical constitution of SN38 is as follows:
Vitro cytotoxicity research shows, the effect relatively CPT-11 of some tumor cell SN-38 is strong l000 times.
The different crystal forms dissolubility of SN38 is different with humidity stability and difference is very big, and dissolubility is to prepare the important indicator in antitumor drug process, and the too small meeting of dissolubility has a strong impact on the quality of medicine.
Chinese patent document CN101686968A discloses the polymorph of a kind of SN38, and its x-ray diffraction pattern has peak at 10.9 ± 0.2,13.2 ± 0.2,23.9 ± 0.2 and 26.1 ± 0.22 θ degree places. But, the dissolubility of the polymorph of this SN38 is not high.
Summary of the invention
For the deficiencies in the prior art, the invention provides two kinds of SN38 novel crystal forms, be designated as crystal form II and crystalline form III respectively. The preparation method that present invention also offers above-mentioned two kinds of novel crystal forms of SN38.
Technical scheme is as follows:
A kind of SN38 crystal form II, this crystal form II uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles the angle of diffraction be 5.64,10.80,12.55,13.48,17.09,17.65,18.21,18.79,24.52 and 26.84 degree of places have characteristic peak, 2 θ range of error are ± 0.2 degree.
According to the present invention, preferably, SN38 crystal form II uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles the angle of diffraction be 5.64,10.80,11.84,12.55,13.48,17.09,17.65,18.21,18.79,20.92,24.52,25.22,26.84 and 33.98 degree of places have characteristic peak, 2 θ range of error are ± 0.2 degree.
SN38 crystal form II of the present invention uses the X-ray powder diffraction pattern that BrukerD8Advance diffractometer obtains to see Fig. 1. Condition determination is as follows: Cu-K α, 40KV, 40mV light source, step-length 1 °/min of 0.02 ° of scanning speed, sweep limits 2-40 °, room temperature.
The single crystal diffractometer that the present invention adopts BrukerAXS model to be SmartAPEXII measures the mono-crystalline structures of SN38 crystal form II under 100K, with graphite monochromator MoK alpha rayThe mode of Multi Slice Mode collects data, the reduction of data and absorption correction APEX2SoftwareSuite (Bruker, 2009) program package. Space group is determined according to the delustring rule of system, and by refine result verification. All of crystal structure all uses SHELXL-97 (Sheldrick, 2008), direct method solve, with SHELXL-97 (Sheldrick, 2008) program is with complete matrix least square refinement structure, and hydrogen atom coordinate is added by Theoretical Calculation. Obtaining SN38 crystal form II is Methanol Solvate, its structure cell is rhombic system, space group is P212121, a=7.307 (5) b=8.478 (5) c=31.944 (5), unit cell volume V=1978.9 (18)Its crystal structure is as in figure 2 it is shown, structure cell is piled up as shown in Figure 3. The crystallographic parameter of SN38 crystal form II is as shown in table 1 below.
Table 1
The thermal analysis curue of SN38 crystal form II of the present invention is composed as shown in Figure 4, and 90-120 DEG C of weightlessness about 1% has an endothermic peak at 112 DEG C; 200-320 DEG C of weightlessness about 12%, has continuous print heat absorption, exothermic phenomenon.
The infared spectrum of SN38 crystal form II of the present invention is at 3241cm-1、1732cm-1、1653cm-1、1515cm-1、1170cm-1There are bands of a spectrum at place. Its infared spectrum is as shown in Figure 5.
The Raman collection of illustrative plates of SN38 crystal form II of the present invention is as shown in Figure 6.
The preparation method of SN38 crystal form II of the present invention, comprises the following steps that
SN38 is dissolved in mixed solution or the methanol solution of methanol and chloroform, stirring, to dissolving, evaporates solvent crystallization, isolated by filtration solid under the environment of 10-20 DEG C, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II;
Or, SN38 is dissolved in methanol and chloroform mixed solution, obtains suspension, stirring, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II;
Or, SN38 is dissolved in methanol and chloroform mixed solution, obtains suspension, stirring, isolated by filtration solid;Filtrate evaporates solvent crystallization, isolated by filtration solid in the environment of 10-20 DEG C, and solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II;
Or, SN38 is dissolved into N, in dinethylformamide solution, stirring, to dissolving, adds Pyrazinamide, and anti-solvent adopts methanol, utilize the method crystallization that steam spreads, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II.
A kind of SN38 crystalline form III, this crystalline form III uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles the angle of diffraction be 4.58,9.34,10.42,11.12,12.30,13.40,14.40,16.34,16.86,17.20,17.70,18.72,19.32,21.48,22.44,24.90,25.40,25.68,27.44 degree of places have characteristic peak, 2 θ range of error are ± 0.2 degree.
According to the present invention, preferably, SN38 crystalline form III uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles the angle of diffraction be 4.58,9.34,10.42,11.12,12.30,13.40,14.02,14.40,15.44,16.34,16.86,17.20,17.70,18.72,19.32,20.78,21.48,22.44,24.10,24.90,25.40,25.68,27.44 degree of places have characteristic peak, 2 θ range of error are ± 0.2 degree.
SN38 crystalline form III of the present invention uses the X-ray powder diffraction pattern that BrukerD8Advance diffractometer obtains to see Fig. 7. Condition determination is as follows: Cu-K α, 40KV, 40mV light source, step-length 1 °/min of 0.02 ° of scanning speed, sweep limits 2-40 °, room temperature.
The single crystal diffractometer that the present invention adopts BrukerAXS model to be SmartAPEXII measures the mono-crystalline structures of SN38 crystalline form III under 296K, with graphite monochromator MoK alpha rayThe mode of Multi Slice Mode collects data, the reduction of data and absorption correction APEX2SoftwareSuite (Bruker, 2009) program package. Space group is determined according to the delustring rule of system, and by refine result verification. All of crystal structure all uses SHELXL-97 (Sheldrick, 2008), direct method solve, with SHELXL-97 (Sheldrick, 2008) program is with complete matrix least square refinement structure, and hydrogen atom coordinate is added by Theoretical Calculation. Obtaining SN38 crystalline form III is dimethylformamide (DMF) solvate, its structure cell is rhombic system, space group is P212121, a=7.0526 (5) b=8.7052 (6) c=37.845 (3) unit cell volume V=2323.5 (18)Its crystal structure as shown in Figure 8, pile up as shown in Figure 9 by structure cell. The crystallographic parameter of SN38 crystalline form III is as shown in table 2 below.
Table 2
The thermal analysis curue of SN38 crystalline form III of the present invention is composed as shown in Figure 10, and 100-150 DEG C of weightlessness about 6% has an endothermic peak at 129.4 DEG C; 180-210 DEG C of weightlessness about 7%, has an endothermic peak at 204 DEG C; 220-320 DEG C of weightlessness about 11%, has continuous print heat absorption, exothermic phenomenon.
The infared spectrum of SN38 crystalline form III of the present invention is at 2936cm-1、1752cm-1、1653cm-1、1592cm-1、1509cm-1、1158cm-1There are bands of a spectrum at place. Its infared spectrum is as shown in figure 11.
The Raman collection of illustrative plates of SN38 crystalline form III of the present invention is as shown in figure 12.
The preparation method of SN38 crystalline form III of the present invention, comprises the following steps that
SN38 is dissolved in N, in dinethylformamide solution, then it is added drop-wise in anti-solvent, described anti-solvent is ethyl acetate or acetone, put into evaporation solvent crystallization in 10-20 DEG C of environment, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III;
Or, SN38 is dissolved in DMF solution, anti-solvent adopts acetonitrile, utilizes the method crystallization that steam spreads, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III;
Or, SN38 is dissolved in DMF solution, stirring, to dissolving, adds Pyrazinamide, and anti-solvent adopts ethanol, utilizing the method crystallization that steam spreads, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III.
SN38 crystal form II of the present invention, III for the preparation of antitumor drug.
The raw material of the present invention and reagent are all commercially.
The excellent effect of the present invention is in that:
1, two kinds of crystal formation dissolubility of the SN38 of the present invention are high.
2, the preparation method of two kinds of crystal formations of the SN38 of the present invention is simple to operation, is suitable for technology and produces.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern (XRD) of SN38 crystal form II of the present invention;
Fig. 2 is the monomer structure figure that the present invention passes through the crystal type SN38 crystal form II that monocrystalline parsing obtains;
Fig. 3 is the structure cell accumulation graph of SN38 crystal form II of the present invention;
Fig. 4 is the thermal analysis curue of SN38 crystal form II of the present invention;
Fig. 5 is the infared spectrum of SN38 crystal form II of the present invention;
Fig. 6 is the Raman spectrogram of SN38 crystal form II of the present invention;
Fig. 7 is the X-ray powder diffraction pattern (XRD) of SN38 crystalline form III of the present invention;
Fig. 8 is the monomer structure figure that the present invention passes through the SN38 crystalline form III that monocrystalline parsing obtains;
Fig. 9 is the structure cell accumulation graph of SN38 crystalline form III of the present invention;
Figure 10 is the thermal analysis curue of SN38 crystalline form III of the present invention;
Figure 11 is the infared spectrum of SN38 crystalline form III of the present invention;
Figure 12 is the Raman spectrogram of SN38 crystalline form III of the present invention;
Figure 13 is SN38 crystalline form I in experimental example of the present invention, II, III solubility curve.
Detailed description of the invention
Below by specific embodiment, the present invention will be further described, but is not limited to this.
The raw materials used convenient source that is in embodiment, commercial products, device therefor is conventional equipment.
Embodiment 15, is the preparation of the crystal form II of SN38, and embodiment 6-10 is the preparation of the crystalline form III of SN38.
Embodiment 1, SN38 crystal form II preparation
Weigh 50mg7-ethyl-10-hydroxycamptothecin in reaction bulb, adding 20ml volume ratio is the methanol of 1:1: the mixed solvent of chloroform, stirring makes it dissolve, solvent flashing at 10-20 DEG C, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II.
Embodiment 2, SN38 crystal form II preparation
Weighing 30mg7-ethyl-10-hydroxycamptothecin in reaction bulb, add 210ml methanol solvate, stirring makes it dissolve, solvent flashing at 10-20 DEG C, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II.
Embodiment 3, SN38 crystal form II preparation
Weigh 50mg7-ethyl-10-hydroxycamptothecin in reaction bulb, adding 12ml volume ratio is the methanol of 1:1: the mixed solvent of chloroform, stirs, isolated by filtration solid under room temperature, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II.
Embodiment 4, SN38 crystal form II preparation
Weighing 50mg7-ethyl-10-hydroxycamptothecin in reaction bulb, adding 12ml volume ratio is the methanol of 1:1: the mixed solvent of chloroform, stirs, isolated by filtration solid under room temperature; Filtrate evaporates solvent crystallization, isolated by filtration solid in the environment of 10-20 DEG C, and solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II.
Embodiment 5, SN38 crystal form II preparation
Weigh 40mg7-ethyl-10-hydroxycamptothecin in reaction bulb, add 2.75mlN, dinethylformamide, stirring makes it dissolve, add 20mg Pyrazinamide, put into crystallization in methanol atmosphere, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II.
Embodiment 6, SN38 crystalline form III preparation
Weigh 30mg7-ethyl-10-hydroxycamptothecin in reaction bulb, add 3mlN, dinethylformamide, stirring makes it dissolve, it is added dropwise in 2ml ethyl acetate solution, puts into evaporation solvent crystallization, isolated by filtration solid in 10-20 DEG C of environment, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III.
Embodiment 7, SN38 crystalline form III preparation
Weigh 30mg7-ethyl-10-hydroxycamptothecin in reaction bulb, add 3mlN, dinethylformamide, stirring makes it dissolve, it is added dropwise in 2ml acetone soln, puts into evaporation solvent crystallization, isolated by filtration solid in 10-20 DEG C of environment, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III.
Embodiment 8, SN38 crystalline form III preparation
Weigh 30mg7-ethyl-10-hydroxycamptothecin in reaction bulb, add 3mlN, dinethylformamide, stirring makes it dissolve, and puts into crystallization in acetonitrile atmosphere, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III.
Embodiment 9, SN38 crystalline form III preparation
Weigh 40mg7-ethyl-10-hydroxycamptothecin in reaction bulb, add 2.75mlN, dinethylformamide, stirring makes it dissolve, add the Pyrazinamide of 20mg, put into crystallization in alcohol atmosphere, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III.
Embodiment 10, SN38 crystalline form III preparation
Weigh 30mg7-ethyl-10-hydroxycamptothecin in reaction bulb, add 3mlN, dinethylformamide, stirring makes it dissolve, and filters, and adds 10mg polymethyl methacrylate in filtrate, put into crystallization in alcohol atmosphere, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III.
Experimental example
Measure the SN38 crystal form II that obtains of the embodiment of the present invention 1, the crystal formation (being designated as crystalline form I) of SN38 crystalline form III that embodiment 6 obtains and Chinese patent document CN101686968A report, the dissolubility in pH=1.2 aqueous solution at 25 DEG C.
Method of testing is: crystalline form I, II and III sample cross 100 mesh sieves, make sample particle at 75-150 μm, the powder sample taking 10mg respectively is respectively put in the hydrochloric acid solution of pH=1.2 of 15ml, 500rpm stirs 4h, 15,30,45,60,90,120,180 and 240min, obtain suspension; From suspension, take a certain amount of solution cross 0.45 μm of filter membrane, the methanol dilution of the solution 1ml of every 0.5ml. Concentration measures uses high performance liquid chromatography (HPLC), agilent1260LC, chromatographic column C18 (VenusilASB, 5um,4.6*150mm, China), Cary50 ultraviolet spectrophotometer has maximum absorption wavelength at 384nm place, selects 384nm for detection wavelength. Mobile phase is chromatograph methanol: phosphate buffer (pH=2.15)=80:20 (volume ratio), flow velocity 1ml/min, column temperature 30 DEG C. Test result is as shown in figure 13.
Found out by Figure 13, crystal form II, III dissolubility bigger than the dissolubility of crystalline form I, crystalline form I, II, III maxima solubility be 0.46,0.98 and 1.27mg/L. But crystal form II and III dissolubility constantly decline, 2h-4h solubility equilibria, after dissolubility reaches balance, crystalline form I, II, III dissolubility be 0.45,0.65 and 0.80mg/L respectively, it can be seen that the dissolubility of crystal form II provided by the invention, III is greatly improved.
Claims (10)
1. a SN38 crystal form II, it is characterized in that, this crystal form II uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles the angle of diffraction be 5.64,10.80,12.55,13.48,17.09,17.65,18.21,18.79,24.52 and 26.84 degree of places have characteristic peak, 2θRange of error is ± 0.2 degree.
2. a SN38 crystal form II, it is characterised in that this crystal form II uses Cu-K α radiation, and X-ray powder diffraction pattern is as shown in Figure 1.
3. a SN38 crystal form II, it is characterised in that the infared spectrum of this crystal form II is at 3241cm-1、1732cm-1、1653cm-1、1515cm-1、1170cm-1There are bands of a spectrum at place.
4. a preparation method for the SN38 crystal form II described in any one of claim 1-3, comprises the following steps that
SN38 is dissolved in mixed solution or the methanol solution of methanol and chloroform, stirring, to dissolving, evaporates solvent crystallization, isolated by filtration solid under the environment of 10-20 DEG C, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II;
Or, SN38 is dissolved in methanol and chloroform mixed solution, obtains suspension, stirring, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II;
Or, SN38 is dissolved in methanol and chloroform mixed solution, obtains suspension, stirring, isolated by filtration solid; Filtrate evaporates solvent crystallization, isolated by filtration solid in the environment of 10-20 DEG C, and solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II;
Or, SN38 is dissolved into N, in dinethylformamide solution, stirring, to dissolving, adds Pyrazinamide, and anti-solvent adopts methanol, utilize the method crystallization that steam spreads, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystal form II.
5. a SN38 crystalline form III, it is characterised in that this crystalline form III uses Cu-K α radiation, with 2θThe X-ray powder diffraction that angle represents is that 4.58,9.34,10.42,11.12,12.30,13.40,14.40,16.34,16.86,17.20,17.70,18.72,19.32,21.48,22.44,24.90,25.40,25.68,27.44 degree of places have characteristic peak in the angle of diffraction, 2θRange of error is ± 0.2 degree.
6. SN38 crystalline form III according to claim 5, it is characterized in that, this crystalline form III uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles the angle of diffraction be 4.58,9.34,10.42,11.12,12.30,13.40,14.02,14.40,15.44,16.34,16.86,17.20,17.70,18.72,19.32,20.78,21.48,22.44,24.10,24.90,25.40,25.68,27.44 degree of places have characteristic peak, 2θRange of error is ± 0.2 degree.
7. a SN38 crystalline form III, it is characterised in that this crystalline form III uses Cu-K α radiation, and X-ray powder diffraction pattern is as shown in Figure 7.
8. a preparation method for the SN38 crystalline form III described in any one of claim 5-7, comprises the following steps that
SN38 is dissolved in N, in dinethylformamide solution, then it is added drop-wise in anti-solvent, described anti-solvent is ethyl acetate or acetone, put into evaporation solvent crystallization in 10-20 DEG C of environment, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III;
Or, SN38 is dissolved in DMF solution, anti-solvent adopts acetonitrile, utilizes the method crystallization that steam spreads, isolated by filtration solid, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III;
Or, SN38 is dissolved in DMF solution, stirring, to dissolving, adds Pyrazinamide, and anti-solvent adopts ethanol, utilizing the method crystallization that steam spreads, solid vacuum drying at 50 DEG C, to constant weight, obtains SN38 crystalline form III.
9. the pharmaceutical applications of the SN38 crystal form II described in any one of claim 1-3 or the SN38 crystalline form III described in any one of claim 5-7.
10. the antineoplastic pharmaceutical compositions of the SN38 crystalline form III described in one kind includes described in any one of claim 1-3 SN38 crystal form II or any one of claim 5-7.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101686968A (en) * | 2007-06-25 | 2010-03-31 | 台湾神隆股份有限公司 | crystalline polymorph of 7-ethyl-10-hydroxycamptothecin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101686968A (en) * | 2007-06-25 | 2010-03-31 | 台湾神隆股份有限公司 | crystalline polymorph of 7-ethyl-10-hydroxycamptothecin |
Non-Patent Citations (1)
| Title |
|---|
| 《Total Synthesis of Camptothecin and SN-38》;Shanbao Yu;《The Journal of Organic Chemistry》;20121231;第77卷;717页左栏第3-4行 * |
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