CN104557961B - SN38 crystal formation and preparation method thereof and application - Google Patents

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

Crystal form of 7-ethyl-10-hydroxycamptothecin and its preparation method and application

technical field

The invention relates to two new crystal forms of 7-ethyl-10 hydroxycamptothecin and a preparation method thereof, belonging to the technical field of medicinal chemistry.

Background technique

Irinotecan (mnotecan, CPT-11) is a semi-synthetic water-soluble derivative of camptothecin. Its antitumor activity is higher than that of camptothecin, and its side effects are lower than that of camptothecin. The anti-tumor mechanism of irinotecan is mainly to inhibit the activity of topoisomerase-I, which affects DNA replication and leads to cell death. CPT-11 is an important drug for the treatment of small-cell lung cancer (SCLC). In 2010, the National Comprehensive Cancer Network (NCCN) in the United States recommended CPT-11 as the first-line treatment drug for advanced SCLC, and it can also be used for second-line treatment. . Irinotecan is an ester prodrug, which is mainly metabolized by carboxylesterase into 7-ethyl-10-hydroxycamptothecin (SN-38) with better activity in vivo to exert anti-tumor activity. The chemical structure of 10-hydroxycamptothecin is as follows:

In vitro cytotoxicity studies have shown that SN-38 is 1000 times more effective than CPT-11 against certain tumor cells.

The solubility and humidity stability of different crystal forms of 7-ethyl-10-hydroxycamptothecin are different and vary greatly, and the solubility is an important index in the process of preparing antitumor drugs, and too small solubility will seriously affect the quality of the drug.

Chinese patent document CN101686968A discloses a polymorph of 7-ethyl-10-hydroxycamptothecin, whose X-ray diffraction patterns are at 10.9±0.2, 13.2±0.2, 23.9±0.2 and 26.1±0.22θ degrees There are peaks. However, the solubility of this polymorphic form of 7-ethyl-10-hydroxycamptothecin is not high.

Contents of the invention

Aiming at the deficiencies of the prior art, the present invention provides two new crystal forms of 7-ethyl-10-hydroxycamptothecin, which are respectively denoted as crystal form II and crystal form III. The present invention also provides the preparation method of the above two new crystal forms of 7-ethyl-10-hydroxycamptothecin.

Technical scheme of the present invention is as follows:

A 7-ethyl-10-hydroxycamptothecin crystal form II, the crystal form II uses Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles at diffraction angles of 5.64, 10.80, 12.55, 13.48, 17.09, There are characteristic peaks at 17.65, 18.21, 18.79, 24.52 and 26.84 degrees, and the 2θ error range is ±0.2 degrees.

According to the present invention, preferably, the crystal form II of 7-ethyl-10-hydroxycamptothecin uses Cu-Kα radiation, and the X-ray powder diffraction represented by the angle of 2θ has diffraction angles of 5.64, 10.80, 11.84, 12.55, 13.48, There are characteristic peaks at 17.09, 17.65, 18.21, 18.79, 20.92, 24.52, 25.22, 26.84 and 33.98 degrees, and the 2θ error range is ±0.2 degrees.

The X-ray powder diffraction pattern obtained by using a Bruker D8 Advance diffractometer for the 7-ethyl-10-hydroxycamptothecin crystal form II of the present invention is shown in FIG. 1 . The measurement conditions are as follows: Cu-Kα, 40KV, 40mV light source, step size 0.02°, scanning speed 1°/min, scanning range 2-40°, room temperature.

The present invention adopts the single crystal diffractometer of BrukerAXS model to be SmartAPEXII to measure the single crystal structure of 7-ethyl-10-hydroxycamptothecin crystal form II under 100K, and uses graphite monochromator MoKα ray The data was collected by multi-layer scanning, and the APEX2SoftwareSuite (Bruker, 2009) program package was used for data reduction and absorption correction. The space group is determined according to the extinction law of the system and verified by the refined results. All crystal structures were solved by the direct method using SHELXL-97 (Sheldrick, 2008), and the structures were corrected by the full-matrix least squares method using the SHELXL-97 (Sheldrick, 2008) program, and the coordinates of hydrogen atoms were added by theoretical calculation. Obtained 7-ethyl-10-hydroxycamptothecin crystal form II is a methanol solvate, its unit cell is an orthorhombic crystal system, and the 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 shown in Figure 2, and the unit cell packing is shown in Figure 3. The crystallographic parameters of 7-ethyl-10-hydroxycamptothecin crystal form II are shown in Table 1 below.

Table 1

The thermal analysis spectrum of the 7-ethyl-10-hydroxycamptothecin crystal form II of the present invention is shown in Figure 4, the weight loss is about 1% at 90-120 ° C, and there is an endothermic peak at 112 ° C; the weight loss at 200-320 ° C is 12 % or so, there are continuous endothermic and exothermic phenomena.

The infrared spectrum of the 7-ethyl-10-hydroxycamptothecin crystal form II of the present invention has bands at 3241cm ^-1 , 1732cm ^-1 , 1653cm ^-1 , 1515cm ^-1 , and 1170cm ^-1 . Its infrared spectrum is shown in Figure 5.

The Raman spectrum of the crystal form II of 7-ethyl-10-hydroxycamptothecin of the present invention is shown in FIG. 6 .

The preparation method of 7-ethyl-10-hydroxycamptothecin crystal form II of the present invention comprises the following steps:

Dissolve 7-ethyl-10-hydroxycamptothecin in the mixed solution of methanol and chloroform or methanol solution, stir until dissolved, evaporate the solvent to crystallize at 10-20°C, filter and separate the solid, and the solid at 50°C Vacuum-dried to constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form II;

Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in a mixed solution of methanol and chloroform to obtain a suspension, stir, filter and separate the solid, and vacuum-dry the solid at 50°C to constant weight to obtain 7-ethyl Base-10-hydroxycamptothecin crystal form Ⅱ;

Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in a mixed solution of methanol and chloroform to obtain a suspension, stir, and filter to separate the solid; the filtrate evaporates the solvent in an environment of 10-20°C to crystallize, and filters to separate the solid , the solid was vacuum-dried at 50°C to constant weight to obtain crystalline form II of 7-ethyl-10-hydroxycamptothecin;

Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in N,N-dimethylformamide solution, stir until dissolved, add isonicotinamide, use methanol as the anti-solvent, crystallize by steam diffusion, and filter The solid was separated, and the solid was vacuum-dried at 50° C. to constant weight to obtain crystalline form II of 7-ethyl-10-hydroxycamptothecin.

A 7-ethyl-10-hydroxycamptothecin crystal form III, the crystal form III uses Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles at diffraction angles of 4.58, 9.34, 10.42, 11.12, 12.30, There are characteristic peaks at 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 degrees, and the 2θ error range is ±0.2 degrees.

According to the present invention, preferably, 7-ethyl-10-hydroxycamptothecin crystal form III uses Cu-Kα radiation, and the X-ray powder diffraction represented by 2θ angle is 4.58, 9.34, 10.42, 11.12, 12.30, There are characteristic peaks at 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 degrees, and the 2θ error range is ±0.2 degrees.

The X-ray powder diffraction pattern obtained by using a Bruker D8 Advance diffractometer for the 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention is shown in FIG. 7 . The measurement conditions are as follows: Cu-Kα, 40KV, 40mV light source, step size 0.02°, scanning speed 1°/min, scanning range 2-40°, room temperature.

The present invention adopts BrukerAXS model to be the single crystal diffractometer of SmartAPEXII to measure the single crystal structure of 7-ethyl-10-hydroxycamptothecin crystal form III at 296K, and use graphite monochromator MoKα ray The data was collected by multi-layer scanning, and the APEX2SoftwareSuite (Bruker, 2009) program package was used for data reduction and absorption correction. The space group is determined according to the extinction law of the system and verified by the refined results. All crystal structures were solved by the direct method using SHELXL-97 (Sheldrick, 2008), and the structures were corrected by the full-matrix least squares method using the SHELXL-97 (Sheldrick, 2008) program, and the coordinates of hydrogen atoms were added by theoretical calculation. The obtained 7-ethyl-10-hydroxycamptothecin crystal form III is dimethylformamide (DMF) solvate, its unit cell is orthorhombic, the 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 is shown in Figure 8, and the unit cell packing is shown in Figure 9. The crystallographic parameters of 7-ethyl-10-hydroxycamptothecin crystal form III are shown in Table 2 below.

Table 2

The thermal analysis spectrum of the 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention is shown in Figure 10, with a weight loss of about 6% at 100-150°C and an endothermic peak at 129.4°C; a weight loss of 7% at 180-210°C %, there is an endothermic peak at 204°C; the weight loss is about 11% at 220-320°C, and there are continuous endothermic and exothermic phenomena.

The infrared spectrum of the 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention has bands at 2936cm ^-1 , 1752cm ^-1 , 1653cm ^-1 , 1592cm ^-1 , 1509cm ^-1 , and 1158cm ^-1 . Its infrared spectrum is shown in Figure 11.

The Raman spectrum of the 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention is shown in FIG. 12 .

The preparation method of 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention comprises the following steps:

7-Ethyl-10-Hydroxycamptothecin is dissolved in N,N-dimethylformamide solution, then added dropwise to the anti-solvent, the anti-solvent is ethyl acetate or acetone, put into 10- The solvent was evaporated at 20°C to crystallize, the solid was separated by filtration, and the solid was vacuum-dried at 50°C to constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form III;

Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in N,N-dimethylformamide solution, use acetonitrile as the anti-solvent, crystallize by vapor diffusion, separate the solid by filtration, and store the solid under vacuum at 50°C Dry to constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form III;

Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in N,N-dimethylformamide solution, stir until dissolved, add isonicotinamide, use ethanol as anti-solvent, and crystallize by steam diffusion method, solid Vacuum-dry at 50°C until constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form III.

The 7-ethyl-10-hydroxycamptothecin crystal forms II and III of the invention are used for the preparation of antitumor drugs.

The starting materials and reagents of the present invention are all commercially available.

The excellent effect of the present invention is:

1. The two crystal forms of 7-ethyl-10-hydroxycamptothecin of the present invention have high solubility.

2. The preparation method of the two crystal forms of 7-ethyl-10-hydroxycamptothecin of the present invention is simple and easy to operate, and is suitable for technological production.

Description of drawings

Fig. 1 is the X-ray powder diffraction pattern (XRD) of 7-ethyl-10-hydroxycamptothecin crystal form II of the present invention;

Fig. 2 is the monomer structure diagram of the crystalline 7-ethyl-10-hydroxycamptothecin crystal form II obtained by single crystal analysis in the present invention;

Fig. 3 is a unit cell packing diagram of 7-ethyl-10-hydroxycamptothecin crystal form II of the present invention;

Fig. 4 is the thermogram of 7-ethyl-10-hydroxycamptothecin crystal form II of the present invention;

Fig. 5 is the infrared spectrum of 7-ethyl-10-hydroxycamptothecin crystal form II of the present invention;

Fig. 6 is the Raman spectrum of 7-ethyl-10-hydroxycamptothecin crystal form II of the present invention;

Fig. 7 is the X-ray powder diffraction pattern (XRD) of 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention;

Figure 8 is a monomer structure diagram of 7-ethyl-10-hydroxycamptothecin crystal form III obtained by single crystal analysis in the present invention;

Fig. 9 is a unit cell packing diagram of 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention;

Fig. 10 is a thermogram of 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention;

Figure 11 is the infrared spectrum of 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention;

Figure 12 is the Raman spectrum of 7-ethyl-10-hydroxycamptothecin crystal form III of the present invention;

Fig. 13 is the solubility curve of 7-ethyl-10-hydroxycamptothecin crystal forms I, II and III in the experimental examples of the present invention.

detailed description

The present invention will be further described below through specific examples, but not limited thereto.

The raw materials used in the examples are conventional raw materials, commercially available products, and the equipment used are conventional equipment.

Examples 1-5 are the preparation of crystalline form II of 7-ethyl-10-hydroxycamptothecin, and examples 6-10 are the preparation of crystalline form III of 7-ethyl-10-hydroxycamptothecin.

Embodiment 1, the preparation of 7-ethyl-10-hydroxycamptothecin crystal form II

Weigh 50mg of 7-ethyl-10-hydroxycamptothecin into a reaction flask, add 20ml of a mixed solvent of methanol: chloroform with a volume ratio of 1:1, stir to dissolve, evaporate the solvent at 10-20°C, and separate the solid by filtration , and the solid was vacuum-dried at 50°C to constant weight to obtain crystalline form II of 7-ethyl-10-hydroxycamptothecin.

Example 2, Preparation of 7-ethyl-10-hydroxycamptothecin crystal form II

Weigh 30mg of 7-ethyl-10-hydroxycamptothecin into a reaction bottle, add 210ml of methanol solvent, stir to dissolve, evaporate the solvent at 10-20°C, filter and separate the solid, and dry the solid under vacuum at 50°C to constant weight , that is, 7-ethyl-10-hydroxycamptothecin crystal form II.

Example 3, Preparation of 7-ethyl-10-hydroxycamptothecin crystal form II

Weigh 50mg of 7-ethyl-10-hydroxycamptothecin into a reaction flask, add 12ml of a mixed solvent of methanol: chloroform with a volume ratio of 1:1, stir at room temperature, filter and separate the solid, and dry the solid in vacuum at 50°C to Constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form II.

Example 4, Preparation of 7-ethyl-10-hydroxycamptothecin crystal form II

Weigh 50mg of 7-ethyl-10-hydroxycamptothecin into a reaction flask, add 12ml of methanol: chloroform mixed solvent with a volume ratio of 1:1, stir at room temperature, filter and separate the solid; The solvent was evaporated to crystallize, the solid was separated by filtration, and the solid was vacuum-dried at 50°C to constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form II.

Example 5, Preparation of 7-ethyl-10-hydroxycamptothecin crystal form II

Weigh 40mg of 7-ethyl-10-hydroxycamptothecin into a reaction flask, add 2.75ml of N,N-dimethylformamide, stir to dissolve, then add 20mg of isonicotinamide, crystallize in methanol atmosphere, filter The solid was separated, and the solid was vacuum-dried at 50° C. to constant weight to obtain crystalline form II of 7-ethyl-10-hydroxycamptothecin.

Example 6, Preparation of 7-ethyl-10-hydroxycamptothecin crystal form III

Weigh 30mg of 7-ethyl-10-hydroxycamptothecin into a reaction bottle, add 3ml of N,N-dimethylformamide, stir to dissolve, add dropwise to 2ml of ethyl acetate solution, and put it in an environment of 10-20°C The solvent was evaporated to crystallize, the solid was separated by filtration, and the solid was vacuum-dried at 50°C to constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form III.

Example 7, Preparation of 7-ethyl-10-hydroxycamptothecin crystal form III

Weigh 30mg of 7-ethyl-10-hydroxycamptothecin into a reaction flask, add 3ml of N,N-dimethylformamide, stir to dissolve, add dropwise to 2ml of acetone solution, and evaporate in an environment of 10-20°C The solvent was crystallized, the solid was separated by filtration, and the solid was vacuum-dried at 50° C. to constant weight to obtain the crystalline form III of 7-ethyl-10-hydroxycamptothecin.

Example 8, Preparation of 7-ethyl-10-hydroxycamptothecin crystal form III

Weigh 30mg of 7-ethyl-10-hydroxycamptothecin into a reaction flask, add 3ml of N,N-dimethylformamide, stir to dissolve, put it in an acetonitrile atmosphere to crystallize, and separate the solid by filtration. Vacuum drying to constant weight yielded 7-ethyl-10-hydroxycamptothecin crystal form III.

Example 9, Preparation of 7-ethyl-10-hydroxycamptothecin crystal form III

Weigh 40mg of 7-ethyl-10-hydroxycamptothecin into a reaction flask, add 2.75ml of N,N-dimethylformamide, stir to dissolve, then add 20mg of isonicotinamide, and put it into an ethanol atmosphere to crystallize. The solid was separated by filtration, and the solid was vacuum-dried at 50° C. to a constant weight to obtain the crystalline form III of 7-ethyl-10-hydroxycamptothecin.

Example 10, Preparation of 7-ethyl-10-hydroxycamptothecin crystal form III

Weigh 30mg of 7-ethyl-10-hydroxycamptothecin into a reaction flask, add 3ml of N,N-dimethylformamide, stir to dissolve, filter, add 10mg of polymethyl methacrylate to the filtrate, add ethanol Crystallization in the atmosphere, the solid was separated by filtration, and the solid was vacuum-dried at 50°C to constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form III.

Experimental example

Determination of the 7-ethyl-10-hydroxycamptothecin crystal form II obtained in Example 1 of the present invention, the 7-ethyl-10-hydroxycamptothecin crystal form III obtained in Example 6, and the crystals reported in Chinese patent document CN101686968A Form (referred to as crystal form I), solubility in aqueous solution at pH = 1.2 at 25°C.

The test method is as follows: samples of crystal forms I, II and III are passed through a 100-mesh sieve, so that the sample particles are 75-150 μm, and 10 mg of powder samples are respectively put into 15 ml of hydrochloric acid solution with pH=1.2, stirred at 500 rpm for 4 hours, 15, 30, 45, 60, 90, 120, 180, and 240 minutes to obtain a suspension; take a certain amount of solution from the suspension to pass through a 0.45 μm filter membrane, and dilute each 0.5ml of the solution with 1ml of methanol. High performance liquid chromatography (HPLC) for concentration determination, agilent1260LC, chromatographic column C18 (VenusilASB, 5um, 4.6*150mm, China), the Cary50 ultraviolet spectrophotometer has a maximum absorption wavelength at 384nm, and 384nm is selected as the detection wavelength. The mobile phase is chromatographic methanol:phosphate buffer (pH=2.15)=80:20 (volume ratio), flow rate 1ml/min, column temperature 30°C. The test results are shown in Figure 13.

It can be seen from Figure 13 that the solubility of crystal forms II and III is greater than that of crystal form I, and the maximum solubility of crystal forms I, II and III are 0.46, 0.98 and 1.27mg/L. However, the solubility of crystal forms II and III keeps decreasing, and the solubility is balanced in 2h-4h. After the solubility reaches equilibrium, the solubility of crystal forms I, II, and III are respectively 0.45, 0.65, and 0.80mg/L. It can be seen that the crystal forms provided by the present invention The solubility of Ⅱ and Ⅲ has been greatly improved.

Claims (10)

1. A 7-ethyl-10-hydroxycamptothecin crystal form II, characterized in that the crystal form II uses Cu-Kα radiation, and the X-ray powder diffraction represented by the 2θ angle is 5.64, 10.80, There are characteristic peaks at 12.55, 13.48, 17.09, 17.65, 18.21, 18.79, 24.52 , and 26.84 degrees, and the 2θ error range is ±0.2 degrees. 2. A 7-ethyl-10-hydroxycamptothecin crystal form II, characterized in that the crystal form II uses Cu-Kα radiation, and the X-ray powder diffraction pattern is shown in FIG. 1 . 3. A crystal form II of 7-ethyl-10-hydroxycamptothecin, characterized in that, the infrared spectrum of the crystal form II is at 3241cm ^-1 , 1732cm ^-1 , 1653cm ^-1 , 1515cm ^-1 , 1170cm ^-1 There are bands. 4. A method for preparing the 7-ethyl-10-hydroxycamptothecin crystal form II described in any one of claims 1-3, comprising the following steps: Dissolve 7-ethyl-10-hydroxycamptothecin in the mixed solution of methanol and chloroform or methanol solution, stir until dissolved, evaporate the solvent to crystallize at 10-20°C, filter and separate the solid, and the solid at 50°C Vacuum-dried to constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form II; Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in a mixed solution of methanol and chloroform to obtain a suspension, stir, filter and separate the solid, and vacuum-dry the solid at 50°C to constant weight to obtain 7-ethyl Base-10-hydroxycamptothecin crystal form Ⅱ; Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in a mixed solution of methanol and chloroform to obtain a suspension, stir, and filter to separate the solid; the filtrate evaporates the solvent in an environment of 10-20°C to crystallize, and filters to separate the solid , the solid was vacuum-dried at 50°C to constant weight to obtain crystalline form II of 7-ethyl-10-hydroxycamptothecin; Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in N,N-dimethylformamide solution, stir until dissolved, add isonicotinamide, use methanol as the anti-solvent, crystallize by steam diffusion, and filter The solid was separated, and the solid was vacuum-dried at 50° C. to constant weight to obtain crystalline form II of 7-ethyl-10-hydroxycamptothecin. 5. A 7-ethyl-10-hydroxycamptothecin crystal form III, characterized in that the crystal form III uses Cu-Kα radiation, and the X-ray powder diffraction represented by the 2 θ angle is 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 degrees have characteristic peaks, and the 2 θ error range is ±0.2 degrees. 6. The 7-ethyl-10-hydroxycamptothecin crystal form III according to claim 5, characterized in that, the crystal form III uses Cu-Kα radiation, and the X-ray powder diffraction represented by the 2θ angle is at the diffraction angle 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, 54.480, 27 Peak, 2θ margin of error is ±0.2 degrees. 7. A 7-ethyl-10-hydroxycamptothecin crystal form III, characterized in that the crystal form III uses Cu-Kα radiation, and the X-ray powder diffraction pattern is shown in FIG. 7 . 8. A preparation method of 7-ethyl-10-hydroxycamptothecin crystal form III described in any one of claims 5-7, comprising the following steps: 7-Ethyl-10-Hydroxycamptothecin is dissolved in N,N-dimethylformamide solution, then added dropwise to the anti-solvent, the anti-solvent is ethyl acetate or acetone, put into 10- The solvent was evaporated at 20°C to crystallize, the solid was separated by filtration, and the solid was vacuum-dried at 50°C to constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form III; Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in N,N-dimethylformamide solution, use acetonitrile as the anti-solvent, crystallize by vapor diffusion, separate the solid by filtration, and store the solid under vacuum at 50°C Dry to constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form III; Alternatively, dissolve 7-ethyl-10-hydroxycamptothecin in N,N-dimethylformamide solution, stir until dissolved, add isonicotinamide, use ethanol as anti-solvent, and crystallize by steam diffusion method, solid Vacuum-dry at 50°C until constant weight to obtain 7-ethyl-10-hydroxycamptothecin crystal form III. 9. The 7-ethyl-10-hydroxycamptothecin crystal form II described in any one of claims 1-3 or the 7-ethyl-10-hydroxycamptothecin described in any one of claims 5-7 Pharmaceutical use of crystal form III. 10. A 7-ethyl-10-hydroxycamptothecin crystal form II comprising any one of claims 1-3 or a 7-ethyl-10-hydroxyl group according to any one of claims 5-7 An antineoplastic pharmaceutical composition of camptothecin crystal form III.