CN111187337B - Romidepsin-isopropanol solvate and crystal form, preparation method and application thereof - Google Patents

Romidepsin-isopropanol solvate and crystal form, preparation method and application thereof Download PDF

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CN111187337B
CN111187337B CN201811360492.XA CN201811360492A CN111187337B CN 111187337 B CN111187337 B CN 111187337B CN 201811360492 A CN201811360492 A CN 201811360492A CN 111187337 B CN111187337 B CN 111187337B
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romidepsin
isopropanol
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isopropanol solvate
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胡海峰
熊磊
陈昌发
闵涛玲
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Abstract

The invention discloses a romidepsin-isopropanol solvate, a crystal form, a preparation method and application thereof. The romidepsin-isopropanol solvate shown as I has the advantages of simple preparation method, larger granularity of crystal particles, higher purity, uniform shape and good fluidity. The crystal form is beneficial to the processability, the manufacturability and the separation and purification of medicines, and has better application market.

Description

Romidepsin-isopropanol solvate and crystal form, preparation method and application thereof
Technical Field
The invention relates to a romidepsin-isopropanol solvate, a crystal form, a preparation method and application thereof.
Background
Romidepsin (also known as FK228, FR901228, trade name isotodax) is a class of cyclic peptide antitumor antibiotics, and achieves the purpose of inhibiting tumor cell growth mainly by inhibiting the activity of Histone Deacetylase (HDAC). Romidepsin has been approved by the FDA for the treatment of relapsed cutaneous T-cell lymphoma (CTCL) and peripheral cutaneous T-cell lymphoma (PCTL) at present. In recent years, romidepsin is not only widely applied to treatment of tumors, but also has been found by researchers to activate latent HIV virus in human bodies, and the findings of the research provide a new possibility for treatment of HIV. Therefore, the method has great application value in research on romidepsin.
Romidepsin is a cyclic peptide structure, each amino acid or amino acid derivative is connected through peptide bonds, a disulfide bond structure exists in the chemical structure of the Romidepsin, the disulfide bond is a key position of the Romidepsin which plays a role as a histone deacetylase inhibitor (HDACI), after the Romidepsin enters cells, the disulfide bond of the Romidepsin can be reduced into a sulfhydryl group by reduced glutathione, and the sulfhydryl group and Zn of an HDAC active center at the moment 2+ Coupling, thereby inhibiting HDAC activity. The chemical structure of romidepsin is shown in the following chart:
Figure BDA0001867202310000011
romidepsin was originally isolated from a strain of Chromobacterium violacea WB968 by Ueda (J.Antibiott.1994, 47 (3): 301-310).
Patent US7611724B2 discloses crystalline form a and crystalline form B of romidepsin. Patent W02012009336 discloses crystalline forms C, D, E, F, H, 1, J, K, L and N of romidepsin, as well as amorphous forms thereof. Patent application CN104262456 discloses crystalline form O of romidepsin.
The particle size of the crystalline form has an impact on the processability, manufacturability, bioavailability, and post-pharmaceutical safety of the drug product. At present, in China, the problem of crystal form granularity is considered in the research of new drugs imitating compounds except for the research of high-bioavailability preparations.
Disclosure of Invention
The invention provides a romidepsin-isopropanol solvate which is different from the prior art, and a crystal form, a preparation method and application thereof. The crystal has larger particle size, high purity, uniform shape and good fluidity, and is beneficial to the processability, manufacturability, separation and purification of medicines; and the preparation method is simple to operate.
The invention solves the technical problems through the following technical scheme.
The invention provides a romidepsin-isopropanol solvate shown as I,
Figure BDA0001867202310000021
the invention also provides the romidepsin-isopropanol solvate, which has characteristic peaks at 8.971 +/-0.2 degrees, 10.283 +/-0.2 degrees, 10.616 +/-0.2 degrees, 11.76 +/-0.2 degrees, 13.18 +/-0.2 degrees, 20.146 +/-0.2 degrees, 20.461 +/-0.2 degrees and 23.107 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle; andor, the crystal system belongs to the orthorhombic system, P2 1 2 1 2 1 Space group, cell parameter of
Figure BDA0001867202310000022
Figure BDA0001867202310000023
α=β=γ=90°。
Preferably, the X-ray powder diffraction pattern of romidepsin-isopropanol solvate shown in I, expressed in terms of 2 theta, has characteristic peaks at 8.971 + -0.2 °, 10.283 + -0.2 °, 10.616 + -0.2 °, 11.048 + -0.2 °, 11.76 + -0.2 °, 13.18 + -0.2, 17.362 + -0.2 °, 17.659 + -0.2 °, 20.146 + -0.2 °, 20.461 + -0.2 °, 22.335 + -0.2 °, 22.554 + -0.2 °, 23.107 + -0.2 °, 24.747 + -0.2 °, 25.099 + -0.2 ° and 29.009 + -0.2 °.
More preferably, the X-ray powder diffraction pattern of romidepsin-isopropanol solvate expressed as I, at 2 θ angles, has peaks at 6.742. + -. 0.2 °, 8.971. + -. 0.2 °, 10.283. + -. 0.2 °, 10.616. + -. 0.2 °, 11.048. + -. 0.2 °, 11.76. + -. 0.2 °, 13.18. + -. 0.2 °, 14.678. + -. 0.2 °, 15.823. + -. 0.2 °, 16.56. + -. 0.2 °, 17.362. + -. 0.2 °, 17.659. + -. 0.2 °, 18.548. + -. 0.2 °, 19.357. + -. 0.2 °, 20.146. + -. 0.2 °, 20.461. + -. 0.2 °, 21.865. + -. 0.2 °, 22.335. + -. 0.2 °, 22.554. + -. 0.2 °, 23.107. + -. 0.2 °, 24.747. + -. 0.2 °, 25.099. + -. 0.2 °, 21.588. + -. 0.2 °, 29.29. + -. 0.009. + -. 0.2 °.
Even more preferably, the 2 θ angles, spacing (d) values and relative intensities in the X-ray powder diffraction pattern of the romidepsin-isopropanol solvate shown in I are shown in table 1:
TABLE 1 XRPD data for romidepsin-isopropanol solvate shown as I
Figure BDA0001867202310000031
Figure BDA0001867202310000041
Figure BDA0001867202310000051
Further preferably, the X-ray powder diffraction pattern of romidepsin-isopropanol solvate shown in I is substantially as shown in figure 1.
The X-ray powder diffraction is measured by using a K alpha line of a Cu target.
Preferably, the main parameters of the romidepsin-isopropanol solvate shown as I are shown in Table 2:
TABLE 2
Figure BDA0001867202310000052
Figure BDA0001867202310000061
The infrared absorption spectrum (IR) of the romidepsin-isopropanol solvate shown as I can have characteristic peaks at the following positions: 3377cm -1 、3325cm -1 、2966cm -1 、2928cm -1 、2873cm -1 、1736cm -1 、1685cm -1 、1671cm -1 、1640cm -1 、1523cm -1 、1437cm -1 、1401cm -1 、1370cm -1 、1338cm -1 、1254cm -1 、1179cm -1 、1156cm -1 、1081cm -1 、997cm -1 、981cm -1 、951cm -1 、931cm -1 、815cm -1 、750cm -1 、652cm -1 And 636cm -1
Preferably, the infrared spectrum of the romidepsin-isopropanol solvate shown in I is basically as shown in figure 3.
The differential scanning thermal spectrum (DSC) of the romidepsin-isopropanol solvate shown as I has three endothermic peaks at 150.9 +/-2 ℃, 156.6 +/-2 ℃ and 256.3 +/-2 ℃.
Preferably, the differential scanning thermal spectrum of the romidepsin-isopropanol solvate shown in I is substantially as shown in FIG. 4.
The mean particle size of the primary particle size of the romidepsin-isopropanol solvate shown in I may be 3 to 8mm.
The invention also provides a preparation method of the crystal form of romidepsin-isopropanol solvate shown in the formula I, which comprises the following steps:
recrystallizing romidepsin in a mixed solvent of a solvent A and isopropanol to obtain the romidepsin, wherein the solvent A is halogenated C 1-4 Alkane solvent and/or C 3-4 A ketone solvent; the volume ratio of the isopropanol to the solvent A is more than or equal to 1,
Figure BDA0001867202310000071
said halo C 1-4 The alkane solvent may be halogenated C 1-2 An alkane solvent. Said halo C 1-2 The alkane solvent is one or more of dichloroethane, dichloromethane and chloroform, preferably dichloromethane.
Said C is 3-4 The ketone solvent may be acetone and/or butanone, preferably acetone.
The volume ratio of the isopropanol to the solvent A may be 1 to 4, preferably 1 to 2.
The amount of the solvent A may be an amount conventionally used in recrystallization operations in the art. The volume-mass ratio of the volume of the solvent A to the mass of the romidepsin is preferably 4 to 30ml/g.
The recrystallization preferably comprises the steps of: dissolving the romidepsin in halogenated alkanes and/or C 3-4 And (3) adding isopropanol into the mixed solution to obtain a mixed solution, and thus obtaining the product.
The means of dissolution may be conventional in the art for such procedures, preferably dissolution under ultrasonic conditions.
Preferably, the mixed solution is subjected to filtration treatment. The filtration treatment may be carried out in a manner conventional in the art for such operations, and is preferably membrane filtration. The filter membrane may be conventional in the art for such procedures. Preferably, the pore size of the filter membrane is 0.2 to 0.4 μm.
The manner of addition may be as conventionally used in such operations in the art, and the manner of dropwise addition is preferred.
In the present invention, after the recrystallization is finished, the separation can be performed according to a conventional operation method in the art, and preferably, the method further comprises the following operation steps: and filtering and drying the product obtained in the recrystallization process.
The filtration can be carried out by a method conventionally used in the art, such as suction filtration under reduced pressure.
The drying can be carried out by a method conventionally used in the art, for example, drying under atmospheric pressure or drying under reduced pressure. The reduced pressure drying may be carried out by methods and conditions conventional in the art, preferably under vacuum. The temperature of the vacuum drying may be 45 to 55 ℃, for example 40 ℃. The vacuum drying time can be 10-60 h, such as 48h.
The invention also provides a solvate, which is prepared according to the preparation method of the romidepsin-isopropanol solvate shown in the formula I.
The invention also provides application of the compound in preparing an anti-tumor medicament, wherein the compound is the romidepsin-isopropanol solvate shown in the formula I, and/or the romidepsin-isopropanol solvate shown in the formula I is prepared according to the preparation method of the romidepsin-isopropanol solvate shown in the formula I.
The tumor may be a T-lymphoma, non-small cell lung cancer, or breast cancer.
The invention also provides a pharmaceutical composition which comprises the romidepsin-isopropanol solvate shown in the formula I, and/or the romidepsin-isopropanol solvate shown in the formula I prepared by the preparation method of the romidepsin-isopropanol solvate shown in the formula I, and one or more pharmaceutically acceptable auxiliary materials.
The choice of such adjuvants will vary with the route of administration and the nature of the action, and will generally be fillers, diluents, surfactants, binders, wetting agents, disintegrating agents, preservatives, buffers and isotonizing agents, lubricants, emulsifiers or suspending agents.
It is known to those skilled in the art that the peak intensity and/or peak condition of X-ray powder diffraction may vary depending on experimental conditions. Meanwhile, due to different accuracies of the instruments, the measured 2 theta value has an error of about +/-0.2 degrees. The relative intensity values of the peaks depend more on certain properties of the measured sample, such as the size of the crystals and the purity than the position of the peaks, so that the measured peak intensities may deviate by about + -20%. One skilled in the art can obtain sufficient information to identify each crystal form from the X-ray powder diffraction data provided herein, despite experimental errors, instrumental errors, and orientation preference, etc.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The positive progress effects of the invention are as follows: the romidepsin solvate has high crystal purity, larger crystal particle size, uniform shape, better medicine processability, manufacturability and fluidity, and is beneficial to separation and purification.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of example 2 to obtain romidepsin-isopropanol solvate shown in I.
FIG. 2 example 2 gives the X-ray single crystal diffraction pattern of romidepsin-isopropanol solvate shown in I.
FIG. 3 is an infrared absorption spectrum of romidepsin-isopropanol solvate obtained in example 2 as shown in I.
FIG. 4 is a differential scanning thermal map of the romidepsin-isopropanol solvate obtained in example 2 as shown in I.
FIG. 5 is an appearance chart of crystals of romidepsin-isopropanol solvate shown in I obtained in examples 2 to 7, wherein 3mm,5mm and 8mm refer to average particle diameters of main particle sizes of the crystals of romidepsin-isopropanol solvate shown in I.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The romidepsin in the following examples is prepared by a method in US 8691534 B2, and the purity of the romidepsin is 99.2%; other reagents were commercially available in analytical purity.
The purity of romidepsin was checked by High Performance Liquid Chromatography (HPLC). And (3) testing conditions: the chromatographic column is Waters C 18 4.6mm × 150m; the mobile phase is acetonitrile: water =40:60 (v/v); the detection wavelength is 210nm; the flow rate is 1ml/min; the column temperature was 25 ℃.
Detection method
Powder X-ray diffraction
The instrument comprises: x-polycrystal diffraction Instrument model D8 ADVANCE polycrystal diffraction instrument (Bruker, germany).
The test method comprises the following steps: the romidepsin-isopropanol solvate was weighed at 40mg, and the sample was placed in the center of the sample holder groove, with the sample surface level with the sample holder surface.
And (3) testing conditions are as follows: cuK alpha 40kV 40mA; 1.0mm of divergent slit, 0.4 degrees of cable-stayed slit and continuous scanning; step size 0.02 °; the range is 3-45 degrees; speed 8 °/min, detector LynxEye.
Single crystal diffraction by X-ray
The instrument comprises: bruker SMART APEX-II diffractometer.
And (3) testing conditions: cuK alpha radiation; a graphite monochromator; single catheter diameter Φ =0.50mm; the distance d =60.3mm between the crystal and the CCD detector; the pipe pressure is 40kV; pipe flow 30mA; the scanning mode comprises the following steps:
Figure BDA0001867202310000101
and (6) scanning.
Infrared absorption Spectrum (IR)
The instrument comprises: the infrared spectrophotometer is a BRWKER VECTOR22.
The test method comprises the following steps: adopts KBr tablet pressing method, and the scanning range is 400-4000 cm -1
Differential Scanning Calorimetry (DSC)
The instrument comprises the following steps: the DSC meter is PERKIN ELMER DSC8000.
The test method comprises the following steps: the heating rate is 10 ℃/min, and the temperature is 20-280 ℃.
The instrument comprises the following steps: TGA model Perkinelmer TGA400.
The test method comprises the following steps: the heating rate is 10 ℃/min, and the temperature range is 30-300 ℃.
High performance liquid chromatography
And (3) testing conditions are as follows: the chromatographic column is Waters C 18 4.6mm × 150m; the mobile phase is acetonitrile: water one (40): 60; the detection wavelength is 210nm; the flow rate is 1ml/min; the column temperature was room temperature.
Example 1
Weighing 1g of romidepsin, dissolving the romidepsin in 30ml of acetone, performing ultrasonic assisted dissolution, filtering the romidepsin solution through a 0.22 mu m membrane to obtain a clear romidepsin acetone solution, finally adding 45ml of isopropanol into the clear romidepsin acetone solution to obtain a solid, and characterizing the solid, wherein the molecular formula of the solid is C 24 H 36 N 4 O 6 S 2 ·C 3 H 8 O, relative molecular weight 600.78. Example 2
Weighing 1g of romidepsin, dissolving the romidepsin in 30ml of acetone, assisting the dissolution by ultrasound, filtering the romidepsin solution through a 0.22 mu m membrane to obtain a clear romidepsin acetone solution, finally adding 30ml of isopropanol into the solution, filtering for 48 hours to obtain romidepsin crystals, and drying the romidepsin crystals in vacuum at 40 ℃ for 48 hours to obtain 0.89g of solid, wherein the yield is 89%, the purity is 99.7%, the crystals are transparent, and the average particle size of the particles is 4-5 mm.
The X-ray powder diffraction pattern is shown in figure 1, and the XRPD pattern expressed by the angle of 2 theta has characteristic peaks at 8.971 +/-0.2 degrees, 10.283 +/-0.2 degrees, 10.616 +/-0.2 degrees, 11.76 +/-0.2 degrees, 13.18 +/-0.2 degrees, 20.146 +/-0.2 degrees, 20.461 +/-0.2 degrees and 23.107 +/-0.2 degrees.
Detecting, and obtaining romidepsin-isopropanol solvate shown as I with molecular formula C by X-ray single crystal diffraction as shown in figure 2 24 H 36 N 4 O 6 S 2 ·C 3 H 8 O; cell parameters of
Figure BDA0001867202310000111
Figure BDA0001867202310000112
α = β = γ =90 °, cell volume of
Figure BDA0001867202310000113
The main parameters are shown in table 3:
table 3 single crystal data for the crystal form obtained in example 2
Figure BDA0001867202310000114
Figure BDA0001867202310000121
The infrared absorption spectrum is shown in FIG. 3, which is at 3377cm -1 、3325cm -1 、2966cm -1 、2928cm -1 、2873cm -1 、1736cm -1 、1685cm -1 、1671cm -1 、1640cm -1 、1523cm -1 、1437cm -1 、1401cm -1 、1370cm -1 、1338cm -1 、1254cm -1 、1179cm -1 、1156cm -1 、1081cm -1 、997cm -1 、981cm -1 、951cm -1 、931cm -1 、815cm -1 、750cm -1 、652cm -1 、636cm -1 A characteristic peak is formed;
the differential scanning heat map is shown in FIG. 3, which has three endothermic peaks at 150.9 + -2 deg.C, 156.6 + -2 deg.C and 256.3 + -2 deg.C;
example 3
Weighing 1g of romidepsin, dissolving the romidepsin in 30ml of acetone, assisting the dissolution by ultrasound, filtering the romidepsin solution through a 0.22 mu m membrane to obtain a clear romidepsin acetone solution, finally adding 60ml of isopropanol into the solution, filtering for 48 hours to obtain romidepsin crystals, and drying the romidepsin crystals in vacuum at 40 ℃ for 48 hours to obtain 0.93g of solid, wherein the yield is 93%, the purity is 99.6%, the crystals are transparent, and the average particle size of the particles is 5mm-8mm. The identification data were the same as in example 2.
Example 4
Weighing 1g of romidepsin, dissolving the romidepsin in 30ml of acetone, assisting the dissolution by ultrasound, filtering the romidepsin solution through a 0.22 mu m membrane to obtain a clear romidepsin acetone solution, finally adding 120ml of isopropanol into the solution, filtering for 48 hours to obtain romidepsin crystals, and drying the romidepsin crystals in vacuum at 40 ℃ for 48 hours to obtain 0.93g of solid with the purity of more than 99.2 percent, the yield of 87 percent, transparent crystals and the average particle size of 3mm-4mm. The identification data were the same as in example 2.
Example 5
Weighing 1g of romidepsin, dissolving the romidepsin in 4ml of dichloromethane, assisting in dissolving by ultrasound, filtering the romidepsin solution through a 0.22 mu m membrane to obtain a clear romidepsin solution, finally adding 4ml of isopropanol into the clear romidepsin solution, filtering for 48 hours to obtain romidepsin crystals, and drying in vacuum at 40 ℃ for 48 hours to obtain 0.9g of solid, wherein the yield is 90%, the purity is 99.8%, the crystals are transparent, and the average particle size of the particles is 4-6 mm. The identification data were the same as in example 2.
Example 6
Weighing 1g of romidepsin, dissolving the romidepsin in 4ml of dichloromethane, assisting in dissolving by ultrasound, filtering the romidepsin solution through a 0.22 mu m membrane to obtain a clear romidepsin solution, finally adding 8ml of isopropanol into the clear romidepsin solution, filtering for 48 hours to obtain romidepsin crystals, and drying in vacuum at 40 ℃ for 48 hours to obtain 0.93g of solid, wherein the yield is 93%, the purity is 99.8%, the crystals are transparent, and the average particle size of the particles is 5-6 mm. The identification data were the same as in example 2.
Example 7
Weighing 1g of romidepsin, dissolving the romidepsin in 4ml of dichloromethane, assisting in dissolving by ultrasound, filtering the romidepsin solution through a 0.22 mu m membrane to obtain a clear romidepsin solution, finally adding 12ml of isopropanol into the clear romidepsin solution, filtering for 48 hours to obtain romidepsin crystals, and drying in vacuum at 40 ℃ for 48 hours to obtain 0.85g of solid, wherein the yield is 85%, the purity is 99.3%, the crystals are transparent, and the average particle size of the particles is 3-5 mm.
Example 8
Weighing 1g of romidepsin, dissolving the romidepsin in 30ml of acetone, performing ultrasonic assisted dissolution, filtering the romidepsin solution through a 0.22 mu m membrane to obtain a clear romidepsin acetone solution, finally adding isopropanol with different volumes, standing until crystals are separated out, and characterizing crystal forms of the crystals, wherein the experimental results are shown in the following table 4.
TABLE 4 Effect of solvent volume on romidepsin-isopropanol solvate
Figure BDA0001867202310000131
By X-ray powder diffraction detection, the compound a is crystalline form a of romidepsin obtained by purification step 1 in the preparation method of example 4 in patent US7611724B 2.
The compound P is the romidepsin-isopropanol solvate shown in the formula I obtained in the example 2 through X-ray powder diffraction and X-ray single crystal diffraction detection.
Example 8
Purification step 1 of the preparation method according to example 4 of patent US7611724B2 gives romidepsin form a.
Purification step 3 of the preparation method according to example 4 of patent US7611724B2 gives crystalline form B of romidepsin.
Romidepsin form H was obtained according to the preparation method of example 6 in patent W02012009336.
Romidepsin form I was obtained according to the preparation method of example 7 of patent W02012009336.
Crystalline form L of romidepsin was obtained according to the preparation method of example 11 in patent W02012009336.
The romidepsin crystal form O is prepared according to the preparation method of example 1 in patent CN 104262456.
The appearance and crystal grain of the crystalline forms a, B, H, I and L of romidepsin are shown in table 5:
TABLE 5
Figure BDA0001867202310000141
It can be seen that the romidepsin-isopropanol solvate shown in I of the present application has a large particle size, high purity, and a regular rectangular parallelepiped shape, is advantageous for post-processing, and has good drug processability and manufacturability.

Claims (14)

1. A romidepsin-isopropanol solvate according to I, characterized in that it has an X-ray powder diffraction pattern expressed in 2 Θ angles with characteristic peaks at 8.971 ± 0.2 °, 10.283 ± 0.2 °, 10.616 ± 0.2 °, 11.76 ± 0.2 °, 13.18 ± 0.2 °, 20.146 ± 0.2 °, 20.461 ± 0.2 ° and 23.107 ± 0.2 °; the crystal system belongs to the orthorhombic system, P2 1 2 1 2 1 Space group, cell parameter of
Figure FDA0003892763640000011
Figure FDA0003892763640000012
α=β=γ=90°;
Figure FDA0003892763640000013
2. The romidepsin-isopropanol solvate according to claim 1, characterized by an X-ray powder diffraction pattern, expressed in degrees 2 Θ, having characteristic peaks at 8.971 ± 0.2 °, 10.283 ± 0.2 °, 10.616 ± 0.2 °, 11.048 ± 0.2 °, 11.76 ± 0.2 °, 13.18 ± 0.2, 17.362 ± 0.2 °, 17.659 ± 0.2 °, 20.146 ± 0.2 °, 20.461 ± 0.2 °, 22.335 ± 0.2 °, 22.554 ± 0.2 °, 23.107 ± 0.2 °, 24.747 ± 0.2 °, 25.099 ± 0.2 ° and 29.009 ± 0.2 °;
and/or the parameters of the romidepsin-isopropanol solvate shown as I are shown as follows:
Figure FDA0003892763640000014
Figure FDA0003892763640000021
and/or the infrared absorption spectrum of the romidepsin-isopropanol solvate shown as I has characteristic peaks at the following positions: 3377cm -1 、3325cm -1 、2966cm -1 、2928cm -1 、2873cm -1 、1736cm -1 、1685cm -1 、1671cm -1 、1640cm -1 、1523cm -1 、1437cm -1 、1401cm -1 、1370cm -1 、1338cm -1 、1254cm -1 、1179cm -1 、1156cm -1 、1081cm -1 、997cm -1 、981cm -1 、951cm -1 、931cm -1 、815cm -1 、750cm -1 、652cm -1 And 636cm -1
And/or the differential scanning thermal spectrum of the romidepsin-isopropanol solvate shown as I has three endothermic peaks at 150.9 +/-2 ℃, 156.6 +/-2 ℃ and 256.3 +/-2 ℃;
and/or the average particle size of the main particle size of the romidepsin-isopropanol solvate shown as I is 3-8 mm.
3. The romidepsin-isopropanol solvate according to claim 2, characterized by an X-ray powder diffraction pattern expressed in degrees 2 Θ, characterized by peaks at 6.742 ± 0.2 °, 8.971 ± 0.2 °, 10.283 ± 0.2 °, 10.616 ± 0.2 °, 11.048 ± 0.2 °, 11.76 ± 0.2 °, 13.18 ± 0.2, 14.678 ± 0.2 °, 15.823 ± 0.2 °, 16.56 ± 0.2 °, 17.362 ± 0.2 °, 17.659 ± 0.2 °, 18.548 ± 0.2 °, 19.357 ± 0.2 °, 20.146 ± 0.2 °, 20.461 ± 0.2 °, 21.865 ± 0.2 °, 22.335 ± 0.2 °, 22.554 ± 0.2 °, 23.107 ± 0.2 °, 24.747 ± 0.25.25 ± 0.588 ± 0.27.27 °, 29 ± 0.009 ± 0.2 °.
4. The romidepsin-isopropanol solvate of claim 1, as represented by I, having an X-ray powder diffraction pattern with 2 Θ angles, spacing values and relative intensities as follows:
Figure FDA0003892763640000031
Figure FDA0003892763640000041
Figure FDA0003892763640000051
and/or the infrared absorption spectrum of the romidepsin-isopropanol solvate shown as I is basically shown as figure 3;
and/or the differential scanning thermal spectrum of the romidepsin-isopropanol solvate shown as I is basically shown as figure 4.
5. The romidepsin-isopropanol solvate of claim 4, as represented by I, having an X-ray powder diffraction pattern substantially as shown in figure 1.
6. A method for preparing romidepsin-isopropanol solvate shown as I is characterized by comprising the following steps:
recrystallizing romidepsin in a mixed solvent of a solvent A and isopropanol to obtain the romidepsin, wherein the solvent A is halogenated C 1-4 Alkane solvents and/or C 3-4 A ketone solvent; the volume ratio of the isopropanol to the solvent A is more than or equal to 1;
Figure FDA0003892763640000052
7. the method of claim 6, wherein said halo C is 1-4 The alkane solvent is halogenated C 1-2 An alkane solvent;
and/or, said C 3-4 The ketone solvent is acetone and/or butanone;
and/or the volume ratio of the isopropanol to the solvent A is 1-4;
and/or the volume-mass ratio of the volume of the solvent A to the mass of the romidepsin is 4-30 ml/g;
and/or, the recrystallization comprises the following steps: dissolving the romidepsin in halogenated alkane and/or C 3-4 Adding isopropanol into the mixed solution to obtain a mixed solution;
and/or after the recrystallization is finished, the method also comprises the following operation steps: and filtering and drying the product obtained in the recrystallization process.
8. The method of claim 7, wherein said halo C is 1-2 The alkane solvent is one or more of dichloroethane, dichloromethane and chloroform;
and/or, said C 3-4 The ketone solvent is acetone;
and/or the volume ratio of the isopropanol to the solvent A is 1-2.
9. The method of claim 8, wherein said halo C is 1-2 The alkane solvent is dichloromethane.
10. The method according to claim 7,
in the recrystallization step, the mixed solution is filtered;
and/or in the recrystallization step, the adding mode is a dropping mode.
11. The method according to claim 10, wherein the filtration treatment is membrane filtration.
12. The method according to claim 11, wherein the membrane filtration is a membrane filtration having a pore size of 0.2 to 0.4 μm.
13. Use of a compound as defined in any one of claims 1 to 5, which is romidepsin-iso-propanol solvate represented by I, in the preparation of an anti-tumor medicament.
14. A pharmaceutical composition comprising romidepsin-iso-propanol solvate of I as defined in any one of claims 1 to 5.
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