CN116217628B - Eutectic of oxaliplatin Pt (IV) complex and preparation method thereof - Google Patents
Eutectic of oxaliplatin Pt (IV) complex and preparation method thereof Download PDFInfo
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- CN116217628B CN116217628B CN202310507243.3A CN202310507243A CN116217628B CN 116217628 B CN116217628 B CN 116217628B CN 202310507243 A CN202310507243 A CN 202310507243A CN 116217628 B CN116217628 B CN 116217628B
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- dihydroxyoxaliplatin
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- hydroquinone
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- 230000005496 eutectics Effects 0.000 title claims abstract description 38
- 229960001756 oxaliplatin Drugs 0.000 title claims abstract description 34
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 238000010668 complexation reaction Methods 0.000 title description 2
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- 239000000843 powder Substances 0.000 claims description 20
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- 238000001757 thermogravimetry curve Methods 0.000 claims description 5
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
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- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
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- -1 oxaliplatin compound Chemical class 0.000 description 1
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- 229910052697 platinum Inorganic materials 0.000 description 1
- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical compound [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
- C07C39/08—Dihydroxy benzenes; Alkylated derivatives thereof
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention discloses an oxaliplatin Pt (IV) complex eutectic with advantages of acid stability and reduction rate and a preparation method thereof, and relates to the technical field of pharmaceutical eutectic.
Description
Technical Field
The invention relates to the technical field of pharmaceutical co-crystals, in particular to an oxaliplatin Pt (IV) complex co-crystal with acid stability and reduction rate advantages, and a preparation method and application thereof.
Background
Oxaliplatin (OXA) is one of the representative drugs of bivalent platinum-based anticancer drugs, is approved worldwide for clinical treatment of colorectal and gastric pancreas, but is limited by side effects, inherent or acquired drug resistance and inconvenient intravenous administration modes, and one of strategies for overcoming the limitation of oxaliplatin is to synthesize a Pt (IV) complex with oxaliplatin as a matrix as a prodrug, wherein the Pt (IV) complex has a hexacoordinated and octahedral geometry, and the ligand thereof is difficult to undergo substitution reaction in dynamics, so that adverse reactions with other biomolecules are minimized before the binding with deoxyribonucleic acid (DNA), thereby reducing side effects, and is suitable for oral administration.
In the gastrointestinal tract environment, the stability of Pt (IV) complexes is critical, particularly orally administered Pt (IV) complexes, which can be activated by a bioreductive agent (such as ascorbic acid) and reduced to Pt (II) homologs with cytotoxicity in cancer cells, and thus the reduction rate of Pt (IV) complexes by the bioreductive agent must be considered, however, it is still a challenge for Pt (IV) complexes based on oxaliplatin to combine excellent gastrointestinal tract environmental stability with reduction rate by the bioreductive agent.
Therefore, the invention applies the pharmaceutical eutectic technology to the important field of developing a new oxaliplatin Pt (IV) complex and a preparation thereof so as to improve the solubility, the acid stability, the reduction rate and the antitumor activity of the oxaliplatin Pt (IV) complex, prepares the pharmaceutical eutectic of the dihydroxyoxaliplatin, improves the solubility and the acid stability of a buffer solution with the pH value of 1.2, improves the reduction rate of converting the dihydroxyoxaliplatin into the oxaliplatin under the action of a biological reducing agent, improves the toxicity to human gastric adenocarcinoma cells and improves the safety of the dihydroxyoxaliplatin to human gastric mucosal cells.
Dihydroxyoxaliplatin (trans- [ Pt (R, R-DACH) (oxolate) (OH) 2 DHOXA) is an oxidation product of oxaliplatin through hydrogen peroxide, contains two axial hydroxyl groups, and is a Pt (IV) complex taking oxaliplatin as a matrix, and the chemical formula is shown in the specificationC 8 H 16 N 2 Ｏ 6 PtThe molecular weight is: 431.31, the chemical structural formula is as follows:
disclosure of Invention
The invention aims to apply the pharmaceutical co-crystal technology to the important field of developing a novel oxaliplatin Pt (IV) complex and a preparation thereof, and provides a bishydroxy oxaliplatin co-crystal and a preparation method thereof, which have good solubility, acid stability, reduction rate advantage and antitumor activity and have potential as an oral administration preparation.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a bishydroxy oxaliplatin eutectic with advantages of acid stability and reduction rate, comprising a eutectic formed by combining bishydroxy oxaliplatin with a eutectic forming substance; the eutectic formation is hydroquinone, namely dihydroxyoxaliplatin and hydroquinone eutectic.
Preferably, in the X-ray powder diffraction spectrum of the dihydroxyoxaliplatin and hydroquinone co-crystal, the characteristic peak (°) expressed by an angle 2θ is provided: 6.218,9.66, 11.498, 12.443, 14.943, 15.159, 16.398, 17.822, 18.361, 19.484, 19.66, 21.559, 23.103, 23.423, 23.961, 24.258, 24.86, 29.562, 29.923, 31.72, 31.917, 36.82, 39.021, 43.021, have an error margin of ±0.2°.
Preferably, the thermogravimetric analysis spectrogram of the dihydroxyoxaliplatin and hydroquinone eutectic shows that 6.9% of weight loss occurs at 25-75 ℃, the eutectic is a desolvation phenomenon, the eutectic is a hydrate, and after desolvation, the thermogravimetric analysis spectrogram of the dihydroxyoxaliplatin and hydroquinone eutectic has continuous weight loss phenomenon.
Preferably, the dihydroxy oDifferential scanning calorimetric thermogram of the co-crystal of thalidomide and hydroquinone is shown at T peak =98.3 ℃ has an endothermic peak, which is attributed to desolvation.
Preferably, the thermal analysis spectrogram of the dihydroxyoxaliplatin and hydroquinone eutectic does not have a melting process at 100-175 ℃, which means that the dihydroxyoxaliplatin and hydroquinone eutectic gradually start to decompose after desolvation.
Preferably, in the co-crystal of the dihydroxyoxaliplatin and hydroquinone, the dihydroxyoxaliplatin and hydroquinone are present in a 1:1 molar ratio.
The preparation method of the dihydroxyoxaliplatin eutectic powder comprises the following specific steps: dihydroxyoxaliplatin (431 mg, 1 mmol) and equimolar co-crystal formation were combined with 75μL water-acetonitrile mixed solvent (V/v=1:1) was mixed in an agate milling vessel, milled with a 12 mm agate milling ball at 25 Hz frequency for 45 min, then the resulting material was stirred in the same mixed solvent at room temperature for 2 hours, the solid powder was collected by centrifugation and dried under vacuum at 50 ℃ for 2 h.
Compared with the prior art, the invention has the beneficial effects that:
the use of a co-crystal of dihydroxyoxaliplatin, without changing the chemical structure of dihydroxyoxaliplatin, to prepare a co-crystal by synthesizing with a pharmaceutically acceptable co-crystal formation by a green mechanochemical grinding method, for improving the acid stability and the reduction rate of an antitumor platinum (IV) complex, and providing a co-crystal solid form suitable for oral administration.
On the other hand, the eutectic preparation method of the dihydroxyoxaliplatin is simple, has good repeatability and is suitable for industrial production.
Drawings
FIG. 1 shows the hydrogen spectrum nuclear magnetism of the dihydroxyoxaliplatin compound prepared in example 1 1 H-NMR) spectra;
FIG. 2 is an X-ray powder diffraction (XRPD) spectrum of the dihydroxyoxaliplatin compound prepared in example 1;
FIG. 3 is an X-ray powder diffraction (XRPD) spectrum of a co-crystal of dihydroxyoxaliplatin and hydroquinone obtained in example 2;
FIG. 4 is a Differential Scanning Calorimeter (DSC) and thermogravimetric analysis (TGA) spectrum of a co-crystal of dihydroxyoxaliplatin and hydroquinone prepared in example 2;
FIG. 5 is a thermogram of a hot stage microscopic analysis (HSM) of a co-crystal of dihydroxyoxaliplatin and hydroquinone prepared in example 2;
FIG. 6 is a unit cell diagram of single crystal X-ray diffraction (SCXRD) of a co-crystal of dihydroxyoxaliplatin and hydroquinone prepared in example 3;
FIG. 7 is a graph of the powder dissolution profile of example 4 for 4 hours of bisoxaliplatin and co-crystals in a phosphate buffered saline at 37 ℃ (pH 7.4);
FIG. 8 is a powder dissolution profile of example 4 for dihydroxyoxaliplatin and a co-crystal in 37℃hydrochloric acid buffer (pH 1.2) for 4 hours;
FIG. 9 is a graph of percent vs. time for the dihydroxyoxaliplatin content tested in example 5 as reduced at 37℃in phosphate buffered saline (pH 7.4);
FIG. 10 is a graph showing the evaluation of cytotoxicity of dihydroxyoxaliplatin, a co-crystal of dihydroxyoxaliplatin and hydroquinone against human gastric cancer cells (SGC-7901) and gastric mucosal cells (GES-1) by the cell proliferation assay method of example 6.
Detailed Description
In order to make the description of the present invention easier to understand, the technical solution of the present invention will be further described with reference to specific examples, but the present invention is not limited thereto, and all techniques implemented based on the above description of the present invention are included in the scope of the present invention, and unless otherwise indicated, raw materials and reagents used in the examples are commercial products, and reagents, instruments or operation steps not described herein are those conventionally determined by those skilled in the art.
1-10, the present invention provides a co-crystal of oxaliplatin Pt (IV) complex with acid stability and reduction advantages, and a co-crystal formed by combining dihydroxyoxaliplatin with a co-crystal former; the eutectic formation is hydroquinone.
Example 1
The preparation method of the dihydroxyoxaliplatin is summarized in the following figures 1-2:
oxaliplatin (OXA, 1000 mg, 2.53 mmol) was suspended in water (20 ml) and stirred for 5 minutes under ice bath conditions, then 30% hydrogen peroxide (10 ml) was added under heating and stirring for 2 hours at 70 ℃ in a water bath, the reaction solution was naturally cooled to room temperature, cooled overnight at low temperature, then vacuum filtered, dried under reduced pressure at 50 ℃ for 2 hours to obtain pale yellow crystals, and the nuclear magnetic resonance was measured as dihydroxyoxaliplatin, the yield was 78.9%, and the purity of high performance liquid chromatography was 98.6%.
Example 2
The preparation of the dihydroxyoxaliplatin and hydroquinone co-crystals is shown in FIGS. 3-5.
Dihydroxyoxaliplatin (431 mg, 1 mmol) and hydroquinone (110 mg, 1 mmol) were mixed with 75 μl of a water-acetonitrile mixed solvent (V/v=1:1) in an agate milling vessel, milled on a mixing mill with a 12 mm agate mill ball at 25 hz frequency for 45 minutes, dried in vacuo at 50 ℃ for 2 hours, and the solid powder was collected as a dihydroxyoxaliplatin and hydroquinone co-crystal.
In this example, the X-ray powder diffraction pattern of the co-crystal of dihydroxyoxaliplatin and hydroquinone has the following characteristic peaks (°) expressed in terms of angle 2θ:6.218,9.66, 11.498, 12.443, 14.943, 15.159, 16.398, 17.822, 18.361, 19.484, 19.66, 21.559, 23.103, 23.423, 23.961, 24.258, 24.86, 29.562, 29.923, 31.72, 31.917, 36.82, 39.021, 43.021, have an error margin of ±0.2°.
In this embodiment, thermogram of the co-crystal of dihydroxyoxaliplatin and hydroquinone shows that 6.9% of weight loss occurs before decomposition, the weight loss temperature ranges from 25 ℃ to 75 ℃, the co-crystal is a desolvation phenomenon, the co-crystal is a hydrate, and meanwhile, the differential scanning calorimeter of the co-crystal of dihydroxyoxaliplatin and hydroquinone shows that there is a desolvation endothermic peak, T peak After desolvation, the thermogravimetric analysis spectrum shows continuous weight loss, and the combination of the thermogravimetric analysis spectrum and the hot stage microscope analysis spectrum shows no melting process at 100-175 ℃, which indicates that the dihydroxyoxaliplatin and hydroquinone eutectic gradually start to decompose after desolvation.
Example 3
FIG. 6 shows a single crystal X-ray diffraction structure of a bishydroxy oxaliplatin co-crystal
The crystal structure parameters of the dihydroxyoxaliplatin and hydroquinone are shown in the following table:
the dihydroxyoxaliplatin and hydroquinone crystals belong to an orthorhombic system,P2 1 2 1 2 space group, wherein the unit cell contains 4 dihydroxyoxaliplatin molecules, 4 hydroquinone molecules and 8 water molecules.
Example 4
Powder dissolution experiments of the bishydroxy oxaliplatin co-crystals in combination with figures 7-8
To investigate the powder dissolution behavior of the bisoxaplatin and co-crystals in phosphate buffer (pH 7.4) and hydrochloric acid buffer (pH 1.2), the hydrolytic and acidolytic stability at 37 ℃ was analyzed to demonstrate that the bisoxaplatin co-crystals can be developed as prodrugs for oral administration, the specific experimental method is as follows: the excess of dihydroxyoxaliplatin and dihydroxyoxaliplatin-hydroquinone cocrystal powder were added to a glass bottle containing 10 ml of phosphate buffer (pH 7.4) or hydrochloric acid buffer (pH 1.2) dissolution medium, the water bath temperature was set to 37.+ -. 0.5 ℃ and the stirring speed was 200 revolutions per minute, samples were taken at preset time points (1, 3,5,7, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 minutes), 600 microliters of supernatant was taken and then an equal volume of fresh dissolution medium was timely replenished, the supernatant was immediately filtered with a 0.22 micron cellulose ester membrane filter, and the concentration of dihydroxyoxaliplatin was monitored by high performance liquid chromatography after appropriate dilution.
The powder dissolution results of the dihydroxyoxaliplatin and the co-crystal in phosphate buffered saline (pH 7.4) are as follows:
the dihydroxyoxaliplatin powder was gradually dissolved in a pH 7.4 buffer and maintained at the highest concentration at all times, with a solubility of about 6.0 mg/ml.
The dihydroxyoxaliplatin and hydroquinone co-crystal powder dissolved rapidly in pH 7.4 buffer, reached a maximum concentration of 6.25 mg/ml for the first 3 minutes, and remained nearby after the concentration had fallen to about 5.6 mg/ml in the presence of the parachute effect.
In summary, the dissolution of the powder in phosphate buffered saline (pH 7.4) was found to be almost identical for the dissolution behavior of the dihydroxyoxaliplatin and the co-crystal, reaching equilibrium after a rapid release in half an hour, both at a concentration of around 6.0 mg/ml, and they did not hydrolyze, indicating that the co-crystal has no adverse effect on the hydrolytic stability of the dihydroxyoxaliplatin.
The powder dissolution results of the dihydroxyoxaliplatin and the co-crystals in hydrochloric acid buffer (pH 1.2) are as follows:
the dihydroxyoxaliplatin rapidly dissolves in a buffer solution with a pH of 1.2, reaches the highest concentration of 14.8 mg/ml in the first 3 minutes, rapidly undergoes degradation, and has a degradation half-life of about 20 minutes, so that the acidic environment increases the solubility of the dihydroxyoxaliplatin, but the dihydroxyoxaliplatin is not acid-resistant and is extremely unstable.
The dihydroxyoxaliplatin and hydroquinone eutectic powder are gradually dissolved in a buffer solution with pH of 1.2, the highest concentration is reached to 16.0 mg/ml in 1 hour, and the highest concentration is stably maintained in 4 hours.
In summary, in an acidic environment with hydrochloric acid buffer (pH 1.2) as the simulated stomach, free dihydroxyoxaliplatin rapidly released and dissolved within 3 minutes, followed by rapid acidolysis, indicating poor acid stability of dihydroxyoxaliplatin, it is notable that the dissolution behavior of the dihydroxyoxaliplatin and hydroquinone co-crystals appears to be relatively stable under strongly acidic conditions.
Example 5
As shown in fig. 9, the reduction test was performed on dihydroxyoxaliplatin, a co-crystal of dihydroxyoxaliplatin and hydroquinone, and the operation and analysis steps were as follows:
the reduction of dihydroxyoxaliplatin or co-crystals (0.3 mM) with a reducing agent (ascorbic acid, 3 mM) respectively was monitored by High Performance Liquid Chromatography (HPLC) in phosphate buffer saline (pH 7.4), the reaction mixture was incubated in a water bath at 37.+ -. 0.5 ℃, sampled at a predetermined time point, immediately filtered, and after appropriate dilution the concentration of dihydroxyoxaliplatin or oxaliplatin was determined by HPLC, and fresh phosphate buffer saline was supplemented in an equivalent amount in time to maintain the reducing environment, and the reduction test was independently performed three times and then averaged.
Half-life of all dihydroxyoxaliplatin and co-crystalsT 1/2 ) The method is obtained by the following formula:T 1/2 = ln 2/k，kis a rate constant, and is defined by ln (A t /A 0 ) The linear relation diagram from the incubation time t is determined according to a first-order rate equation: [ A ]] = [A 0 ]e -kt ，A 0 And A t Peak areas of dihydroxyoxaliplatin at 0 h and t h, respectively, indicate that ln after treatment (a t /A 0 ) The reduction data are well-linear with incubation time t.
The results according to the reduction test are as follows:
dihydroxyoxaliplatin, after reaching the highest concentration of 5.0 mg/mL at 5min, decreases in concentration at the primary reaction rate, the remaining powder is oxaliplatin, so that tetravalent dihydroxyoxaliplatin is reduced to divalent oxaliplatin, the reduction reaction being of the primary reaction type: y= -0.0037x+ 1.5171, r= 0.9558, constant rate of reduction k=0.0037, constant of reduction half-life independent of initial concentration, i.eT 1/2 =ln 2/k = 187 min。
The rapid dissolution of the dihydroxyoxaliplatin with hydroquinone co-crystal powder immediately reached a maximum concentration of 8 mg/ml, followed by a decrease in the primary reaction rate, and the residual powder was centrifuged and dried to measure the X-ray powder diffraction and showed to contain oxaliplatin, so that tetravalent dihydroxyoxaliplatin was reduced to divalent oxaliplatin, the reduction reaction being of the primary reaction type: y= -0.0179x+1.627, r=0.9613, the constant rate of reduction k=0.0179, a constant of the reduction half-life independent of the initial concentration, i.eT 1/2 ==ln 2/k = 39 min。
In sum, the dihydroxyoxaliplatin and hydroquinone eutectic is formedT 1/2 =39 min) has a significantly lower reduction half-life than free dihydroxyoxaliplatin @T 1/2 =187 min), a reduction of 4.8 times, and a graph of the relative percentages of residual oxaliplatin and dihydroxyoxaliplatin over time illustrates that dihydroxyoxaliplatin is reduced to oxaliplatin after loss of both axial hydroxyl functionalities.
Example 6
In vitro cytotoxicity studies, as shown in fig. 10, were combined with specific experimental procedures: the cytotoxicity of dihydroxyoxaliplatin and dihydroxyoxaliplatin-hydroquinone cocrystal (S1) on human gastric adenocarcinoma cells and human gastric mucosa cells was studied by using a CCK-8 method.
The in vitro cell experiments were as follows: for human gastric cancer cells, dihydroxyoxaliplatin (IC) 50 =0.641 mM) has low cytotoxicity, and the co-crystal of dihydroxyoxaliplatin and hydroquinone (IC 50 =0.204 mM) is significantly better than the cytotoxicity of dihydroxyoxaliplatin, the normal cells (IC) of human gastric mucosal cells are treated by the eutectic of dihydroxyoxaliplatin and hydroquinone 50 =0.267 mM) is less cytotoxic than human gastric adenocarcinoma cells (IC 50 =0.204 mM), indicating that the dihydroxyoxaliplatin and hydroquinone co-crystals have a certain safety, and the results indicate that the dihydroxyoxaliplatin and hydroquinone co-crystals have higher cytotoxicity and higher safety than the dihydroxyoxaliplatin.
It should be noted that: unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, all patents and publications to which this invention pertains are herein incorporated by reference, although any methods and materials similar or identical to those described herein may be used in the practice or testing of this invention, the preferred methods, devices and materials are described herein.
The bishydroxy oxaliplatin co-crystals can be identified by a variety of techniques such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, raman spectroscopy, X-ray single crystal diffraction, and the like.
The X-ray powder diffraction (XRPD) can detect changes in crystalline forms, crystallinity, crystalline states, etc., and is a common means of identifying crystalline forms, the peak positions of the X-ray powder diffraction patterns are largely dependent on the structure of the crystalline forms, they are relatively insensitive to experimental details, and their relative peak heights are dependent on many factors related to sample preparation and instrument geometry, therefore, in some embodiments, the crystalline forms of the present invention are characterized by X-ray powder diffraction patterns having certain peaks, which are substantially as shown in the X-ray powder diffraction patterns provided in the present figures, while the measure of 2θ of the X-ray powder diffraction patterns may have experimental errors, the measure of 2θ of the X-ray powder diffraction patterns may differ slightly from instrument to instrument and sample to sample, and therefore the values of 2θ cannot be considered absolute, depending on the conditions of the instrument used in the test, the diffraction peaks have error margins of ±0.2°.
Differential Scanning Calorimetry (DSC) is a technique for measuring the change in energy difference with temperature between a sample and an inert reference (commonly used α -Al2O 3) under program control by continuously heating or cooling, the endothermic peak height of the differential scanning calorimetry profile is dependent on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details, and therefore, in some embodiments, the co-crystals of the present invention are characterized by a differential scanning calorimeter profile having characteristic peak positions, while the differential scanning calorimeter profile may have experimental errors, the peak position and peak value of the differential scanning calorimeter profile may differ slightly from instrument to instrument and from sample to sample, and therefore the peak position or peak value of the differential scanning calorimeter profile endothermic peak cannot be considered absolute, with a margin of error of ± 3 ℃ depending on the instrument conditions used in the test.
Thermogravimetric analysis is a technology for measuring the mass change of a substance along with the temperature under the control of a program, is suitable for checking the loss of a solvent in a crystal or the sublimation and decomposition processes of a sample, and can infer the condition of containing crystal water or a crystallization solvent in the crystal, wherein the mass change displayed by a thermogravimetric analysis curve depends on a plurality of factors such as sample preparation, an instrument and the like; the quality change detected by thermogravimetric analysis is slightly different between different instruments and different samples, and the quality change has an error margin of +/-0.5 according to the conditions of the instruments used in the test
In the context of the present invention, the 2 theta values in the X-ray powder diffraction pattern are all in degrees (°).
The term "peak" when referring to a spectrogram or/and data appearing in the graph refers to a feature that one skilled in the art can recognize that is not attributable to background noise.
The present invention relates to the dihydroxyoxaliplatin co-crystals which are present in a substantially pure crystalline form.
By "substantially pure" is meant that one form is substantially free of the other form or forms, i.e., the purity of the form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the form contains less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or total weight of the forms.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline forms is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
The "relative intensity" (or "relative peak height") in an X-ray powder diffraction pattern refers to the ratio of the intensity of the first strong peak to the intensity of the first strong peak in all diffraction peaks of the X-ray powder diffraction pattern (XRPD) at 100%.
"room temperature" in the present invention refers to a temperature from about 10 ℃ to about 40 ℃, and in some embodiments "room temperature" refers to a temperature from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃,22.5 ℃,25 ℃,27.5 ℃, and so forth.
All analyses below were performed at room temperature unless otherwise specified in the parameters.
X-ray powder diffraction (XRPD), for the examples the co-crystal was performed using a powder diffractometer using Cu target irradiation (40 kV,40 mA), using a D/texUltra detector at room temperature, scanning in the 2 theta range from 3 DEG to 45 DEG, scanning speed 20 DEG/min
Differential Scanning Calorimetry (DSC) analysis was performed on the co-crystals or salts of the examples, and the procedure and analysis steps were as follows: using TAQ2000 differential scanning calorimeter, using N 2 The temperature rise rate of the atmosphere was 10℃per minute, and in the differential scanning calorimetry, the abscissa represents the temperature (calorimeter, DEGC.) and the ordinate represents the heat flow rate (HeatFlow, W/g) per unit mass of the substance.
Thermogravimetric (TGA) analysis was performed on the co-crystals of the examples, operating and analytical steps as follows: using TAQ500 thermogravimetric analyzer, using N 2 The atmosphere and the temperature rise rate were 10℃per minute, and in the TGA, the abscissa represents the temperature and the ordinate represents the Weight%.
The eutectic in the examples was subjected to dissolution analysis, the procedure and analysis steps were as follows: adopts Agilent 1260 series high performance liquid chromatograph, column temperature: 25 ℃; sample injection amount: 5. mu L; detection wavelength: 210 nm; flow rate: 0.75 mL/min; the retention time of the dihydroxyoxaliplatin compound was 5.1 min; the retention time of oxaliplatin compound was 9.9 min, mobile phase gradient elution: phase A is water and phase B is methanol; elution procedure: 0 min-95% A/5% B;5 min-95% A/5% B;7 min-99% A/1% B;10 min-95% A/5% B;15 min-95% A/5% B.
In vitro cell proliferation and cytotoxicity method, firstly, human gastric cancer cell and gastric mucosa cell line are prepared into 5×10 concentration 4 Cell suspension per mL, 100 againμInoculating L cell suspension onto 96-well plate cell culture plate, taking culture medium (90% RPMI 1640 culture solution+10% foetal calf serum) as culture medium, and culturing at 37deg.C and 5% CO 2 Incubating the incubator overnight, adding dihydroxyoxalis with different concentrations into the cell suspensionPlatinum and dihydroxyoxaliplatin-hydroquinone cocrystals, three wells per concentration, medium was removed after 24 hours incubation, cell counting reagent solution (110 μl) was added to each well, after 1 hour incubation with cells, the optical density value per well (optical density at λ=450 nm, the optical density) was read using a microplate reader (Multiskan Spectrum), and cell proliferation rate was calculated according to the formula: cell proliferation rate (%) = optical density (experimental group)/optical density (control group) ×100, half inhibition concentration IC was calculated by fitting a nonlinear curve of concentration and cell proliferation rate using a prism scientific plotting tool 50 Values.
Single crystal X-ray diffraction (SCXRD) analysis in the examples, procedure and analytical steps were as follows: single crystal X-ray diffractometer (Bruker, karlsruhe, germany) was used in Cu-KαDiffraction data were collected using a CCD under radiation (λ=0.83 a), data integration and reduction was performed using APEX3 software, structure was resolved by a direct method using olax 2 software and refinement was performed by full matrix least squares using the SHELXL program.
The model of the polarized light microscope is DM750P, and the model of the heating device is XRN-350. The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiment, but a person having ordinary skill in the art will be able to follow the present disclosure.
Claims (7)
1. The dihydroxyoxaliplatin eutectic is characterized by comprising a eutectic formed by combining dihydroxyoxaliplatin and a eutectic formation, wherein the eutectic formation is hydroquinone, namely dihydroxyoxaliplatin and hydroquinone eutectic, and the dihydroxyoxaliplatin hydroquinone eutectic has characteristic peaks expressed in angle 2 theta in an X-ray powder diffraction spectrogram: 6.218,9.66, 11.498, 12.443, 14.943, 15.159, 16.398, 17.822, 18.361, 19.484, 19.66, 21.559, 23.103, 23.423, 23.961, 24.258, 24.86, 29.562, 29.923, 31.72, 31.917, 36.82, 39.021, 43.021, have an error margin of ±0.2°.
2. The bisoxaliplatin co-crystal according to claim 1, wherein a thermogravimetric analysis spectrum of the bisoxaliplatin and hydroquinone co-crystal shows that 6.9% of weight loss occurs at 25-75 ℃, and the co-crystal is a desolvation phenomenon.
3. The dihydroxyoxaliplatin co-crystal of claim 1, wherein a differential scanning calorimeter thermogram of the dihydroxyoxaliplatin and hydroquinone co-crystal is shown at T peak =98.3 ℃ has an endothermic peak, which is assigned to the desolvation endothermic peak.
4. The dihydroxyoxaliplatin eutectic according to claim 1, wherein a thermal state analysis spectrogram of the dihydroxyoxaliplatin and hydroquinone eutectic has no melting process at 100-175 ℃, which indicates that the dihydroxyoxaliplatin and hydroquinone eutectic gradually starts to decompose after desolvation.
5. The dihydroxyoxaliplatin co-crystal according to claim 1, wherein in the dihydroxyoxaliplatin and hydroquinone co-crystal, the dihydroxyoxaliplatin and hydroquinone are present in a 1:1 molar ratio.
6. The method for preparing a powder of a bishydroxy oxaliplatin co-crystal according to one of claims 1 to 5, characterized by the specific steps of: the dihydroxyoxaliplatin and equimolar eutectic formation are combined with 75μMixing the L water-acetonitrile mixed solvent in an agate grinding container; a powder sample of the co-crystal was prepared by grinding with a 12 mm agate ball for 45 min at 25 Hz frequency.
7. Use of a bishydroxy oxaliplatin co-crystal according to one of the claims 1 to 5, characterized in that: the eutectic formed by the dihydroxyoxaliplatin and hydroquinone is a pharmaceutically acceptable eutectic formed product for synthesis to prepare the eutectic, which is used for preparing antitumor drugs.
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