WO2019205909A1 - Eutectic crystal of temozolomide and baicalein and preparation method therefor - Google Patents

Abstract

An eutectic crystal of temozolomide and baicalein and a preparation method therefor. Specifically, the X-ray powder diffraction pattern of the eutectic crystal has characteristic peaks at 2theta values of 7.7 ± 0.2°, 8.6 ± 0.2°, and 12.7 ± 0.2°. Compared with the existing temozolomide and baicalein active pharmaceutical ingredients, the two drug components in the eutectic crystal have obvious advantages in terms of stability, solubility, pharmacokinetic properties and the like, being of great value for the future development of the combination of the two drugs.

Description

Eutectic of temozolomide and baicalein and preparation method thereof Technical field

The invention relates to the field of chemical medicine, in particular to a eutectic of temozolomide and baicalein and a preparation method thereof.

Background technique

Temozolomide (TMZ) is an alkylating agent antitumor drug containing an imidazolium ring, chemical name 3,4-dihydro-3-methyl-4-oxoimidazole [5,1-d] And 1,2,3,5-tetrazine-8-carboxamide, the chemical structural formula is:

Temozolomide is a prodrug and is not active by itself. It is converted to the active compound MITC (5-(3-methyltriazol-1-yl)imidazole-4-amide) by a non-enzymatic pathway at physiological pH. Further hydrolysis to AIC (5-amino-imidazole-4-amide) and methyldiazolium, followed by methyldiazonium methylation by methylation of DNA at the O6 and N7 sites on guanine, making it impossible to interact with the thymus Pyrimidine pairing produces cytotoxicity and exerts antitumor activity. The drug can pass the blood-brain barrier, so it has a good effect on brain tumors, and has obvious effects on leukemia, melanoma, lymphoma and solid tumor.

The drug was approved by the European Medicines Agency (EMEA) on January 20, 1999. The approved indication is a glioblastoma multiforme (brain cancer) with normal development or recurrence after routine treatment; 1999 8 Approved by the US Food and Drug Administration (FDA) on the 11th, the indications were glioblastoma multiforme and degenerative astrocytoma. Oral capsules are commonly used in clinical practice. After oral administration, the absorption is rapid and the bioavailability is high. The pharmacokinetics shows that the blood concentration reaches a peak within 1 hour, and then disappears rapidly. The average half-life is 1.7-1.8 hours, which is difficult to maintain effectively in the lesion. Drug concentration. In order to ensure the safety and efficacy of temozolomide, there is an urgent need to improve its stability and prolong its oral half-life.

The chemical name of baicalein is 5,6,7-trihydroxyflavone, and its chemical structural formula is:

Baicalein is a flavonoid in the scutellariae of the Labiatae family. It has a variety of pharmacological effects, such as anti-oxidation, scavenging free radicals, anti-inflammatory, anti-viral, anti-allergic, etc., also on the cerebral blood vessels, kidneys, liver, nervous system. Both have a protective effect. In addition, baicalein has a broad spectrum of anti-tumor activity and has a significant inhibitory effect on various tumors including lung cancer, ovarian cancer, liver cancer, and breast cancer. Recent studies have shown that baicalein can inhibit the proliferation of mouse glioma by inhibiting the expression of HIF-1α, VEGF and VEGFR2 in U87 glioma, inhibiting cell proliferation, inducing apoptosis and arresting cell cycle. Extend its survival (F. Wang and Y. Jiang, J. Neurooncol., 2015, 124, 5-11).

The baicalein compound is yellow needle crystal, soluble in methanol, ethanol, acetone, ethyl acetate and hot glacial acetic acid, and slightly soluble in chloroform. Baicalein is insoluble in water and has poor hydrophilicity, so it is difficult to be absorbed by the digestive tract mucosa, and oral absorption is poor, which greatly limits its clinical application. At present, it is mainly used for antibacterial, anti-inflammatory and anti-infection in China, and there is no preparation of baicalein in foreign countries.

Co-crystallization of drugs means that the drug molecules are combined with other physiologically acceptable acids, bases, salts and non-ionic compounds in the same lattice by hydrogen bonding, π-π stacking, van der Waals force and other non-covalent bonds. Crystal. The formation of eutectic can change the physical and chemical properties of the drug, including stability, solubility and bioavailability, without destroying the covalent bond of the drug. In addition, after the formation of eutectic, it is also possible to change the pharmacokinetic parameters of some drugs, such as C _max (peak peak concentration), T _max (peak time), t _1/2 (elimination of half-life) and AUC (blood drug). Area under concentration-time curve), etc. (AHSmith, P. Kavuru, KK Arora, S. Kesani, J. Tan, MJ Zaworotko, RDShytle, Mol Pharmaceutics, 2013, 10(8), 2948-2961). When the two drugs form a eutectic, the purpose of the combination can be achieved while improving the physical and chemical properties and pharmacokinetic parameters of both (R.Thipparaboina, D.Kumar, RB Chavan, NR Shastri, Drug Discov. Today, 2016, 21, 481 -490).

So far, patent WO 2011/036676 reports the co-crystals of temozolomide and oxalic acid, succinic acid, salicylic acid, anthranilic acid, D,L-malic acid, D,L-tartaric acid, and the stability is compared with the temozolomide bulk drug. Significantly improved, and the half-life of temozolomide in the eutectic under physiological conditions is also significantly prolonged. Co-crystals of temozolomide with nicotinamide, isonicotinic acid, saccharin, caffeine, pyrazinamide, p-hydroxybenzamide have also been reported in the literature (P. Sanphui, NJ Babu, A. Nangia, Cryst. Growth Des., 2013). , 13(5), 2208-2219). Patent CN103848803A relates to a eutectic of baicalein and nicotinamide, which has a solubility about 2 times higher than that of baicale itself. Patent CN105218500A discloses a eutectic formed by baicalein and caffeine, and its maximum dissolution concentration is more than three times that of baicalein drug substance, and the oral bioavailability of rats is increased by four times. In addition, eutectic of baicalein with isoniazid, nicotinamide and theophylline has been reported in the literature (B.Zhu, Q.Zhang, J.Wang, X.Mei, Cryst.Growth Des., 2017,17(4) ), 1893-1901). At present, there have been no reports on the co-crystal formation of two active pharmaceutical ingredients, temozolomide and baicalein.

Summary of the invention

In order to solve the above problems, the present invention has discovered a eutectic of temozolomide and baicalein, on the one hand, which can improve the stability, solubility and pharmacokinetic properties of the two drugs; on the other hand, it can be combined with temozolomide and Baicalein is used in the treatment of cancer, especially glioma.

It is an object of the present invention to provide temozolomide-xanthocin co-crystals and methods for their preparation and use.

The technical solution adopted by the present invention is:

a eutectic of temozolomide and baicalein having a eutectic structural formula as shown in formula (I), comprising temozolomide and baicalein in a molar ratio of 1:1;

Further, the X-ray powder diffraction pattern of the eutectic measured by CuKα ray has a characteristic peak at 2θ values of 7.7±0.2°, 8.6±0.2°, and 12.7±0.2°.

Further, the X-ray powder diffraction pattern of the eutectic described above has a characteristic peak at one or more of the 2θ values of 18.4±0.2°, 26.9±0.2°, and 27.6±0.2°.

Further, the X-ray powder diffraction pattern of the eutectic described above has a characteristic peak at one or more of 2θ values of 10.7±0.2°, 15.4±0.2°, 21.5±0.2°, and 22.6±0.2°.

Further, the X-ray powder diffraction pattern of the eutectic described above is also at a 2θ value of 18.4±0.2°, 26.9±0.2°, 27.6±0.2°, 10.7±0.2°, 15.4±0.2°, 21.5±0.2°, 22.6. There are characteristic peaks at ±0.2°.

Further, the above-mentioned eutectic exhibits an exothermic peak when heated to 192 to 202 °C.

Further, the above-mentioned eutectic starts to decompose when heated to about 180 ° C, and there is no weight loss before this temperature.

Providing a eutectic single crystal of mozolamide and baicalein, the eutectic single crystal is monoclinic, and the space group is P2 ₁ /c, unit cell parameters

α = 90°, β = 99.2 ± 0.2°, γ = 90°. In a specific embodiment, the unit cell parameter is

α = 90°, β = 99.157°, γ = 90°.

Further, the asymmetric structural unit of the eutectic single crystal comprises a temozolomide molecule, a baicalein molecule; the crystal unit cell comprises four temozolomide molecules, and four baicalein molecules.

A method for preparing a eutectic of temozolomide and baicalein, comprising temozolomide and baicalein in a molar ratio of 1:0.9 to 1.1 in water, alcohols, esters, ketones, ethers, alkylnitrile Mixing in one or more solvent systems, and decomposing by stirring to obtain a solid is temozolomide and baicalein cocrystal.

Further, the alcohol solvent is at least one of methanol and ethanol; the ester solvent is methyl acetate; the ketone solvent is acetone; and the ether solvent is methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane. At least one of the rings; the alkyl nitrile solvent is acetonitrile.

Further, the solvent system is selected from one or more of water, methanol, ethanol, methyl acetate, acetone, and acetonitrile.

Further, the stirring temperature is 0 to 50 °C.

Further, the ratio of the feed quality of the mixture of temozolomide and baicalein to the solvent system is 10 to 50 mg/mL.

A pharmaceutical composition comprising the above-described co-crystals of temozolomide and baicalein and a pharmaceutically acceptable excipient.

The use of the eutectic of temozolomide and baicalein described above for the preparation of a pharmaceutical preparation for treating cancer.

The beneficial effects of the invention are:

The invention provides the eutectic of temozolomide and baicalein for the first time, and the preparation method thereof is simple in operation, the crystallization process is easy to control, and the reproducibility is good. The formation of eutectic can significantly improve the stability and oral half-life of temozolomide, and improve the water solubility and oral bioavailability of baicalein, which has a strong practical application value.

DRAWINGS

Figure 1 is an X-ray powder diffraction (XRPD) pattern of temozolomide-xanthocin co-crystal;

Figure 2 is a differential scanning calorimetry (DSC) analysis chart of temozolomide-xanthocin co-crystal;

Figure 3 is a graph showing the thermogravimetric analysis (TG) of temozolomide-xanthocin co-crystal;

Figure 4 is a nuclear magnetic ( ¹ H NMR) diagram of temozolomide-xanthocin co-crystal;

Figure 5 is a schematic diagram of an asymmetric unit of temozolomide-xanthocin co-crystal;

Figure 6 is a schematic diagram of a unit cell of temozolomide-xanthocin co-crystal;

Figure 7 is a graph showing changes in the content of temozolomide and temozolomide-xanthophyll co-crystals at 40 ° C / 75% RH for 3 months;

Figure 8 is a powder dissolution profile of temozolomide, baicalein and temozolomide-xanthophyll cocrystal.

detailed description

The technical concept and the features of the present invention will be further clarified by the specific embodiments, which are intended to enable those skilled in the art to understand the present invention and to implement the present invention. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention. The scope of the invention is to be determined by the appended claims.

Example 1

1.94 g of temozolomide and 2.70 g of baicalein were weighed and added to 150 ml of methanol to obtain a suspension. The suspension was stirred at room temperature for 21 h, and filtered, and the obtained yellow solid was dried to obtain a solid sample of temozolomide-xanthin cocrystal.

Example 2

19.48 mg of temozolomide and 27.12 mg of baicalein were weighed, and a suspension was added to 2 mL of distilled water. The suspension was stirred at room temperature for 24 hours, and the yellow solid was removed by centrifugation, and dried to obtain a solid sample of temozolomide-xanthin cocrystal.

Example 3

19.84 mg of temozolomide and 27.95 mg of baicalein were weighed, and a suspension of 1 mL of methanol and 1 mL of distilled water was added to obtain a suspension, and the suspension was stirred at room temperature for 4 hours, and filtered, and the obtained yellow solid was dried to obtain temozolomide-xanthin. Crystal solid sample.

Example 4

20.37 mg of temozolomide and 28.11 mg of baicalein were weighed and added to 2 mL of ethanol to obtain a suspension. The suspension was stirred at 50 ° C for 18 hours, and filtered, and the obtained yellow solid was dried to obtain a solid sample of temozolomide-xanthocin cocrystal. .

Example 5

20.02 mg of temozolomide and 27.60 mg of baicalein were weighed, and 2 mL of acetonitrile was added to obtain a suspension. The suspension was stirred at room temperature for 18 hours, and filtered, and the obtained yellow solid was dried to obtain a solid sample of temozolomide-xanthin cocrystal.

Example 6

19.58 mg of temozolomide and 27.41 mg of baicalein were weighed and added to 2 mL of acetone to obtain a suspension. The suspension was stirred at 50 ° C for 16 h, filtered, and the obtained yellow solid was dried to obtain a solid sample of temozolomide-xanthocin cocrystal. .

Example 7

19.76 mg of temozolomide and 27.48 mg of baicalein were weighed, and 2 mL of methyl acetate was added to obtain a suspension. The suspension was stirred at 50 ° C for 18 hours, and filtered, and the obtained yellow solid was dried to obtain temozolomide-xanthocin cocrystal. Solid sample.

Example 8

22.64 mg of temozolomide and 27.32 mg of baicalein were weighed, and a mixed solvent of 1 mL of acetone and 1 mL of distilled water was added to obtain a suspension, and the suspension was stirred at room temperature for 4 hours, and filtered, and the obtained yellow solid was dried to obtain temozolomide-xanthocin cocrystal. Solid sample.

Example 9

19.40 mg of temozolomide and 26.95 mg of baicalein were weighed, and a suspension of 1 mL of acetonitrile and 1 mL of distilled water was added to obtain a suspension, and the suspension was stirred at room temperature for 4 hours, and filtered, and the obtained yellow solid was dried to obtain temozolomide-xanthin. Crystal solid sample.

Example 10

19.24 mg of temozolomide and 26.62 mg of baicalein were weighed, and a suspension of 1 mL of methyl acetate and 1 mL of distilled water was added to obtain a suspension. The suspension was stirred at room temperature for 4 hours, and filtered, and the obtained yellow solid was dried to give temozolomide-xanthine. A solid sample of eutectic.

The temozolomide-xanthine cocrystal provided by the invention is characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and nuclear magnetic resonance spectroscopy (NMR).

The solid sample of the temozolomide-xanthoquine eutectic prepared in Example 1 was subjected to X-ray powder diffraction analysis using a Bruker D2 PHASER type diffractometer of Bruker Instruments Co., Ltd., CuKα ray, voltage of 30 kV, current of 10 m. Ann, step length 0.01 °, scanning speed 6 ° / min, scanning range 5.0 ~ 60 °, test temperature is room temperature. The analysis results are shown in Fig. 1, and the X-ray powder diffraction data are shown in Table 1.

Table 1 X-ray powder diffraction results of temozolomide-xanthocin co-crystal of the present invention

It is well known to those skilled in the art that crystalline materials including eutectics can be characterized by X-ray diffraction techniques, but X-ray diffraction patterns typically vary with the instrument's test conditions. It is particularly pointed out that the relative intensity of the X-ray diffraction pattern may vary with experimental conditions, so the relative intensity order of the X-ray diffraction peaks cannot be the sole or decisive factor for eutectic characterization. In addition, the peak angle typically allows for an error of ±0.2°. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of the eutectic according to the present invention need not be identical to the X-ray diffraction pattern in this embodiment. Anything having the same or similar characteristics as the characteristic peaks in this map is within the scope of the present invention. Those skilled in the art will be able to compare the maps listed herein with an unknown eutectic map to verify whether the two sets of spectra reflect the same or different eutectic.

The solid sample of the temozolomide-xanthoquinone eutectic prepared in Example 1 was subjected to differential scanning calorimetry, which was detected by a DSC 200 F3 differential calorimeter from the German Benz Scientific Instrument Co., Ltd., and the atmosphere was nitrogen gas, and the heating rate was increased. It is 10 ° C / min. The analysis results are shown in Figure 2. The DSC curve shows that the temozolomide-xanthine cocrystal has an exothermic peak when heated to about 192-202 °C.

The solid sample of the temozolomide-xanthoquinone eutectic prepared in Example 1 was subjected to thermogravimetric analysis using a thermogravimetric analyzer of the German TG Scientific Model TG 209 F3 type, the atmosphere was nitrogen, and the heating rate was 10 ° C / min. . The analysis results are shown in Figure 3. The TG curve shows that the temozolomide-xanthocin eutectic is heated to around 180 ° C to begin decomposition, and there is no weight loss before this temperature.

The temozolomide-xanthine eutectic sample prepared in Example 1 was subjected to nuclear magnetic resonance spectrum analysis, which was detected at room temperature using an Avance III 400M nuclear magnetic resonance spectrometer from Bruker, Germany. The results of the analysis are shown in Fig. 4, wherein the peak of temozolomide is: ¹ H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 3.87 (s, 3H); The peak of baicalein is: ¹ H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 10.57 (s, 1H), 8.82 (s, 1H), 8.06 (d, J = 6.8 Hz, 2H) ), 7.64 - 7.51 (m, 3H), 6.94 (s, 1H), 6.63 (s, 1H). According to the integration results of the respective peaks, the stoichiometric ratio of temozolomide and baicalein in the eutectic molecule was 1:1.

Example 11

Study on the molar ratio of temozolomide to baicalein in eutectic

The molar ratio of temozolomide to baicalein in the eutectic was determined by high performance liquid chromatography in which the sample was dissolved in acetonitrile. The results showed that the molar ratio of temozolomide to baicalein in the eutectic was 1:1, as shown in Table 2.

Table 2 Molar ratio of temozolomide to baicalein in the eutectic of the invention

Compound	Temozolomide-xanthocin co-crystal
Temozolomide concentration (mmol/L)	0.440
Baicalein concentration (mmol/L)	0.448
The molar ratio of	1:1

Example 12

Single crystal study of temozolomide-xanthocin eutectic:

2 mL of methyl ethyl ketone was added, and the eutectic sample prepared in Example 1 was added to a supersaturated state, filtered through a 0.22 μm filter, and then left at room temperature, and slowly evaporated for about 2 weeks to obtain yellow transparent rod crystals.

X-ray single crystal diffractometer model: Agilent Xcalibur Nova

wavelength:

Test temperature: 100K

Computer program for structural analysis: Olex2

Experimental formula: C ₂₁ H ₁₆ N ₆ O ₇

Molecular weight: 464.40

Crystal system: monoclinic system

Space group: P2 ₁ /c

Cell parameters:

α=90°

β=99.157(2)°

γ=90°

Unit cell volume:

Z (the number of experimental formulas contained in the unit cell): 4

Calculated density: 1.551g/cm ³

Structural Description: Single crystal diffraction and structural analysis indicate that the asymmetric structural unit of the crystal contains a temozolomide molecule, a baicalein molecule. The unit cell of the crystal contains four temozolomide molecules, four baicale molecules, the schematic diagram of the asymmetric structural unit is shown in FIG. 5, and the unit cell diagram is shown in FIG.

Example 13

Comparative study on the stability of temozolomide-xanthocin eutectic and temozolomide bulk drug

Accelerated stability test: a certain amount of temozolomide bulk drug and temozolomide-xanthophyll were co-crystallized in a 10 mL small beaker, and the open place was placed under constant temperature and humidity conditions of 40 ° C / 75% RH. The content of temozolomide was determined by high performance liquid chromatography at the end of month at 0, 1, 2, and 3 months.

The experimental results are shown in Figure 7. The drug content of temozolomide bulk drug decreased sharply with time. At the end of 1 month, the drug content at the end of 2 months and 3 months decreased to 96.62%±2.36%, 84.54%±3.33% and decreased to 15.95%±0.84%. In contrast, the content of temozolomide in the eutectic showed only a slight decrease, still 96.78% ± 4.94% by the end of 3 months. It can be seen that the stability of the temozolomide-xanthine cocrystal is better than that of the temozolomide bulk drug.

Example 14

Comparative study on powder dissolution curves of temozolomide-xanthocin eutectic with temozolomide and baicalein

Test sample source: temozolomide-xanthocin co-crystal was prepared by the method provided by the present invention; temozolomide bulk drug was purchased from Shanghai Shengde Medical Technology Co., Ltd., purity 98%; baicalein bulk drug was purchased from Shanghai Shengde Medical Technology Co., Ltd. The purity is 98%.

Experimental method: temozolomide-xanthocin eutectic and temozolomide and baicalein raw materials were ground and passed through a 100 mesh sieve, and 500 mg of temozolomide, 135 mg of baicalein and 232 mg of temozolomide-xanthoquine cocrystal were weighed and added to 50 mL of dissolution medium. 1 mL of the solution was taken at intervals of time, filtered through a 0.22 μm microporous membrane, and diluted to an appropriate multiple. The concentration of the solution at each time point was monitored by high performance liquid chromatography to finally obtain a powder dissolution curve of the eutectic and the one-component bulk drug.

Dissolution conditions:

Dissolution medium: hydrochloric acid solution of pH 1.2

Stirring speed: 100 rpm

Dissolution temperature: 37 ± 0.5 ° C

Sampling time: 0.17, 0.5, 1, 3, 5, 10, 20, 30, 60 minutes

Liquid phase conditions:

Instrument: Shimadzu LC-20A

Column: Inertsil ODS-3 (4.6mm × 150mm, 5μm)

UV detection wavelength: temozolomide 329nm, baicalein 276nm

Mobile phase: methanol: pH 2.4 phosphoric acid solution = 40:60

Column temperature: 30 ° C

Flow rate: 0.4mL/min

The experimental results are shown in Figure 8. The temozolomide in the eutectic provided by the invention has a slower dissolution rate compared to the temozolomide bulk drug, and the maximum dissolution concentration in one hour is 0.78±0.01 mg/mL, which is reduced to about 1/10 of the temozolomide bulk drug; and the eutectic The baicalein has a faster dissolution rate than the baicalein drug substance, and it dissolves rapidly in 1 minute, and the maximum dissolution concentration reaches 579.23±57.24 μg/mL, which is more than 25 times that of the baicalein drug substance.

Example 15

Pharmacokinetics of temozolomide single component, baicalein single component and temozolomide-xanthoquine co-crystal in vivo

The pharmacokinetics of temozolomide monocomponent (group A), baicalein single component (group B) and temozolomide-scutellarin co-crystal (group C) were studied in rats. SD rats of standard body weight (about 200 g) were selected as test subjects, and 5 rats in each group were intragastrically administered. The dose in group A was 43.78 mg/kg, the dose in group B was 60.50 mg/kg, and the dose in group C was 103.78 mg/kg (by molecular weight conversion, the doses of temozolomide and baicalein were respectively 43.78 mg/kg, 60.50 mg/kg. ). Rats' iliac vein blood was taken at different time points after administration, and the contents of temozolomide and baicalein were measured. The obtained pharmacokinetic parameters are shown in Table 3.

Table 3 Table of pharmacokinetic parameters in different experimental groups

	C max (μg·mL -1 )	T max (h)	t 1/2 (h)	AUC 0→∞ (μg·h·mL -1 )
Temozolomide (A)	21.13±3.05	0.80±0.21	9.57±1.08	216.33±33.04
Temozolomide in eutectic (C)	6.42±1.90	2.35±1.54	24.64±8.33	208.15±35.01

Baicalein (B)	-	-	-	-
Baicalein in eutectic (C)	13.90±2.90	0.55±0.11	2.56±0.37	24.18±3.77

- not detected

The results showed that under the condition that the doses of the components were basically the same, the area under the curve of temozolomide (AUC _0→∞ ) group A was 216.33±33.04 μg·h·mL ^-1 , and the group C was 208.15±35.01 μg. · h·mL ^-1 , elimination half-life (t _1/2 ) was 9.57±1.08h in group A and 24.64±8.33h in group C, indicating that the exposure of temozolomide in eutectic was comparable to that of temozolomide alone, but the oral half-life was prolonged. 2.6 times; the blood concentration of baicalein alone was too low, which exceeded the detection range of HPLC, and the exposure of baicalein was significantly increased after group C eutectic administration, and AUC _0→∞ reached 24.18±3.77 μg·h. ·mL ^-1 .

In summary, it can be concluded that after the eutectic administration of temozolomide and baicalein, the oral half-life of temozolomide can be prolonged to some extent, and the bioavailability of baicalein can be improved.

The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and combinations thereof may be made without departing from the spirit and scope of the invention. Simplifications should all be equivalent replacements and are included in the scope of the present invention.

Claims (10)

1. A eutectic of temozolomide and baicalein, characterized in that the eutectic structure is as shown in formula (I):

   

   Temozolomide and baicalein in a molar ratio of 1:1 are included.
2. The eutectic according to claim 1, wherein said eutectic has an X-ray powder diffraction pattern measured by Cu Kα ray at a value of 2θ of 7.7±0.2°, 8.6±0.2°, and 12.7±0.2°. Has a characteristic peak.
3. The eutectic according to claim 2, wherein said eutectic X-ray powder diffraction pattern is further at a 2θ value of 18.4±0.2°, 26.9±0.2°, 27.6±0.2°, 10.7±0.2°, One or more of 15.4±0.2°, 21.5±0.2°, and 22.6±0.2° have characteristic peaks.
4. A eutectic single crystal of temozolomide and baicalein, characterized in that the eutectic is a eutectic according to any one of claims 1 to 3, wherein the eutectic single crystal is monoclinic, and the space group is P2 ₁ / c, the unit cell parameter is

   

   

   α = 90°, β = 99.2 ± 0.2°, γ = 90°.
5. The eutectic single crystal of temozolomide and baicalein according to claim 4, wherein the unit cell parameter of the eutectic single crystal is

   

   α = 90°, β = 99.157°, γ = 90°.
6. The method for preparing temozolomide and baicalein cocrystal according to any one of claims 1 to 5, wherein temozolomide and baicalein in a molar ratio of 1:0.9 to 1.1 are in water, alcohols, esters, and ketones. Mixing one or more solvent systems in the class of ethers, ethers, and alkylnitrile, and decomposing by stirring to obtain a solid which is temozolomide and baicalein cocrystal.
7. The preparation method according to claim 6, wherein the alcohol solvent is at least one of methanol and ethanol; the ester solvent is methyl acetate; the ketone solvent is acetone; and the ether solvent is methyl t-butyl. At least one of ether, tetrahydrofuran, and 1,4-dioxane; the alkyl nitrile solvent is acetonitrile.
8. The method for producing a eutectic single crystal of temozolomide and baicalein according to any one of claims 4 to 5, wherein the temozolomide and the baicalein cocrystal prepared according to any one of claims 6 to 7 are added to methyl ethyl ketone to In a state of supersaturation, filtration, the filtrate is naturally volatilized to obtain a yellow transparent rod-like crystal, that is, a eutectic single crystal of temozolomide and baicalein.
9. A pharmaceutical composition comprising the eutectic according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.
10. Use of the co-crystal of temozolomide and baicalein according to any one of claims 1 to 3 for the preparation of a pharmaceutical preparation for treating cancer.

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