CN118406058A - A drug co-crystal of temozolomide-ferulic acid and preparation method thereof - Google Patents

Abstract

The invention relates to the technical field of pharmaceutical co-crystals, in particular to a pharmaceutical co-crystal of temozolomide-ferulic acid and a preparation method thereof, wherein the molecular formula of the pharmaceutical co-crystal of temozolomide and ferulic acid is C ₁₈H₁₉N₇O₆, the crystal structure belongs to a monoclinic system, the space group is P2 (1)/C, and the unit cell parameter is Α=90°, β= 105.216 (5) °, γ=90°, unit cell volumeMinimum asymmetric unit number z=8 in the unit cell. The pharmaceutical co-crystal of temozolomide and ferulic acid prepared by the invention can effectively improve the solubility of single raw material medicines of temozolomide and ferulic acid, and simultaneously provides a new possibility for combined administration. The preparation method of the pharmaceutical co-crystal of temozolomide and ferulic acid is simple and is easy for industrial development and production.

Description

A drug co-crystal of temozolomide-ferulic acid and preparation method thereof

Technical Field

The present invention relates to the technical field of drug co-crystals, and in particular to a drug co-crystal of temozolomide-ferulic acid and a preparation method thereof.

Background technique

Temozolomide (TMZ) is an oral alkylating agent used to treat malignant gliomas. The drug is completely absorbed orally, with a bioavailability of nearly 100%. It shows broad-spectrum activity in mouse tumor models and can penetrate the human blood-brain barrier. The cytotoxic effect of temozolomide stems from its strong methylation effect on DNA bases. Under alkaline conditions, temozolomide can rapidly break to generate active methyldiazonium ions. Since brain tumors are more alkaline than surrounding tissues, the activation of the drug can be relatively concentrated at the tumor site, with strong anti-tumor effects and certain selectivity, improved side effect spectrum, less bone marrow toxicity, and improved patient tolerance. However, it has the disadvantages of short oral biological half-life, poor solubility, stability and tableting properties, which limit its clinical efficacy. TMZ is a prodrug that can be spontaneously hydrolyzed under physiological conditions to form the active compound 5-(3-methyl-1-triazine)imidazole-4-hydroxylamine (MTIC). MTIC is further decomposed into 5-aminoimidazole 4-hydroxylamine (AIC) and methyldiazonium cation (CH ₃ N ₂ ⁺ ), the latter of which is an active alkylating substance that can exert anti-tumor effects through DNA methylation. Currently, TMZ is a first-line chemotherapy drug. However, the rapid elimination after oral administration limits the clinical application of TMZ.

Ferulic acid (FEA) is a phenolic antioxidant naturally found in plants. It has anti-inflammatory, analgesic, anti-radiation, and immunity-enhancing effects. It also has anti-asthmatic properties and has protective effects on the liver and nerves. Ferulic acid is commonly found in Chinese medicinal materials such as propolis, angelica, spiny jujube seeds, and Chuanxiong, but the poor solubility of ferulic acid limits its clinical application.

Pharmaceutical cocrystals are crystals formed by combining active pharmaceutical ingredients and suitable cocrystal reagents through the action of amino bonds or other non-covalent bonds by applying crystal engineering, pharmaceutical science, supramolecular chemistry principles and self-assembly principles. As a new drug crystal form, pharmaceutical cocrystals can introduce new components without affecting the internal structure of the drug, greatly improving the physical and chemical properties of the drug and improving clinical efficacy. It can not only ensure the solubility of the drug, but also greatly change other aspects such as melting point, stability, dissolution rate, etc.

Summary of the invention

The purpose of the present invention is to solve the shortcomings of the prior art and to propose a temozolomide-ferulic acid drug co-crystal and a preparation method thereof. The prepared temozolomide-ferulic acid drug co-crystal has good solubility compared with the raw material drug, and at the same time plays a synergistic effect, prolongs the oral biological half-life, and enhances intestinal absorption.

In order to achieve the above object, the present invention adopts the following technical solutions:

A temozolomide-ferulic acid drug co-crystal, wherein the molecular formula of the temozolomide-ferulic acid drug co-crystal is C ₆ H ₆ N ₆ O ₂ ·C ₁₀ H ₁₀ O ₄ ·CH ₃ CN, the crystal structure belongs to the monoclinic system, the space group is P2(1)/c, and the unit cell parameters are α=90°, β=105.216(5)°, γ=90°, unit cell volume The minimum number of asymmetric units in the unit cell is Z = 8, and the crystal density is 1.358 g/cm ³ ;

The temozolomide-ferulic acid drug co-crystal has characteristic diffraction peaks at 6.38°, 11.06°, 11.53°, 12.96°, 16.38°, 17.81°, 20.85°, 21.33°, 23.70°, and 26.93° in the 2θ angle of the powder X-ray diffraction pattern measured by Cu/Kα ray after grinding;

The temozolomide-ferulic acid drug co-crystal has characteristic absorption peaks at 3644cm ^-1 , 3466cm ^-1 , 3429cm ^-1 , 3371cm -1 , 3214cm ^-1 , 3097cm ^-1 , 1739cm ^-1 , 1680cm ^-1 , 1592cm ^-1 , and 1514cm ^-1 in its infrared absorption spectrum measured by ^a Thermo Scientific infrared spectrometer;

The temozolomide-ferulic acid drug co-crystal has a DSC curve measured by a differential scanning calorimeter, and has an endothermic peak and an exothermic peak within 110-190° C., the peak value of the endothermic peak is 128.6° C., and the peak value of the exothermic peak is 177.1° C.;

The drug co-crystal of temozolomide-ferulic acid is a crystalline powder.

Preferably, the bulk density of the crystalline powder is 0.30 to 0.34 g/cm ³ .

Preferably, the tap density of the crystalline powder is 0.68 to 0.74 g/cm ³ .

A method for preparing a temozolomide-ferulic acid drug co-crystal comprises the steps of mixing a mixed powder of temozolomide and ferulic acid with an acetonitrile solution, dissolving the mixture by ultrasonication, and obtaining a temozolomide-ferulic acid mixed solution; and volatilizing and crystallizing the temozolomide-ferulic acid mixed solution to obtain the temozolomide-ferulic acid drug co-crystal.

Preferably, the molar ratio of temozolomide to ferulic acid is 1:1; the mass volume ratio of the mixed powder of temozolomide and ferulic acid to acetonitrile is 0.2-2mmol:10-50mL; the mass volume ratio of the mixed powder of temozolomide and ferulic acid to acetonitrile is preferably 0.4mmol:15mL.

Preferably, the ultrasonic dissolution has an ultrasonic time of 20-60 min, an ultrasonic temperature of 20-30° C., and a frequency of 30-50 Hz; preferably, the ultrasonic time is 40 min, the ultrasonic temperature is 25° C., and the ultrasonic power is 40 Hz.

Preferably, the crystallization temperature of the volatile crystallization is 23-33° C., and the crystallization time is 1-2 weeks; preferably, the crystallization temperature is 28° C., and the crystallization time is 1 week.

The temozolomide-ferulic acid drug co-crystal obtained by the above preparation method is a yellow transparent block crystal.

The present invention also provides the use of the above-mentioned temozolomide-ferulic acid drug co-crystal in the preparation of anti-tumor drugs.

Preferably, the tumor is a malignant glioma or a malignant melanoma.

It should be noted that the above-mentioned bulk density and tap density are quantities related to the properties of the powder. In general, high bulk density and tap density values are desired. Bulk density refers to the weight of a unit volume of powder under predetermined conditions, expressed as the weight per unit volume, usually in g/cm ^3. Tap density also indicates the weight of a unit volume of powder, in a holder of the powder, subjected to slapping or vibration under predetermined conditions. Therefore, for the same powder, its tap density is higher than the bulk density.

Crystals with high bulk density and tap density tend to have a larger specific gravity, which reflects that the crystal product is relatively thick and has a better texture, and its stability is also relatively good. From another perspective, products with high bulk density generally have better fluidity of particles and are also easy to store and transport.

Among them, the measurement methods of the bulk density and tap density of the crystal powder are as follows:

The bulk density of the granules was determined according to USP Method II (page 1914);

The tap density of the particles is measured according to GB/T5162-2006 by a FZS4-4 economical tap density meter. Specifically, the test conditions are: the vibration stroke of the beating device is 3±0.1MM, and the vibration frequency is 250±15 times per minute.

In addition, the present invention also provides a pharmaceutical composition, which comprises the above-mentioned temozolomide-ferulic acid pharmaceutical cocrystal and pharmaceutically acceptable conventional pharmaceutical excipients; and the use of the above-mentioned temozolomide-ferulic acid pharmaceutical cocrystal or the above-mentioned pharmaceutical composition in the preparation of anti-tumor drugs is also within the protection scope of the present invention.

Compared with the prior art, the present invention has the following beneficial effects:

1. The drug cocrystal of temozolomide and ferulic acid prepared by the present invention can effectively improve the solubility of single raw material drugs of temozolomide and ferulic acid.

2. The drug co-crystal of temozolomide and ferulic acid prepared by the present invention provides a new possibility for combined drug use.

3. The preparation method of the pharmaceutical cocrystal of temozolomide and ferulic acid prepared by the present invention is simple and easy to be industrially developed and produced.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a crystal cell stacking diagram of the drug co-crystal of temozolomide-ferulic acid in Example 1 of the present invention;

FIG2 is an X-ray diffraction diagram of temozolomide, ferulic acid and temozolomide-ferulic acid co-crystal in the present invention;

FIG3 is an infrared spectra of temozolomide, ferulic acid and the drug co-crystal of temozolomide-ferulic acid in the present invention and Example 1;

FIG4 is a thermogravimetric-differential scanning calorimetry (TGA-DSC) analysis diagram of temozolomide, ferulic acid and the drug co-crystal of temozolomide-ferulic acid in the present invention and Example 1;

FIG5 is the ¹ HNMR of temozolomide, ferulic acid and the drug co-crystal of temozolomide-ferulic acid in the present invention and Example 1;

FIG6 is an optical microscope image of the drug co-crystal of temozolomide-ferulic acid in Example 1 of the present invention;

FIG. 7 is a solubility test graph of the drug co-crystal of temozolomide-ferulic acid in Example 1 of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the accompanying drawings, so that those skilled in the art can better understand the advantages and features of the present invention, thereby making a clearer definition of the protection scope of the present invention. The embodiments described in the present invention are only a part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work are within the scope of protection of the present invention.

1. Reagents

The temozolomide raw material used in the embodiment of the present invention was purchased from Shanghai MacLean Biochemical Technology Co., Ltd. with a purity of 99%. The powder X-ray diffraction spectrum of the temozolomide raw material is shown in FIG. 2 .

The ferulic acid raw material used in the embodiment of the present invention was purchased from Nanjing Caozhiyuan Biotechnology Co., Ltd. with a purity of 98%. The powder X-ray diffraction spectrum of the ferulic acid raw material is shown in FIG2 .

2. Experimental methods

Single crystal X-ray diffraction to determine the crystal structure: The cultured single crystal was cut into blocks of about 0.10×0.20×0.30 ^mm3 and subjected to a Bruker APEX-IICCD diffractometer with a Mo/Kα radiation source (graphite monochromator, ) was used to irradiate the sample and collect diffraction data. The diffraction data were reduced by SAINT and then directly analyzed by SHELXTL software. The structure was refined based on the full-matrix least-squares method of F2, and all non-hydrogen atoms were refined by anisotropic refinement.

Powder X-ray diffraction: About 0.1 g of the ground sample was taken and the diffraction data were collected at room temperature using a powder X-ray diffractometer (Bruker D8Advance) with Cu/Kα ray as the light source. The scanning step was 0.02°, the scanning voltage was set to 40 kV, the current was 40 mA, the scanning rate was 0.2 s/0.02°, the scanning range 2θ was 5-35°, the data were processed by Jade software, and the graphs were drawn using Origin.

Fourier transform infrared spectroscopy: 20 mg of the crystalline powder was taken and infrared absorption spectrum data were collected at room temperature using a Fourier transform infrared spectrometer (Thermo Scientific, USA), spectral range: 4000-400 cm ^-1 , resolution: 0.1, linearity: 0.1%T.

Thermal analysis: Using simultaneous thermal analysis (NETZSCH Instrument Manufacturing Co., Ltd., Germany/Nanjing Xinzhonghui Scientific Instrument Co., Ltd.), each sample was placed on an alumina crucible and heated from 40°C to 350°C in a nitrogen atmosphere at a heating rate of 10°C/min. Thermogravimetric and differential thermal data information were obtained simultaneously using the same sample in the same measurement.

Nuclear magnetic resonance measurement: Weigh 10-30 mg of sample, use dimethyl sulfoxide-d6 as solvent and TMS (0 ppm) as internal standard, and measure on AVANCEIII 400 MHz Bruker digital spectrometer to obtain ¹ H NMR spectrum.

Solubility test: Take 200mg of temozolomide, ferulic acid and temozolomide-ferulic acid cocrystal sample powder and add 45mL hydrochloric acid buffer (pH1.2) and phosphate buffer (pH 6.8) in a beaker respectively. Stir the obtained suspension at 37°C, 150rpm (pH 6.8). Take 2mL of dissolution medium at 240 minutes. After treatment with 0.22μm microporous filter membrane, the concentration of temozolomide, ferulic acid and temozolomide-ferulic acid cocrystal was determined by chromatography using UV spectrometer UV-3600. The powder dissolution experiment was repeated 3 times (n=3).

Example 1

Preparation of co-crystals: 0.2 mmol temozolomide and 0.2 mmol ferulic acid were mixed and placed in a 20 ml glass vial, 15 ml acetonitrile was added, and the mixture was ultrasonicated for 40 min at 25°C and 40 Hz until the solution became transparent to obtain a temozolomide-ferulic acid mixed solution. The temozolomide-ferulic acid mixed solution was filtered through a 0.22 μm organic filter head into a 20 mL vial, and the solution was allowed to stand in a constant temperature box at 28°C for evaporation and crystallization. The crystallization time was 1 week, and a yellow transparent temozolomide-ferulic acid drug co-crystal was obtained with a yield of 92%, a bulk density of 0.34 g/cm ³ , and a tap density of 0.74 g/cm ³ .

The obtained temozolomide-ferulic acid drug co-crystal was subjected to X-ray single crystal diffraction, and the unit cell stacking diagram of the crystal is shown in FIG1 .

The drug co-crystal of temozolomide-ferulic acid was ground and subjected to X-ray powder diffraction. The powder X-ray diffraction spectrum is shown in FIG2 .

Example 2

Preparation of co-crystals: 0.2 mmol temozolomide and 0.2 mmol ferulic acid were mixed and placed in a 50 ml beaker, 30 ml acetonitrile was added, and the mixture was ultrasonicated for 60 min at 33°C and 50 Hz until the solution became transparent to obtain a temozolomide-ferulic acid mixed solution. The temozolomide-ferulic acid mixed solution was filtered through a 0.22 μm organic filter head into a 20 mL vial, and the solution was allowed to stand in a constant temperature box at 28°C for evaporation and crystallization. The crystallization time was 2 weeks, and a yellow transparent temozolomide-ferulic acid drug co-crystal was obtained with a yield of 90%, a bulk density of 0.30 g/cm ³ , and a tap density of 0.68 g/cm ³ .

The obtained temozolomide-ferulic acid drug co-crystal was subjected to X-ray single crystal diffraction, and the unit cell stacking diagram of the crystal was consistent with Figure 1.

The drug co-crystal of temozolomide-ferulic acid was ground and subjected to X-ray powder diffraction. The powder X-ray diffraction spectrum is shown in FIG2 .

Example 3

Preparation of co-crystals: 0.2 mmol temozolomide and 0.2 mmol ferulic acid were mixed and placed in a 20 ml glass vial, 10 ml acetonitrile was added, and the mixture was ultrasonicated for 20 min at 23°C and 30 Hz until the solution became transparent to obtain a temozolomide-ferulic acid mixed solution. The temozolomide-ferulic acid mixed solution was filtered through a 0.22 μm organic filter head into a 20 mL vial, and the solution was allowed to stand in a constant temperature box at 28°C for evaporation and crystallization. The crystallization time was 1 week, and a yellow transparent temozolomide-ferulic acid drug co-crystal was obtained with a yield of 92%, a bulk density of 0.31 g/cm ³ , and a tap density of 0.70 g/cm ³ .

The obtained temozolomide-ferulic acid drug co-crystal was subjected to X-ray single crystal diffraction, and the unit cell stacking diagram of the crystal was consistent with Figure 1.

The drug co-crystal of temozolomide-ferulic acid was ground and subjected to X-ray powder diffraction. The powder X-ray diffraction spectrum is shown in FIG2 .

Characterization of cocrystals

(1) The drug co-crystal of temozolomide-ferulic acid obtained in Example 1 was subjected to X-ray single crystal diffraction, and the unit cell stacking diagram of the drug co-crystal is shown in Figure 1. Specific single crystal X-ray diffraction data are shown in Table 1.

As shown in Figure 1 and Table 1, the drug co-crystal of temozolomide-ferulic acid contains 8 temozolomide molecules, 8 ferulic acid molecules and 8 acetonitrile molecules. The molecular formula of the drug co-crystal of temozolomide-ferulic acid is C ₆ H ₆ N ₆ O ₂ ·C ₁₀ H ₁₀ O ₄ ·CH ₃ CN, and the crystal structure belongs to the monoclinic system, the space group is P2(1)/c, and the unit cell parameters are α=90°, β=105.216(5)°, γ=90°, unit cell volume The minimum number of asymmetric units in the unit cell is Z=8, and the crystal density is 1.358 g/cm ³ .

Table 1 Single crystal X-ray diffraction data of drug co-crystal of temozolomide-ferulic acid

(2) After grinding, the drug co-crystal of temozolomide-ferulic acid prepared in Example 1 was subjected to X-ray powder diffraction. The powder X-ray diffraction spectrum is shown in FIG2 . The powder X-ray diffraction pattern of the drug co-crystal of temozolomide-ferulic acid measured by Cu/Kα ray after grinding has characteristic diffraction peaks at 2θ angles of 6.38°, 11.06°, 11.53°, 12.96°, 16.38°, 17.81°, 20.85°, 21.33°, 23.70°, and 26.93°. Among them, the positions of the diffraction peaks of the drug co-crystal of temozolomide-ferulic acid are significantly different from those of the temozolomide raw material and the ferulic acid raw material.

(3) The infrared absorption spectra of temozolomide raw material, ferulic acid raw material and temozolomide-ferulic acid drug co-crystal in the range of 4000-400 cm ^-1 are shown in Figure 3, wherein the infrared absorption spectrum of temozolomide-ferulic acid drug co-crystal has characteristic absorption peaks at 3644 cm ^-1 , 3466 cm ^-1 , 3429 cm ^{- 1} , 3371 cm-1, 3214 cm-1, 3097 cm ^{- 1} , 1739 cm ^-1 , 1680 cm ^-1 , 1592 cm ^-1 and 1514 cm ^-1 .

(4) The thermogravimetric curve of the drug co-crystal of temozolomide-ferulic acid prepared in Example 1 is shown in FIG4 . It can be seen from the TGA curve that neither the temozolomide raw material nor the ferulic acid raw material has a weight loss platform, indicating that the samples do not contain crystal water or other solvents, and begin to decompose at 191.26° C. and 194.23° C., respectively. It can also be seen from the TGA curve that the drug co-crystal of temozolomide-ferulic acid begins to lose solvent when heated to 128.6° C., with a weight loss of about 8.8%, indicating that the sample contains one acetonitrile solvent, which corresponds to the acetonitrile molecule in the single crystal structure, which is consistent with the single crystal structure.

(5) The DSC curve of the temozolomide-ferulic acid drug co-crystal prepared in Example 1 measured by a differential scanning calorimeter is shown in FIG4 . From the differential scanning calorimetry analysis diagram, it can be seen that: (i) the temozolomide raw material has an exothermic peak in the heating process, with a peak temperature of 205.3° C., and no phase change peak is observed in the cooling process, showing an exothermic peak of a single crystal form, indicating that the melting point of the crystal is 205.3° C.; (ii) the ferulic acid raw material has an endothermic peak in the heating process, with a peak temperature of The melting point of the temozolomide-ferulic acid co-crystal was 175.7°C, and no phase transition peak was observed during the cooling process, showing an endothermic peak of a single crystal form, indicating that the melting point of the crystal was 175.7°C; (iii) the temozolomide-ferulic acid co-crystal had both endothermic and exothermic peaks during the heating process, with peak temperatures of 128.06°C and 177.1°C, of which 128.6°C may be the acetonitrile molecule in the structure. Therefore, the melting point of the crystal should be 177.1°C, which is much lower than the melting point of the raw material temozolomide and slightly higher than the melting point of ferulic acid.

The temozolomide raw material sublimates before the melting point (205.3°C), resulting in a certain degree of weight loss, and the weight loss accelerates after reaching the melting point until it is completely sublimated; the ferulic acid raw material sublimates before the melting point (175.7), resulting in a certain degree of weight loss, and the weight loss accelerates after reaching the melting point until it is completely sublimated; the temozolomide-ferulic acid drug cocrystal sublimates before the melting point (177.1°C), resulting in a certain degree of weight loss, accompanied by the loss of acetonitrile solvent in the unit cell, and the weight loss accelerates after reaching the melting point until it is completely sublimated.

(6) The ¹ H NMR spectra of the temozolomide-ferulic acid drug co-crystal prepared in Example 1, the temozolomide raw material, and the ferulic acid raw material are shown in FIG5 , respectively.

The stoichiometric ratio and chemical purity of each cocrystal form were determined by ¹ H NMR measurement. The ¹ H NMR spectrum of the obtained cocrystal is the sum of the characteristic peaks of temozolomide, ferulic acid and acetonitrile, which indicates that these two components exist in a new phase. The ¹ H NMR chemical shift distribution of the co-crystal product is as follows: ¹ H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.54 (s, 1H), 8.82 (s, 1H), 7.79 (s, 1H), 7.67 (s, 1H), 7.49 (d, J = 15.9 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.08 (dd, J = 8.2, 2.0 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.36 (d, J = 5.9 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.08 (s, 3H).

The co-crystallization product of temozolomide, ferulic acid and acetonitrile is ¹ H NMR chemical shifts were assigned as follows: temozolomide (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.79 (s, 1H), 7.67 (s, 1H), 3.87 (s, 3H); ferulic acid (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.54 (s, 1H), 7.49 (d, J = 15.9 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.2, 2.0 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.36 (d, J = 15.9 Hz, 1H), 3.82 (s, 3H); 2.08 (s, 3H) is the ¹ H NMR chemical shift of acetonitrile. Based on the integration of a single characteristic proton signal, the stoichiometric ratio of temozolomide, ferulic acid, and acetonitrile was calculated to be 1:1:1.

(7) The optical microscope image of the temozolomide-ferulic acid drug co-crystal prepared in Example 1 is shown in FIG6 .

(8) The solubility of the temozolomide-ferulic acid drug co-crystal prepared in Example 1 in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8) is shown in FIG. 7 .

The results showed that the temozolomide-ferulic acid drug cocrystals showed better solubility in a simulated intestinal fluid environment, while the solubility of temozolomide in gastric fluid was reduced, which alleviated the possibility of temozolomide decomposition in gastric fluid and was beneficial to the absorption of the drug in the intestine.

In summary, the drug co-crystal of temozolomide and ferulic acid prepared by the present invention can effectively improve the solubility of single raw material drugs of temozolomide and ferulic acid, and at the same time provide a new possibility for combined medication. The preparation method of the drug co-crystal of temozolomide and ferulic acid of the present invention is simple and easy to industrially develop and produce.

The description and practice disclosed in the present invention are easy to think and understand for ordinary technicians in this technical field, and several improvements and modifications can be made without departing from the principles of the present invention. Therefore, modifications or improvements made without departing from the spirit of the present invention should also be regarded as the protection scope of the present invention.

Claims (9)

1. A temozolomide-ferulic acid drug co-crystal, characterized in that the molecular formula of the temozolomide-ferulic acid drug co-crystal is C ₆ H ₆ N ₆ O ₂ ·C ₁₀ H ₁₀ O ₄ ·CH ₃ CN, the crystal structure belongs to the monoclinic system, the space group is P2(1)/c, and the unit cell parameters are α=90°, β=105.216(5)°, γ=90°, unit cell volume The minimum number of asymmetric units in the unit cell is Z = 8, and the crystal density is 1.358 g/cm ³ ; The temozolomide-ferulic acid drug co-crystal has characteristic diffraction peaks at 6.38°, 11.06°, 11.53°, 12.96°, 16.38°, 17.81°, 20.85°, 21.33°, 23.70°, and 26.93° in the 2θ angle of the powder X-ray diffraction pattern measured by Cu/Kα ray after grinding; The temozolomide-ferulic acid drug co-crystal has characteristic absorption peaks at 3644cm ^-1 , 3466cm ^-1 , 3429cm ^-1 , 3371cm -1 , 3214cm ^-1 , 3097cm ^-1 , 1739cm ^-1 , 1680cm ^-1 , 1592cm ^-1 , and 1514cm ^-1 in its infrared absorption spectrum measured by a Thermo Scientific infrared ^spectrometer ; The temozolomide-ferulic acid drug co-crystal has a DSC curve measured by a differential scanning calorimeter, and has an endothermic peak and an exothermic peak within 110-190° C., the peak value of the endothermic peak is 128.6° C., and the peak value of the exothermic peak is 177.1° C.; The drug co-crystal of temozolomide-ferulic acid is a crystalline powder. 2 . The temozolomide-ferulic acid pharmaceutical co-crystal according to claim 1 , wherein the bulk density of the crystalline powder is 0.30 to 0.34 g/cm ³ . 3 . The temozolomide-ferulic acid pharmaceutical co-crystal according to claim 1 , wherein the tap density of the crystalline powder is 0.68 to 0.74 g/cm ³ . 4. The method for preparing a temozolomide-ferulic acid drug co-crystal according to claim 1, characterized in that a mixed powder of temozolomide and ferulic acid is mixed with an acetonitrile solution, and ultrasonically dissolved to obtain a temozolomide-ferulic acid mixed solution; and the temozolomide-ferulic acid mixed solution is volatilized and crystallized to obtain the temozolomide-ferulic acid drug co-crystal. 5. The method for preparing a temozolomide-ferulic acid pharmaceutical cocrystal according to claim 4, characterized in that the molar ratio of temozolomide to ferulic acid is 1:1; and the mass volume ratio of the mixed powder of temozolomide and ferulic acid to acetonitrile is 0.2-2mmol:10-50mL. 6. The method for preparing a temozolomide-ferulic acid pharmaceutical cocrystal according to claim 4, characterized in that the ultrasonic dissolution has an ultrasonic time of 20-60 min, an ultrasonic temperature of 20-30° C., and a frequency of 30-50 Hz. 7. The method for preparing a temozolomide-ferulic acid pharmaceutical co-crystal according to claim 4, characterized in that the crystallization temperature of the volatile crystallization is 23-33°C and the crystallization time is 1-2 weeks. 8. Use of the temozolomide-ferulic acid pharmaceutical co-crystal according to claim 1 in the preparation of anti-tumor drugs. 9. The use according to claim 8, characterized in that the tumor is a malignant glioma or a malignant melanoma.