A temozolomide-coffeic acid pharmaceutical co-crystal and a preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical cocrystal, and particularly relates to a temozolomide-coffee acid pharmaceutical cocrystal and a preparation method thereof. The molecular formula of the temozolomide-coffee acid pharmaceutical cocrystal is 2C6H6N6O2.C9H8O4.0.5H2O, the crystal structure belongs to a monoclinic system, a space group is P2(1) / c, cell parameters are alpha=90 degrees, beta=113.631(5) degrees, gamma=90 degrees, a cell volume is V=2.019(2) nm3, and a minimum asymmetric unit number in the cell is Z=8. Temozolomide, coffee acid and acetone are uniformly mixed to obtain a temozolomide-coffee acid mixed solution, and then the temozolomide-coffee acid pharmaceutical cocrystal is obtained by performing volatilization crystallization on the temozolomide-coffee acid mixed solution. The temozolomide-coffee acid pharmaceutical cocrystal prepared by the application can effectively improve the stability and solubility of temozolomide and coffee acid single raw medicine. The preparation method of the temozolomide-coffee acid pharmaceutical cocrystal prepared by the application is simple and easy for industrial development and production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical cocrystals, and particularly relates to a temozolomide-caffeic acid pharmaceutical cocrystal and a preparation method thereof. BACKGROUND

[0002] Temozolomide (TMZ) is an oral alkylating agent for treating malignant glioma. The drug is completely absorbed orally, with a bioavailability close to 100%, and shows broad-spectrum activity in murine tumor models and can penetrate the blood-brain barrier of humans. The cytotoxic effect of temozolomide is due to its strong methylation of DNA bases. Under alkaline conditions, temozolomide can rapidly break down to form active methyl diazonium ions. Because brain tumors have higher alkalinity than peripheral tissues, the activation of the drug can relatively concentrate in the tumor site, the anti-tumor effect is strong and has a certain selectivity, the side effect spectrum is also improved, the bone marrow toxicity is smaller, and the patient's tolerance is improved. However, it has the shortcomings of short oral biological half-life, poor stability and poor tabletting property, which limits its clinical efficacy. TMZ is a prodrug that can spontaneously hydrolyze into the active compound 5-(3-methyl-1-triazine) imidazole-4-hydroxyamine (MTIC) under physiological conditions. MTIC further decomposes into 5-aminoimidazole 4-hydroxyamine (AIC) and methyl diazonium cation (CH3N2 + ), the latter is an active alkylating substance that can exert an anti-tumor effect through DNA methylation. At present, TMZ is a first-line chemotherapy drug. However, due to rapid elimination after oral administration, the clinical application of TMZ is limited. In addition, TMZ also has stability problems because it degrades to AIC during storage and processing, which also reduces its effectiveness.

[0003]

[0004] Caffeic acid (CA) is a polyphenol compound containing phenolic compounds and acrylic acid functional groups. It is reported that CA has antioxidant, antibacterial, antiviral and anticancer properties. Therefore, CA has gained considerable interest in the scientific community. However, due to the poor solubility of CA in aqueous environments, its bioavailability is low, which limits its application in the food and pharmaceutical industries.

[0005]

[0006] The drug co-crystal is a crystal formed by combining an active pharmaceutical ingredient and a suitable co-crystal reagent under the action of an amine bond or other non-covalent bond (Π-Π conjugation, van der Waals force, halogen bond, etc.) by applying the principles of crystal engineering, pharmaceutical science, supramolecular chemistry and self-assembly. As a new crystal form of a drug, the drug co-crystal can introduce a new component while not affecting the internal structure of the drug, greatly improve the physical and chemical properties of the drug, and improve the clinical efficacy. The drug co-crystal can not only ensure the stability of the drug, but also greatly change the melting point, solubility and other aspects. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a temozolomide-coffee acid drug co-crystal and a preparation method thereof, which can solve the problems of the prior art.

[0008] To solve the above technical problems, the technical scheme adopted by the present application is as follows:

[0009] The present application discloses a temozolomide-coffee acid drug co-crystal, the molecular formula of the temozolomide-coffee acid drug co-crystal is 2C6H6N6O2·C9H8O4·0.5H2O, the crystal structure belongs to a monoclinic system, the space group is P2(1) / c, the unit cell parameters are α=90°, β=113.631(5)°, γ=90°, the unit cell volume is V=2.030(2)nm3, the number of the smallest asymmetric unit in the unit cell is Z=8, and the crystal density is 1.546g / cm 3 ;

[0010] The temozolomide-coffee acid drug co-crystal has characteristic diffraction peaks at 2θ angles of 11.47°, 13.21°, 13.71°, 14.89°, 16.08°, 26.29°, 26.51°, 26.9°, 27.92° and 28.7° in the powder X-ray diffraction pattern measured by using Cu / Kα rays after grinding, expressed in degrees;

[0011] The temozolomide-coffee acid drug co-crystal has infrared absorption spectra measured by using KBr tabletting at 3535cm -1 , 3433cm -1 , 3349cm -1 , 3300cm -1 , 1741cm -1 , 1667cm -1 , 1595cm -1 , 1519cm -1 , 1458cm -1 , 1360cm-1 1265cm -1 1179cm -1 It has a characteristic absorption peak;

[0012] The temozolomide-caffeic acid cocrystal, when measured by differential scanning calorimetry (DSC), exhibits an exothermic peak in the range of 179–201 °C, with a peak value of 184.7 °C.

[0013] The temozolomide-caffeic acid drug cocrystal is a crystalline powder.

[0014] The water molecules in the temozolomide-caffeic acid co-crystal originate from: (1) water in the environment during crystallization in the preparation of the temozolomide-caffeic acid co-crystal; and / or (2) water of crystallization contained in the temozolomide raw material or the caffeic acid raw material.

[0015] In some embodiments, the bulk density of the crystalline powder is 0.59–0.65 g / cm³. 3 .

[0016] In some embodiments, the tap density of the crystalline powder is 1.01–1.08 g / cm³. 3 .

[0017] Furthermore, the present invention discloses a method for preparing the above-mentioned temozolomide-caffeic acid drug cocrystal, wherein temozolomide is mixed with caffeic acid and acetone to obtain a temozolomide-caffeic acid mixed solution; the temozolomide-caffeic acid mixed solution is then subjected to volatilization crystallization to obtain the final product.

[0018] The preparation method of the above-mentioned temozolomide-caffeic acid cocrystal is a solution method.

[0019] In some embodiments, the molar ratio of temozolomide to caffeic acid is 2:1; the molar volume ratio of temozolomide to acetone is 0.2–1 mmol:10 mL.

[0020] In some embodiments, the process of mixing temozolomide with caffeic acid and acetone requires water bath heating and stirring.

[0021] The water bath heating is wherein the heating temperature is 80-90℃ and the heating time is 1-2 hours; preferably, the water bath heating is wherein the heating temperature is 80℃ and the heating time is 2 hours.

[0022] The stirring speed is 400-600 rpm, preferably 500 rpm.

[0023] In some embodiments, the volatile crystallization occurs at a crystallization temperature of 20–40°C, preferably 30°C, and for a crystallization time of 1–2 weeks, preferably 1 week.

[0024] The temozolomide-caffeic acid drug cocrystals prepared by the above method are yellow and transparent.

[0025] The crystals obtained by evaporating and crystallizing the temozolomide-caffeic acid mixed solution were placed in a vacuum drying oven and dried at 40°C for 8 hours to evaporate the solvent, thus obtaining temozolomide-caffeic acid drug co-crystal powder.

[0026] The application of the aforementioned temozolomide-caffeic acid cocrystal in the preparation of antitumor drugs is also within the scope of protection of this invention.

[0027] Specifically, the tumor is a malignant glioma or a malignant melanoma.

[0028] Beneficial effects:

[0029] (1) The temozolomide-caffeic acid drug cocrystal prepared by the present invention can effectively improve the stability and solubility of temozolomide and caffeic acid single raw material drugs.

[0030] (2) The temozolomide-caffeic acid cocrystal prepared by the present invention provides a better drug strategy for combination therapy.

[0031] (3) The preparation method of the temozolomide-caffeic acid drug cocrystal prepared by the present invention is simple and easy to develop and produce industrially. Attached Figure Description

[0032] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0033] Figure 1 This is a unit cell packing diagram of the temozolomide-caffeic acid cocrystal in Example 1 of the present invention.

[0034] Figure 2 This is the X-ray diffraction pattern of the temozolomide-caffeic acid cocrystal in Example 1 of the present invention.

[0035] Figure 3 This is an X-ray diffraction pattern of the temozolomide raw material used in the embodiments of the present invention.

[0036] Figure 4 This is an X-ray diffraction pattern of the caffeic acid raw material used in the embodiments of the present invention.

[0037] Figure 5 This is a differential scanning calorimetry (DSC) analysis diagram of temozolomide, caffeic acid, and temozolomide-caffeic acid eutectic in Example 1 of the present invention.

[0038] Figure 6The thermogravimetric analysis (TGA) diagrams of temozolomide, caffeic acid, and the temozolomide-caffeic acid eutectic crystal in Example 1 of this invention are shown.

[0039] Figure 7 The infrared spectra of temozolomide, caffeic acid, and temozolomide-caffeic acid cocrystal in Example 1 of this invention are shown.

[0040] Figure 8 This is a solubility curve of temozolomide, caffeic acid, and temozolomide-caffeic acid cocrystal in pure water in Example 1 of the present invention.

[0041] Figure 9 This is an optical microscope image of the temozolomide-caffeic acid cocrystal in Example 1 of the present invention.

[0042] Figure 10 The temozolomide raw material in Example 1 of this invention 1 H NMR spectrum.

[0043] Figure 11 The caffeic acid raw material in Example 1 of this invention 1 H NMR spectrum.

[0044] Figure 12 The temozolomide-caffeic acid cocrystal in Example 1 of this invention 1 H NMR spectrum.

[0045] Figure 13 This is an accelerated stability test diagram of the temozolomide-caffeic acid cocrystal in Example 1 of the present invention. Detailed Implementation

[0046] To further illustrate the present invention, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0047] 1. Reagents

[0048] The temozolomide raw material used in this embodiment of the invention was purchased from Shanghai Maclean Biochemical Technology Co., Ltd., with a purity of 99%. The powder X-ray diffraction pattern of the temozolomide raw material is shown below. Figure 3 As shown.

[0049] The caffeic acid raw material used in this embodiment of the invention was purchased from Shanghai Mairui Biochemical Technology Co., Ltd., with a purity of 99%. The powder X-ray diffraction pattern of the caffeic acid raw material is shown below. Figure 4 As shown.

[0050] 2. Measurement Method

[0051] Single-crystal X-ray diffraction determination of crystal structure: The cultured single crystal was cut into pieces approximately 0.10 × 0.20 × 0.30 mm. 3 Blocks of varying sizes, analyzed by a Bruker APEX-IICCD diffractometer with a Mo / Kα radiation source (graphite monochromator). The sample was irradiated and diffraction data were collected. The diffraction data were reduced by SAINT and the structure was analyzed by the direct method of SHELXTL software. The structure was then refined by the full matrix least squares method based on F2. All non-hydrogen atoms were refined by anisotropy.

[0052] Powder X-ray diffraction: Approximately 0.1 g of the ground sample was used for diffraction data collection at room temperature using a powder X-ray diffractometer (Bruker D8 Advance) with Cu / Kα rays as the light source. The scanning step size was 0.02°, the scanning voltage was set to 40kV, the current to 40mA, the scanning rate to 0.2s / 0.02°, and the scanning range 2θ to 5–40°. The data was processed using Jade software and plotted using Origin.

[0053] Fourier transform infrared spectroscopy: 20 mg of crystalline powder was mixed and ground with 400 mg of dry KBr, then pressed into thin tablets using a tablet press. Infrared absorption spectral data were collected at room temperature using a Fourier transform infrared spectrometer (Nicolic Instruments, Inc., USA / Nanjing Xinzhonghui Scientific Instruments Co., Ltd.). Spectral range: 4000–4000 cm⁻¹ -1 Resolution: 0.1, Linearity: 0.1%T.

[0054] Thermal analysis: Using simultaneous thermal analysis (NETZSCH Instruments GmbH, Germany / Nanjing Xinzhonghui Scientific Instruments 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 were obtained simultaneously using the same sample in the same measurement.

[0055] NMR determination: Weigh 10–30 mg of sample, use dimethyl sulfoxide-d6 as solvent and TMS (0 ppm) as internal standard, and measure on an AVANCE III 400 MHz Bruker digital spectrometer to obtain the NMR result. 1 H NMR spectrum.

[0056] Solubility determination method: Weigh excess temozolomide, caffeic acid, and temozolomide-caffeic acid cocrystals separately and place them in 20 mL of pure water. Dissolve them in a water bath at 100 rpm and 37 °C. Start timing from the start of feeding. Take 1 mL of solution at 5 min, 15 min, 30 min, 60 min, 90 min, 120 min, 180 min, and 250 min, and add the same volume of medium at the same time. Filter the collected solution through an aqueous microporous membrane and dilute it to an appropriate factor. Measure the solubility using a Shimadzu UV-3600 ultraviolet spectrophotometer.

[0057] Accelerated stability test: Weigh 100mg of TMZ-CA eutectic crystal powder and spread it evenly in an open petri dish with a thickness of ≤5mm. Place it in a constant temperature incubator at 40℃ and relative humidity of 75±5%. Take samples for testing at 1, 2 and 3 months and compare them with the results at 0 days.

[0058] Example 1

[0059] Preparation of the co-crystal: 1 mmol of temozolomide and 0.5 mmol of caffeic acid were mixed in a 20 mL glass bottle, and 10 mL of acetone solution was added. The mixture was heated in a water bath at 80 °C with a stirring rate of 500 r / min for 2 h. The solution dissolved in the water bath to obtain a transparent liquid, which was the temozolomide-caffeic acid mixed solution. The temozolomide-caffeic acid mixed solution was filtered through a 0.22 μm organic filter into a 20 mL vial. The solution was allowed to stand in a constant temperature oven at 30 °C for one week to allow evaporation and crystallization, yielding a yellow transparent temozolomide-caffeic acid drug co-crystal. The obtained drug co-crystal was placed in a vacuum drying oven and dried at 40 °C for 8 h to evaporate the solvent, yielding a temozolomide-caffeic acid drug co-crystal powder with a yield of 90% and a bulk density of 0.65 g / cm³. 3 The tap density is 1.08 g / cm³. 3 .

[0060] Characterization of temozolomide-caffeic acid cocrystal:

[0061] (1) The obtained temozolomide-caffeic acid cocrystal was subjected to X-ray single-crystal diffraction, and the crystal structure data are as follows: Figure 1 As shown, from Figure 1 It is known that the structure of the temozolomide-caffeic acid cocrystal is channel-type, with two layers: one containing water and the other not.

[0062] The molecular formula of the obtained temozolomide-caffeic acid cocrystal is 2C6H6N6O2·C9H8O4·0.5H2O, the crystal structure belongs to the monoclinic system, the space group is P2(1) / c, and the cell parameters are as follows: α = 90°, β = 113.631(5)°, γ = 90°, cell volume The smallest number of asymmetric units within the unit cell is Z = 8, and the crystal density is 1.546 g / cm³. 3 Crystal size: 0.4 × 0.36 × 0.25 mm 3 The specific single-crystal X-ray diffraction data are shown in Table 1.

[0063] Table 1 Single-crystal X-ray diffraction data of temozolomide-caffeic acid cocrystal

[0064]

[0065]

[0066] (2) The temozolomide-caffeic acid cocrystal was ground and subjected to X-ray powder diffraction. The powder X-ray diffraction pattern is shown below. Figure 2 As shown, the powder X-ray diffraction pattern of the temozolomide-caffeic acid cocrystal, measured using Cu / Kα rays, after grinding, exhibits characteristic diffraction peaks at 2θ angles of 11.47°, 13.21°, 13.71°, 14.89°, 16.08°, 26.29°, 26.51°, 26.9°, 27.92°, and 28.7°. The obtained temozolomide-caffeic acid cocrystal shows significant differences compared to the temozolomide and caffeic acid raw materials. The powder X-ray diffraction patterns of the temozolomide and caffeic acid raw materials are shown below. Figure 3 , Figure 4 As shown.

[0067] (3) The DSC curve of the temozolomide-caffeic acid cocrystal measured using differential scanning calorimetry is shown below. Figure 5 As shown in the differential scanning calorimetry (DSC) diagram, it can be seen that: (i) the temozolomide raw material has an exothermic peak during the heating process, with a peak temperature of 205.3℃, and no phase transition peak is observed during the cooling process, showing an exothermic peak of a single crystal form, indicating that the melting point of the crystal is 205.3℃; (ii) the raw material caffeic acid has an endothermic peak and an exothermic peak during the heating process, with peak temperatures of 234.2℃ and 241.3℃ respectively, and no phase transition peak is observed during the cooling process; (iii) the temozolomide-caffeic acid eutectic crystal has an exothermic peak during the heating process, with a peak temperature of 184.7℃, indicating that its melting point is 184.7℃, which is lower than the melting points of the raw materials temozolomide and caffeic acid.

[0068] (4) The thermogravimetric curve of the temozolomide-caffeic acid cocrystal is shown in Figure 1. Figure 6As shown in the TG curves, neither TMZ nor CA exhibited a weight loss plateau, indicating that neither sample contained water of crystallization or other solvents, and both began to decompose at 191.26℃ and 196.90℃, respectively. The TG curves also show that TMZ-CA (temozolomide-caffeic acid drug cocrystal) began to lose water when heated to 100℃, indicating the presence of water of crystallization. The sample weight loss was 1.6%, corresponding to the content of 1 / 2 water molecule in the single crystal structure, consistent with the single crystal structure.

[0069] Temozolomide undergoes sublimation before its melting point (205.3℃), resulting in some weight loss. After reaching the melting point, the weight loss accelerates until complete sublimation occurs. Caffeic acid undergoes sublimation before its melting point (234.2℃), resulting in some weight loss. After reaching the melting point, the weight loss accelerates until complete sublimation occurs. Temozolomide-caffeic acid eutectic undergoes sublimation before its melting point (184.7℃), resulting in some weight loss. After reaching the melting point, the weight loss accelerates until complete sublimation occurs.

[0070] (5) At 4000-400cm -1 The infrared absorption spectra of temozolomide, caffeic acid, and temozolomide-caffeic acid cocrystals within the range are as follows: Figure 7 As shown, the infrared absorption spectrum of the temozolomide-caffeic acid cocrystal is at 3535 cm⁻¹. -1 3433cm -1 3349cm -1 3300cm -1 1741cm -1 1667cm -1 1595cm -1 1519cm -1 1458cm -1 1360cm -1 1265cm -1 1179cm -1 It has a characteristic absorption peak.

[0071] It can be noted that, compared with the infrared absorption spectra of the raw materials temozolomide and caffeic acid, some absorption peaks in the spectrum of the temozolomide-caffeic acid cocrystal have shifted and changed in shape, and are particularly prominent at 3535 cm⁻¹. -1 The appearance of new characteristic absorptions indicates that temozolomide and caffeic acid molecules participated in the formation of new hydrogen bond interactions, suggesting the formation of a temozolomide-caffeic acid cocrystal. Notably, the shift in the absorption band in the infrared spectrum of the cocrystal signifies that caffeic acid participated in the co-crystallization with temozolomide, indicating the formation of the cocrystal.

[0072] (6) Figure 8The figure shows the solubility curves of temozolomide, caffeic acid, and temozolomide-caffeic acid cocrystal in pure water. As can be seen from the figure, the solubility of temozolomide-caffeic acid cocrystal in pure water is higher than that of the raw drug caffeic acid (CA vs CA in the cocrystal), but lower than that of the raw drug temozolomide in water (TMZ vs TMZ in the cocrystal).

[0073] (7) An optical microscope image of the temozolomide-caffeic acid co-crystal prepared in Example 1 is shown below. Figure 9 As shown.

[0074] (8) The temozolomide raw material, caffeic acid raw material, and the prepared temozolomide-caffeic acid co-crystal in Example 1. 1 The HNMR spectra are as follows: Figure 10 , Figure 11 , Figure 12 As shown.

[0075] use 1 ¹H NMR was used to determine the stoichiometry and chemical purity of each eutectic form. The resulting eutectic... 1 The 1H NMR spectrum is the sum of the characteristic peaks of TMZ and CA, indicating the presence of these two components in the new phase. The eutectic product... 1 The 1H NMR chemical shift distribution is as follows: 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),9.48(s,1H),9.18(s,1H),8.82(s,2H),7.79(s,2H),7.67(s,2H),7.41(d,J=15.9 Hz, 1H), 7.02 (d, J = 2.1Hz, 1H), 6.96 (dd, J = 8.2, 2.1Hz, 1H), 6.76 (d, J = 8.1Hz, 1H), 6.17 (d, J = 15.9Hz, 1H), 3.87 (s, 6H).

[0076] TMZ and CA in the co-crystallized product 1 The 1H NMR chemical shift distribution is as follows: TMZ 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.82 (s, ¹H), 7.79 (s, ¹H), 7.67 (s, ¹H), 3.87 (s, ³H); CA 1¹H NMR (400MHz, DMSO-d⁶) δ 12.11 (s, 1H), 9.52 (s, 1H), 9.14 (s, 1H), 7.42 (d, J = 15.9 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.97 (dd, J = 8.2, 2.1 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.18 (d, J = 15.9 Hz, 1H). Based on the integration of the individual characteristic proton signals, the stoichiometry ratio of TMZ to CA was calculated to be 2:1. Simultaneously, a slight shift in the ¹H NMR peaks of the eutectic was observed, which is likely due to the formation of the eutectic.

[0077] (9) The accelerated stability test of the temozolomide-caffeic acid cocrystal prepared in Example 1 is as follows: Figure 13 As shown in the figure. Stability tests showed that, compared with temozolomide spontaneously hydrolyzing and decomposing into 5-aminoimidazole-4-hydroxyamine (AIC) after three months, the temozolomide-caffeic acid cocrystal did not undergo any phase change within three months, and the temozolomide-caffeic acid cocrystal has significant physical and chemical stability.

[0078] Example 2: Preparation of temozolomide-caffeic acid cocrystal

[0079] 1 mmol of temozolomide and 0.5 mmol of caffeic acid were mixed in a 20 mL glass bottle, and 10 mL of acetone solution was added. The mixture was heated in a water bath at 90 °C with a stirring rate of 500 rpm for 1 hour. The solution dissolved in the water bath to obtain a transparent liquid, which was the temozolomide-caffeic acid mixed solution. The temozolomide-caffeic acid mixed solution was filtered through a 0.22 μm organic filter into a 20 mL vial. The solution was allowed to stand in a constant temperature oven at 30 °C for one week to allow evaporation and crystallization, yielding a yellow, transparent temozolomide-caffeic acid drug cocrystal. The obtained drug cocrystal was placed in a vacuum drying oven and dried at 40 °C for 8 hours to evaporate the solvent, yielding a temozolomide-caffeic acid drug cocrystal powder with a yield of 87% and a bulk density of 0.62 g / cm³. 3 The tap density is 1.03 g / cm³. 3 .

[0080] The obtained eutectic was subjected to X-ray single-crystal diffraction, and the eutectic structure data were consistent with those of the eutectic obtained in Example 1. The eutectic was then ground and subjected to X-ray powder diffraction, and the powder X-ray diffraction pattern was consistent with that of the eutectic obtained in Example 1. Figure 1 To.

[0081] Example 3: Preparation of temozolomide-caffeic acid cocrystal

[0082] 1 mmol of temozolomide and 0.5 mmol of caffeic acid were mixed in a 20 mL glass bottle, and 10 mL of acetone solution was added. The mixture was heated in a water bath at 90 °C with a stirring rate of 500 rpm for 2 hours. The solution dissolved in the water bath to obtain a transparent liquid, which was the temozolomide-caffeic acid mixed solution. The temozolomide-caffeic acid mixed solution was filtered through a 0.22 μm organic filter into a 20 mL vial. The solution was allowed to stand in a constant temperature oven at 30 °C for one week to allow evaporation and crystallization, yielding a yellow, transparent temozolomide-caffeic acid drug cocrystal. The obtained drug cocrystal was placed in a vacuum drying oven and dried at 40 °C for 8 hours to evaporate the solvent, yielding a temozolomide-caffeic acid drug cocrystal powder with a yield of 89% and a bulk density of 0.59 g / cm³. 3 The tap density is 1.01 g / cm³. 3 .

[0083] The obtained crystal was subjected to X-ray single-crystal diffraction, and the crystal structure data were consistent with those of the crystal obtained in Example 1. The crystal was then ground and subjected to X-ray powder diffraction, and the powder X-ray diffraction pattern was consistent with that of Example 1.

[0084] In summary, this invention has yielded a novel drug cocrystal, namely, the temozolomide-caffeic acid cocrystal. The temozolomide-caffeic acid cocrystal provided by this invention improves the solubility of the raw material caffeic acid while reducing the solubility of temozolomide. Without altering the molecular structures of temozolomide and caffeic acid, the temozolomide-caffeic acid cocrystal improves the physicochemical properties of the drug components, such as solubility and stability. With the increasing prevalence of drug cocrystal research, drug cocrystals will undoubtedly gain widespread acceptance in the pharmaceutical industry and become an important part of drug development.

[0085] This invention provides a concept and method for preparing temozolomide-caffeic acid cocrystal and the same. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A temozolomide-caffeic acid cocrystal, characterized in that, The temozolomide-caffeic acid co-crystal has the molecular formula 2C6H6N6O2•C9H8O4•0.5H2O, a monoclinic crystal system, space group P2(1) / c, and cell parameters a=16.7367(16) [Å], b=23.837(2) [Å], c=13.5779(13) [Å], α=90°, β=113.631(5)°, γ=90°, and cell volume V=4962.7(8) Å. 3 The smallest asymmetric unit number within the unit cell is Z = 8, and the crystal density is 1.546 g / cm³. 3 ; The powder X-ray diffraction pattern of the temozolomide-caffeic acid cocrystal, measured by Cu / Kα rays after grinding, shows characteristic diffraction peaks at 11.47°, 13.21°, 13.71°, 14.89°, 16.08°, 26.29°, 26.51°, 26.9°, 27.92°, and 28.7° at the 2θ angle. The infrared absorption spectrum of the temozolomide-caffeic acid cocrystal, measured using KBr pellet compression, is at 3535 cm⁻¹. -1 3433 cm -1 3349 cm -1 3300 cm -1 1741 cm -1 1667 cm -1 1595 cm -1 1519 cm -1 1458 cm -1 1360 cm -1 1265 cm -1 1179 cm -1 It has a characteristic absorption peak; The temozolomide-caffeic acid cocrystal, when measured by differential scanning calorimetry (DSC), exhibits an exothermic peak in the range of 179–201 °C, with a peak value of 184.7 °C. The temozolomide-caffeic acid drug cocrystal is a crystalline powder.

2. The mozolomide-caffeic acid cocrystal according to claim 1, characterized in that, The bulk density of the crystalline powder is 0.59~0.65 g / cm³. 3 .

3. The mozolomide-caffeic acid cocrystal according to claim 1, characterized in that, The tap density of the crystalline powder is 1.01~1.08 g / cm³. 3 .

4. The method for preparing the temozolomide-caffeic acid cocrystal according to claim 1, characterized in that, Temozolomide was mixed with caffeic acid and acetone to obtain a temozolomide-caffeic acid mixed solution; the temozolomide-caffeic acid mixed solution was then volatilized and crystallized to obtain the final product.

5. The preparation method according to claim 4, characterized in that, The molar ratio of temozolomide to caffeic acid is 2:1; the molar volume ratio of temozolomide to acetone is 0.2~1 mmol:10 mL.

6. The preparation method according to claim 4, characterized in that, The process of mixing temozolomide with caffeic acid and acetone requires water bath heating and stirring.

7. The preparation method according to claim 6, characterized in that, The water bath heating is carried out at a temperature of 80-90℃ for 1-2 hours; the stirring is carried out at a speed of 400-600 rpm.

8. The preparation method according to claim 6, characterized in that, The stirring is performed at a speed of 500 revolutions per minute.

9. The preparation method according to claim 4, characterized in that, The volatile crystallization occurs at a temperature of 20-40°C and takes 1-2 weeks.

10. The preparation method according to claim 4, characterized in that, The volatile crystallization occurs at a crystallization temperature of 30°C and a crystallization time of 1 to 2 weeks.

11. The use of the temozolomide-caffeic acid cocrystal as described in claim 1 in the preparation of antitumor drugs.

12. The application according to claim 11, characterized in that, The tumor is either a malignant glioma or a malignant melanoma.

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