A preparation method of honokiol-tetramethylpyrazine co-crystal

Abstract

The application discloses a preparation method of honokiol-tetramethylpyrazine eutectic crystal, which comprises the following steps: mixing honokiol and tetramethylpyrazine, ball milling / stirring, and drying to obtain honokiol-tetramethylpyrazine eutectic crystal. The application further discloses honokiol-tetramethylpyrazine eutectic crystal prepared by the above method. The application further discloses a composition comprising the above honokiol-tetramethylpyrazine eutectic crystal and honey. The application further discloses the use of the above honokiol-tetramethylpyrazine eutectic crystal or the above composition in the preparation of drugs for treating cardiovascular and cerebrovascular diseases, resisting platelet aggregation and resisting tumors.

Description

Technical Field

[0001] This specification relates to the field of pharmaceutical technology, and particularly to a preparation method of honokiol-ligustrazine cocrystal. Background Art

[0002] Traditional Chinese medicine has shown unique advantages and charm in preventing and treating diseases, as well as in rehabilitation and health care. The specific curative effects and functions produced by traditional Chinese medicine have received more and more extensive attention from the domestic and foreign medical communities. Therefore, the modernization of traditional Chinese medicine has always been the research focus in the academic field, and the research content mainly focuses on the discovery, standardization, modern preparation, and pharmacological activities of active ingredients. In fact, due to the ease of use and storage of Chinese patent medicines, they have been generally accepted and widely used in Chinese clinical practice. Chinese patent medicine is a form of modernized traditional Chinese medicine as ready-to-use herbal medicines, such as tablets, pills, oral solutions, or dry suspensions, rather than herbal medicines that need to be cooked (extracted with hot water). Honeyed pills are one of the most popular forms and have been made by mixing several dried herbs since ancient times. These herbs are ground into powder, mixed with adhesives, and traditionally made into pills by hand. Modern honeyed pills are prepared by ball milling the concentrated active ingredients with a grinder. However, the interaction between active ingredients during the ball milling process is often overlooked. Most of the currently discovered active ingredients of traditional Chinese medicine are lipophilic small molecules with weak acidic or weak basic functional groups, which are prone to chemical reactions or form supramolecular structures, thus greatly hindering the clarification of the active ingredients of traditional Chinese medicine, the discovery of new curative effects, and the clinical application in new disease fields.

[0003] Magnolia officinalis and Ligusticum chuanxiong are important traditional Chinese medicines and have been widely used.

[0004] For example, Shijunzi Pills originated from Taiping Huimin Heji Jufang in the Song Dynasty.

[0005]

Composition

[0006]

Usage

[0007]

Effect

[0008]

Treatment

[0009] The extracts of the four Chinese herbal medicines are ground into powder and mixed with honey to make pills, which is more effective than boiling in water. Therefore, we infer that there may be molecular interactions between the active compounds, and the improvement of drug efficacy is shown. Honokiol in Magnolia officinalis and Ligustrazine in Ligusticum chuanxiong are the main active ingredients of this preparation.

[0010] The specific structural formula of honokiol is as shown in I:

[0011]

[0012] Magnolol has been widely used in food, health products, and cosmetics, exhibiting pharmacological effects such as antithrombosis, central nervous system depressant, anti-inflammatory, antibacterial, anti-ulcer, antioxidant, anti-aging, anti-tumor, and cholesterol-lowering properties. However, the poor water solubility of magnolol results in low bioavailability, only 5.3% (J Ethnopharmacol 2014, 155, 1568-1574), limiting its activity and clinical application.

[0013] The specific structural formula of tetramethylpyrazine is shown in Figure II:

[0014]

[0015] Ligustrazine is the main active ingredient of the traditional Chinese medicine Ligusticum chuanxiong. It has been found to possess antiplatelet aggregation activity, antithrombotic activity, anti-ischemia-reperfusion injury activity, and anti-inflammatory pharmacological activities, and has been widely used in the treatment of cardiovascular and cerebrovascular diseases. In addition, it also has anti-tumor and immune-enhancing effects. However, the tendency of ligustrazine to sublimate has a serious negative impact on the controllability of its product quality and its clinical application.

[0016] Currently, there are reports of using encapsulation to solubilize magnolol, but the resulting magnolol encapsulated powder has a low loading capacity, only 20-30%. Compared to magnolol itself, because magnolol is an amphiphilic compound, the encapsulation efficiency is not high, and unencapsulated magnolol still has problems such as instability and easy discoloration; moreover, because the encapsulated powder contains a large amount of starch excipients, its hygroscopicity is further increased. Summary of the Invention

[0017] This application addresses the solubility and stability issues of magnolol and ligustrazine by designing and synthesizing a novel magnolol-ligustrazine drug-drug cocrystal using cocrystal technology. This cocrystal simultaneously improves the water solubility of magnolol and the stability of ligustrazine. Furthermore, mimicking the preparation process of honey pills in traditional Chinese medicine, the cocrystal is formulated with honey, increasing the water solubility of magnolol to four times that of the original form. This provides a practical strategy for the modern development of poorly soluble and unstable active ingredients in traditional Chinese medicine.

[0018] This application provides a method for preparing magnolol-ligustrazine cocrystal, comprising: mixing magnolol and ligustrazine, ball milling / stirring, drying, and obtaining magnolol-ligustrazine cocrystal.

[0019] This application also provides a cocrystal of magnolol-ligustrazine, prepared by the above-described preparation method.

[0020] This application also provides a composition comprising the above-mentioned magnolol-ligustrazine cocrystal and honey.

[0021] This application also provides the use of the above-mentioned magnolol-ligustrazine cocrystal or the above-mentioned composition in the preparation of medicaments for treating cardiovascular and cerebrovascular diseases, antiplatelet aggregation and antitumor.

[0022] The method for preparing magnolol-ligustrazine cocrystal proposed in this specification has beneficial effects including, but not limited to: (1) Compared with magnolol itself, the magnolol-ligustrazine cocrystal of this application increases the water solubility of magnolol by 1.8 times. (2) Compared with ligustrazine itself, the magnolol-ligustrazine cocrystal of this application reduces the instability caused by the sublimation of ligustrazine. Under the conditions of 25°C and 10% RH, ligustrazine loss is 46% in 24 hours, while it remains basically unchanged in the cocrystal. (3) Compared with magnolol, the honey composition containing magnolol-ligustrazine cocrystal prepared by the grinding method in this application increases the water solubility of magnolol by 4 times. (4) Compared with magnolol-ligustrazine cocrystal, the magnolol-ligustrazine cocrystal and its composition prepared by the grinding method in this application have the technical advantages of high yield, low cost, and suitability for large-scale production. Attached Figure Description

[0023] This application will be further described by way of exemplary embodiments, which will be described in detail with reference to the accompanying drawings. These embodiments are not limiting, wherein:

[0024] Figure 1 It is the single-crystal structure of the honokiol-ligustrazine eutectic of Example 6 of this application;

[0025] Figure 2 This is the X-ray powder diffraction (XRPD) pattern of the cocrystal of magnolol-ligustrazine in Example 1 of this application;

[0026] Figure 3 This is a differential scanning calorimetry (DSC) chromatogram of the cocrystal of magnolol-ligustrazine in Example 1 of this application;

[0027] Figure 4 This is the infrared (IR) spectrum of the cocrystal of magnolol-ligustrazine in Example 1 of this application;

[0028] Figure 5 The weight loss curves of the honey composition of magnolol-tetramethylpyrazine cocrystal in Example 1 and Example 8 compared with tetramethylpyrazine under conditions of 25°C and 10% RH.

[0029] Figure 6 The dissolution curves of the magnolol-ligustrazine cocrystal honey composition of Example 1 and Example 8 compared with magnolol in pure water are shown. Detailed Implementation

[0030] To more clearly illustrate the technical solutions of the embodiments in this specification, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are merely some examples or embodiments of this specification. For those skilled in the art, these drawings can be applied to other similar scenarios without creative effort. Unless obvious from the context or otherwise specified, the same reference numerals in the drawings represent the same structures or operations.

[0031] As indicated in this specification and claims, unless the context clearly indicates otherwise, the words "a," "an," "an," and / or "the" do not specifically refer to the singular and may also include the plural. Generally speaking, the terms "comprising" and "including" only indicate the inclusion of expressly identified steps and elements, which do not constitute an exclusive list, and the method or apparatus may also include other steps or elements.

[0032] Flowcharts are used in this specification to illustrate the operations performed by the system according to embodiments of this specification. It should be understood that the preceding or following operations are not necessarily performed in exact order. Instead, the steps can be processed in reverse order or simultaneously. Furthermore, other operations can be added to these processes, or one or more steps can be removed from them.

[0033] This application provides a method for preparing magnolol-ligustrazine cocrystal, comprising: mixing magnolol and ligustrazine, ball milling / stirring, drying, and obtaining magnolol-ligustrazine cocrystal.

[0034] In some embodiments, the molar ratio of magnolol to tebufenozide can be 0.9–1.1:0.9–1.1. In some embodiments, preferably, the molar ratio of magnolol to tebufenozide can be 1:1.

[0035] In some embodiments, an organic solvent may be added during ball milling / stirring. In some embodiments, the volume molar ratio of the organic solvent to magnolol and tetramethylpyrazine may be 0–20 mL: 1 mmol–10 mmol: 1 mmol–10 mmol.

[0036] In some embodiments, preferably, the volume molar ratio of the organic solvent to magnolol and tebufenozide can be 0–300 μL: 1 mmol–10 mmol: 1 mmol–10 mmol. In some embodiments, preferably, the volume molar ratio of the organic solvent to magnolol and tebufenozide can be 0–300 μL: 1 mmol: 1 mmol.

[0037] In some embodiments, the ball milling frequency can be 30Hz to 40Hz. In some embodiments, the ball milling frequency can be 32Hz to 38Hz. In some embodiments, the ball milling frequency can be 34Hz to 36Hz. In some embodiments, the ball milling frequency can be 35Hz.

[0038] In some embodiments, the ball milling time can be 30 min to 60 min. In some embodiments, the ball milling time can be 35 min to 55 min. In some embodiments, the ball milling time can be 40 min to 50 min. In some embodiments, the ball milling time can be 45 min to 50 min.

[0039] In some embodiments, the stirring time can be 1 hour.

[0040] In some embodiments, the stirring temperature can be 60°C to 80°C. In some embodiments, the stirring temperature can be 62°C to 78°C. In some embodiments, the stirring temperature can be 64°C to 76°C. In some embodiments, the stirring temperature can be 68°C to 74°C. In some embodiments, the stirring temperature can be 70°C to 72°C.

[0041] In some embodiments, the mixture can be cooled to -10°C or room temperature after stirring;

[0042] In some embodiments, the drying can be room temperature vacuum drying or room temperature vacuum drying. In some embodiments, preferably, the room temperature vacuum drying time can be 2 hours.

[0043] In some embodiments, the organic solvent may be selected from one or more of methanol, ethanol, n-propanol, n-butanol, isopropanol, isobutanol, isoamyl alcohol, tert-butanol, ethyl formate, ethyl acetate, isopropyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, chloroform, and dichloromethane. In some embodiments, preferably, the organic solvent may be selected from methanol, ethanol, or dichloromethane. In some embodiments, more preferably, the organic solvent may be selected from methanol or dichloromethane. In some embodiments, the solvent may be filtered before drying.

[0044] This application provides a cocrystal of magnolol-ligustrazine, which is prepared by the above-described method.

[0045] In some embodiments, the melting point of the eutectic with magnolol-ligustrazine can be 100±2℃;

[0046] In some embodiments, the unit cell parameters of the co-crystal with magnolol-ligustrazine can be... α=90.211(2)°, β=102.112(2)°, γ=93.805(2)°.

[0047] In some embodiments, the X-ray powder diffraction pattern of the cocrystal of magnolol and tetramethylpyrazine may have characteristic peaks at 5.6±0.2°, 11.0±0.2°, 13.9±0.2°, 14.6±0.2°, 15.0±0.2°, 17.0±0.2°, 21.7±0.2°, 22.8±0.2°, 23.1±0.2° or 23.4±0.2°.

[0048] In some embodiments, the infrared absorption spectrum of the cocrystal containing magnolol and tetramethylpyrazine is at least at 3075, 2970, 1637, 1607, 1503, 1413, 1268, 1232, 1184, 1123, 992, or 905 cm⁻¹. -1 It has characteristic peaks.

[0049] This application provides a composition comprising the above-mentioned magnolol-ligustrazine cocrystal and honey.

[0050] In some embodiments, the composition comprises, by weight, the following components: 0.7 to 0.9 parts of magnolol-ligustrazine cocrystal; and 0.1 to 0.3 parts of honey. In some embodiments, preferably, the composition comprises, by weight, the following components: 0.8 parts of magnolol-ligustrazine cocrystal; and 0.2 parts of honey.

[0051] In some embodiments, in addition to the magnolol-ligustrazine eutectic of this application, the composition may also contain an excess of ligustrazine, an excess of magnolol, and other pharmaceutically acceptable excipients. That is, the molar ratio of magnolol to ligustrazine in the raw materials of the composition is not particularly limited, as long as the raw materials can be used to prepare the aforementioned magnolol-ligustrazine eutectic. For example, the molar ratio of magnolol to ligustrazine in the composition can be 10:1 to 1:10, wherein a portion of the component exists in the form of a magnolol eutectic, while the other portion exists in a free form. Preferably, all magnolol is formed into a eutectic to overcome the defects of ligustrazine's low melting point and poor stability.

[0052] In some embodiments, the raw materials of the composition consist of honokiol and tetramethylpyrazine in a molar ratio of 1:1.01 to 1:3, and the molar amount of free tetramethylpyrazine in the composition is 101% to 200% of the molar amount of honokiol. When the free tetramethylpyrazine in the composition is within this ratio range, the composition has characteristic peaks in X-ray powder diffraction patterns expressed in 2θ angles at diffraction angles of 5.6±0.2, 11.0±0.2, 13.9±0.2, 14.6±0.2, 15.0±0.2, 17.0±0.2, 21.7±0.2, 22.8±0.2, 23.1±0.2, and 23.4±0.2 degrees. These peaks possess the characteristic peaks of the honokiol-tetramethylpyrazine eutectic of this application, thus confirming that the eutectic in this composition has the same crystal form as the eutectic of this invention. Specifically, differential scanning calorimetry (DSC) determined that the melting onset temperature of the composition was 100 ± 2 °C, and the maximum peak temperature was 102 ± 2 °C. When the free tetramethylpyrazine in the composition was within this proportion range, the infrared absorption spectra of the composition were at least at 3075, 2970, 1637, 1607, 1503, 1413, 1268, 1232, 1184, 1123, 992, and 905 cm⁻¹. -1 It has an absorption peak.

[0053] In some embodiments, in addition to the magnolol-ligustrazine cocrystal of the present invention, the composition may also contain other pharmaceutically acceptable excipients, such as honey used in the traditional Chinese medicine Shijunzi Wan. The magnolol-ligustrazine cocrystal honey composition, after ball milling, yields an amorphous cocrystal, which can further increase the water solubility of magnolol. For example... Figure 5 As shown, it contains 20% honey and 80% eutectic, and its water solubility is increased by 4 times.

[0054] This application also provides the use of the above-mentioned magnolol-ligustrazine cocrystal or the above-mentioned composition in the preparation of medicaments for treating cardiovascular and cerebrovascular diseases, antiplatelet aggregation and antitumor.

[0055] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the experimental materials used in the following examples were all purchased from conventional biochemical reagent companies. All quantitative experiments in the following examples were performed in triplicate, and the results were averaged.

[0056] Reagents and Instruments

[0057] Honokiol was purchased from Hunan Heguang Biotechnology Co., Ltd., with a purity of ≥99%.

[0058] The tetramethylpyrazine was purchased from Aladdin Reagents and has a purity of ≥98.5%.

[0059] Methanol and other reagents were all analytical grade and provided by Sinopharm Chemical Reagent Co., Ltd. Unless otherwise specified, the reagents and solvents used were not specially treated.

[0060] The honey is Guanshengyuan multifloral honey.

[0061] Thermal analysis

[0062] Instrument model: TGA 55 / DSC Q2000;

[0063] Heating rate: 10℃ / min;

[0064] Temperature range: 25-410℃;

[0065] Gas atmosphere: nitrogen.

[0066] Fourier transform infrared (FT-IR) spectroscopy

[0067] Instrument Model: ThermoFisher Nicolet TM iS50 FT-IR;

[0068] X-ray powder diffraction pattern (PXRD)

[0069] Instrument model: Bruker D8 Advance powder diffractometer;

[0070] Measurement conditions: copper target, 40 kV / 40 mA, start angle 3°, end angle 40°, step width 0.02, scan speed 0.1 sec / step, wavelength

[0071] X-ray single-crystal diffraction (SCXRD)

[0072] Experimental method: Colorless crystals with sizes of 0.3 mm, 0.2 mm, and 0.05 mm were selected, and Mo-Kα rays were used at a wavelength of [wavelength missing]. The measurement temperature was 150(2) K. The structure refinement and analysis were performed using SHELXT and Olex 2 programs. The atomic positions were determined by the direct method, and then the coordinates of all non-hydrogen atoms were obtained by the difference function method and the least squares method. Finally, the structure was refined by the least squares method.

[0073] Example 1

[0074] Weigh 1.33 g (5 mmol) of magnolol and 0.68 g (5 mmol) of ligustrazine (stoichiometric ratio 1:1), place them in a ball mill jar (Shanghai Jingxin grinder), add 200 μL of methanol, add an appropriate amount of grinding balls, and ball mill at 40 Hz for half an hour at room temperature. Dry under reduced pressure at room temperature for 2 hours to obtain magnolol-ligustrazine eutectic, which is a free-flowing crystalline powder with a yield of 98%.

[0075] Example 2

[0076] Weigh 1.33 g (5 mmol) of magnolol and 0.68 g (5 mmol) of ligustrazine (stoichiometric ratio 1:1), place them in a ball mill jar, add an appropriate amount of grinding balls, and ball mill at 40 Hz for 1 hour at room temperature. Then dry under reduced pressure at room temperature for 2 hours to obtain magnolol-ligustrazine eutectic, which is a free-flowing crystalline powder with a yield of 98%.

[0077] Example 3

[0078] Weigh 2.66 g (10 mmol) of magnolol and 1.36 g (10 mmol) of ligustrazine (stoichiometric ratio 1:1), place them in a ball mill jar, add 300 μL of dichloromethane, add an appropriate amount of grinding balls, and ball mill at 30 Hz for half an hour at room temperature. Dry under reduced pressure at room temperature for 2 hours to obtain magnolol-ligustrazine eutectic, which is a free-flowing crystalline powder with a yield of 99%.

[0079] Example 4

[0080] Weigh 266 mg (1 mmol) of magnolol and 136 mg (1 mmol) of ligustrazine (stoichiometric ratio 1:1), place them in a ball mill jar (Shanghai Jingxin grinder), add 100 μL of methanol, add an appropriate amount of grinding balls, and ball mill at 35 Hz for half an hour at room temperature. Dry under reduced pressure at room temperature for 2 hours to obtain magnolol-ligustrazine eutectic, which is a crystalline powder with good flowability and a yield of 97%.

[0081] Example 5

[0082] 1.33 g (5 mmol) of magnolol and 0.68 g (5 mmol) of ligustrazine (stoichiometric ratio 1:1) were added to 20 mL of ethanol. After stirring at 60 °C for 1 h, the mixture was cooled to room temperature and recrystallized to obtain a white precipitate. The precipitate was filtered and placed in a vacuum drying oven to dry at room temperature to obtain magnolol-ligustrazine cocrystal with a yield of 89%.

[0083] Example 6

[0084] 1.33 g (5 mmol) of magnolol and 0.68 g (5 mmol) of ligustrazine (stoichiometric ratio 1:1) were added to 20 mL of dichloromethane. After stirring at 80 °C for 1 h, the mixture was cooled to room temperature and recrystallized to obtain a white precipitate. The precipitate was filtered and placed in a vacuum drying oven to dry at room temperature to obtain magnolol-ligustrazine cocrystal with a yield of 85%.

[0085] The mother liquor (5 mL) was evaporated at room temperature to obtain bulk single crystals with the following cell parameters: α=90.211(2)°, β=102.112(2)°, γ=93.805(2)°.

[0086] Example 7

[0087] 1.33 g (5 mmol) of magnolol and 0.68 g (5 mmol) of ligustrazine (stoichiometric ratio 1:1) were added to 20 mL of methanol. After stirring at 70 °C for 1 h, the mixture was cooled to -10 °C and recrystallized to obtain a white precipitate. The precipitate was filtered and placed in a vacuum drying oven to dry at room temperature to obtain magnolol-ligustrazine cocrystal with a yield of 91%.

[0088] Example 8

[0089] 0.8g of the cocrystal of magnolol-ligustrazine prepared in Example 1 was placed in a ball mill jar (Shanghai Jingxin grinder), 0.2g of honey was added, and an appropriate amount of grinding balls were added. The mixture was ball-milled at a frequency of 40Hz for half an hour at room temperature to obtain the magnolol-ligustrazine honey composition, which is an amorphous powder with good flowability and a yield of 98%.

[0090] Example 9 - Stability Test

[0091] Instrument Model: DVS Intrinsic Dynamic Moisture Adsorption Analyzer (SMS Corporation)

[0092] Experimental method: The sample is passed through a 100-mesh sieve. 20-40 mg of the test sample is weighed and placed in an open aluminum dish. Under the conditions of 25℃ and 10% RH, the weight change of the sample is recorded over 24 hours.

[0093] Experimental results are as follows Figure 5 As shown, the co-crystal of magnolol and tetramethylpyrazine significantly reduced the sublimation properties of tetramethylpyrazine. Within 24 hours, the weight loss rate of the magnolol-tetramethylpyrazine co-crystal was only 0.12%, while the weight loss rate of the tetramethylpyrazine raw material was 46%. Due to the hydrogen bond interactions in the magnolol-tetramethylpyrazine co-crystal, the energy required for tetramethylpyrazine to escape from the co-crystal molecules increased, resulting in a significant improvement in the stability of the tetramethylpyrazine raw material.

[0094] Example 10 - Solubility Experiment Test

[0095] Experimental method: The sample was passed through a 100-mesh sieve. 50 mg of the test sample was weighed and added to 15 mL of deionized water. The mixture was stirred at 37℃ and 25 rpm. 0.5 mL samples were taken at 5, 10, 15, 30, 45, 60, 75, and 90 min, filtered through a membrane, and the filtrate was used as the test sample for analysis. The experiment was performed in triplicate.

[0096] Liquid chromatography conditions: High performance liquid chromatograph: SHIMADZO LC-20AT; Column: ZORBAX Extend C 18 4.6 × 150 mm, 5 μm column; mobile phase: acetonitrile:water = 60:40; detection wavelength: 290 nm; flow rate: 1 mL / min; column temperature: 35 ℃; injection volume: 20 μL; run time: 15 min. Retention time of magnolol: 4.74 min.

[0097] Experimental results are as follows Figure 6 As shown in the figure, the formation of cocrystals significantly improves the solubility of magnolol compared to magnolol-tetracycline alone. At 90 minutes, the dissolution value of the cocrystals is 1.8 times that of magnolol, and the cocrystal honey composition is 4 times that of magnolol.

[0098] The basic concepts have been described above. Obviously, for those skilled in the art, the detailed disclosure above is merely illustrative and does not constitute a limitation of this specification. Although not explicitly stated herein, those skilled in the art may make various modifications, improvements, and corrections to this specification. Such modifications, improvements, and corrections are suggested in this specification and therefore remain within the spirit and scope of the exemplary embodiments described herein.

[0099] Furthermore, this specification uses specific terms to describe embodiments thereof. For example, "an embodiment," "one embodiment," and / or "some embodiments" refer to a particular feature, structure, or characteristic associated with at least one embodiment of this specification. Therefore, it should be emphasized and noted that references to "an embodiment," "one embodiment," or "an alternative embodiment" in different locations throughout this specification do not necessarily refer to the same embodiment. Moreover, certain features, structures, or characteristics in one or more embodiments of this specification can be appropriately combined.

[0100] In some embodiments, numbers describing the quantity of components and attributes are used. It should be understood that such numbers used in the description of embodiments are modified in some examples with the terms "approximately," "approximately," or "generally." Unless otherwise stated, "approximately," "approximately," or "generally" indicates that the numbers are allowed to vary by ±20%. Accordingly, in some embodiments, the numerical parameters used in the specification and claims are approximate values, which may be changed depending on the characteristics required by individual embodiments. In some embodiments, numerical parameters should take into account specified significant digits and employ a general method of digit reservation. Although the numerical ranges and parameters used to confirm their breadth of range in some embodiments of this specification are approximate values, in specific embodiments, such values ​​are set as precisely as feasible.

[0101] Finally, it should be understood that the embodiments described in this specification are merely illustrative of the principles of the embodiments described herein. Other variations may also fall within the scope of this specification. Therefore, alternative configurations of the embodiments described herein are intended to be illustrative rather than limiting, and should be considered consistent with the teachings of this specification. Accordingly, the embodiments described herein are not limited to those explicitly introduced and described herein.

Claims

1. A method for preparing a co-crystal of magnolol and tetramethylpyrazine, characterized in that, include: Honokiol and tetramethylpyrazine were mixed, ball-milled / stirred, and dried to obtain honokiol-tetramethylpyrazine eutectic. The molar ratio of magnolol and tetramethylpyrazine is 1:1; The unit cell parameters of the co-crystal of magnolol and tetramethylpyrazine are as follows: α=90.211(2)°, β=102.112(2)°, γ=93.805(2)°.

2. The preparation method according to claim 1, characterized in that, During the ball milling / stirring, an organic solvent is added; the volume molar ratio of the organic solvent to magnolol and tetramethylpyrazine is 0-20 mL: 1 mmol-10 mmol: 1 mmol-10 mmol. And / or, the frequency of the ball mill is 30Hz to 40Hz; And / or, the ball milling time is 30 min to 60 min; And / or, the stirring time is 1 hour; And / or, the stirring temperature is 60℃~80℃; And / or, the stirring is followed by cooling to -10°C or room temperature; And / or, the drying is room temperature vacuum drying or room temperature vacuum drying.

3. The preparation method according to claim 2, characterized in that, The organic solvent is selected from one or more of methanol, ethanol, n-propanol, n-butanol, isopropanol, isobutanol, isoamyl alcohol, tert-butanol, ethyl formate, ethyl acetate, isopropyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, chloroform, and dichloromethane; And / or, the pre-drying filtration; And / or, the volume molar ratio of the organic solvent to magnolol and tetramethylpyrazine is 0–300 μL: 1 mmol–10 mmol: 1 mmol–10 mmol; And / or, the drying time under reduced pressure at room temperature is 2 hours.

4. The preparation method according to claim 3, characterized in that, The organic solvent is selected from methanol, ethanol or dichloromethane.

5. The preparation method according to claim 3, characterized in that, The organic solvent is selected from methanol or dichloromethane.

6. A cocrystal of magnolol-ligustrazine, prepared by the preparation method according to any one of claims 1-5, wherein the melting point of the cocrystal of magnolol-ligustrazine is 100±2℃; And / or, the X-ray powder diffraction pattern of the cocrystal of magnolol-ligustrazine has characteristic peaks at 5.6±0.2°, 11.0±0.2°, 13.9±0.2°, 14.6±0.2°, 15.0±0.2°, 17.0±0.2°, 21.7±0.2°, 22.8±0.2°, 23.1±0.2° or 23.4±0.2°.

7. The co-crystal of magnolol and tetramethylpyrazine as described in claim 6, characterized in that, The infrared absorption spectra of the cocrystal containing magnolol and tetramethylpyrazine are at 3075, 2970, 1637, 1607, 1503, 1413, 1268, 1232, 1184, 1123, 992, or 905 cm⁻¹. -1 It has characteristic peaks.

8. A composition comprising the cocrystal of magnolol-ligustrazine as described in claim 6 or 7 and honey.

9. The composition according to claim 8, characterized in that, The composition comprises the following components by weight: 0.7-0.9 parts of magnolol-ligustrazine eutectic; and 0.1-0.3 parts of honey.

10. The composition according to claim 8, characterized in that, The composition comprises the following components by weight: 0.8 parts of magnolol-ligustrazine eutectic; and 0.2 parts of honey.

11. Use of the composition as described in claim 6 or 7 and the composition as described in any one of claims 8 to 10 in the preparation of medicaments for treating cardiovascular and cerebrovascular diseases, inhibiting platelet aggregation and antitumor activity.

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