Berberine hydrochloride-maleic acid eutectic crystal and preparation and application thereof

Abstract

The invention relates to the technical field of pharmaceutical co-crystals, in particular to a berberine hydrochloride-maleic acid co-crystal as well as preparation and application thereof. The berberine hydrochloride-maleic acid eutectic crystal is a crystal formed by taking berberine hydrochloride as an active pharmaceutical ingredient (API) and taking maleic acid as a eutectic former (CCF), the berberine hydrochloride-maleic acid eutectic crystal is a monoclinic system, the space group is P-21 / c, and the cell parameters are as follows: # imgabs 0 # alpha / degree = 90, beta / degree = 94.793 (3), gamma / degree = 90 and # imgabs 1 #. The berberine hydrochloride-maleic acid eutectic crystal provided by the invention can improve the thermal stability of berberine hydrochloride, does not influence the dissolution rate and dissolution rate of berberine hydrochloride, and can enhance the pharmaceutical and therapeutic application of berberine hydrochloride.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical co-crystals, and in particular to a berberine hydrochloride-maleic acid co-crystal and a preparation method and application thereof. Background Art

[0002] In recent years, during the drug development research stage, it is generally necessary to determine the optimal solid form of the drug based on the drug properties and the requirements of the target formulation. According to the structure and composition classification, the solid forms of drugs mainly include salts, hydrates, solvates, cocrystals and amorphous forms. In the drug cocrystal system, the interactions between API (active pharmaceutical ingredient) and CCF (cocrystal former) include hydrogen bonds, halogen bonds, π-π conjugation and van der Waals forces, among which the most common are hydrogen bonds and π-π conjugation. Different solid forms of the same drug often have different physical and chemical properties. The main purpose of studying drug cocrystals is to improve the physical and chemical properties of drugs, such as melting point, stability, solubility, bioavailability, etc., without changing the covalent structure of the drug.

[0003] The drug cocrystal formed by active drug molecules and appropriate compounds has many advantages: (1) Due to the introduction of CCF, the spatial stacking structure of API drugs is changed, thereby changing its solubility and dissolution, and ultimately improving the bioavailability of drugs in the body; (2) Due to the interaction between API and CCF, the melting point of drug cocrystals will be different from the melting point of the original drug, and the melting point of drug cocrystals is usually between API and CCF; (3) Most drugs are stable under low humidity conditions, while at high humidity, API is easy to interact with water and hydrate or degrade. If the drug is prepared into a cocrystal, the hydrogen bonds formed between API and CCF make it difficult for API to hydrogen bond with water molecules, reducing the hygroscopicity of the drug. It is concluded that cocrystals are an effective way to reduce the hygroscopicity of drugs. Based on the above characteristics, the synthesis and properties of drug cocrystals have shown attractive application prospects in the fields of pharmacology and biomedicine. Cocrystals are a new solid form of drugs that have been widely studied by scholars at home and abroad in recent years and are expected to become an important aspect of new drug research and development.

[0004] The research on drug cocrystals has developed rapidly at home and abroad. Crystalline drugs have important research significance in improving the properties of raw materials and increasing their bioavailability, and have broad application prospects. Berberine hydrochloride is an isoquinoline alkaloid, mainly used to treat gastroenteritis, bacterial dysentery and other intestinal infections, conjunctivitis, suppurative otitis media, etc., and also has antiarrhythmic effects by blocking α receptors; berberine hydrochloride has multiple pharmacological activities and good clinical efficacy, but its oral bioavailability (less than 5%) is low, the half-life is short, and the therapeutic effect is poor. It also exhibits solid-state instability. During the production or transportation of drugs, the content of crystal water will change with changes in humidity and temperature, and solid-state conversion will be carried out between monohydrate, dihydrate and tetrahydrate. Its solid-phase instability seriously affects the quality control and clinical treatment effect of drugs.

[0005] Therefore, it is very important to provide a berberine hydrochloride-maleic acid cocrystal that can solve the above technical problems. Summary of the invention

[0006] In order to solve the above problems, the purpose of the present invention is to provide a berberine hydrochloride-maleic acid cocrystal and its preparation and application. The berberine hydrochloride-maleic acid cocrystal provided by the present invention can improve the thermal stability of berberine hydrochloride, does not affect the solubility and dissolution rate of berberine hydrochloride, and can also enhance the pharmaceutical and therapeutic applications of berberine hydrochloride.

[0007] The chemical name of berberine hydrochloride is 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolane[5,6-a]quinolizine hydrochloride, and its molecular formula is C 20 H 18 ClNO4, the structural formula is shown in formula (I):

[0008]

[0009] Maleic acid (C4H4O4, MW is 116.07) is a crystalline, colorless crystalline solid that is in solid form at room temperature. Its melting point is in the range of 130-135°C. Under standard conditions, maleic acid is soluble in solvents such as water, ethanol and acetone. The structural formula is shown in formula (II):

[0010]

[0011] In the present invention, the grinding method (dry grinding method and liquid-assisted grinding method) generates hydrogen bonds or other intermolecular forces between solid molecules through mechanical forces to form eutectics. The suspension method is to fully dissolve the eutectic former to saturation and then add the active pharmaceutical ingredient, and stir thoroughly to allow the two solid molecules to generate hydrogen bonds or other intermolecular forces to form eutectics.

[0012] The purpose of the present invention can be achieved by the following technical solutions:

[0013] The first object of the present invention is to provide a berberine hydrochloride-maleic acid cocrystal, wherein the berberine hydrochloride-maleic acid cocrystal has berberine hydrochloride as an active pharmaceutical ingredient (API) and maleic acid as a cocrystal former (CCF), and the crystal formed is a monoclinic system with a space group of P-2 1 / c , the unit cell parameters are: α / °=90, β / °=94.793(3), γ / °=90,

[0014] Furthermore, the berberine hydrochloride-maleic acid cocrystal has characteristic peaks at diffraction angles 2θ of 8.0°±0.2, 10.5°±0.2, 13.6°±0.2, 17.5°±0.2, 18.2°±0.2, 24.6°±0.2, 25.6°±0.2, and 27.4°±0.2.

[0015] Further, the berberine hydrochloride-maleic acid eutectic is at 2860±5cm -1 、1590±5cm -1 、1690±5cm -1 There are characteristic peaks.

[0016] Furthermore, the hydrogen atom in the berberine hydrochloride molecule acts as a hydrogen bond acceptor, and the oxygen atom of the carboxyl group in the maleic acid molecule acts as a hydrogen bond donor to form intermolecular hydrogen bonds.

[0017] Furthermore, the quaternary ammonium cations of the berberine hydrochloride are stacked along the a-axis to form columns, and interact with the adjacent chloride anions of the berberine hydrochloride to maintain charge neutrality; between the two berberine hydrochloride columnar layers, there is a layer of maleic acid molecules; each chloride anion of berberine hydrochloride is connected to the berberine hydrochloride columnar layer by two OH…Cl - The hydrogen bond interaction connects with the OH in an adjacent maleic acid molecule and connects with the OH in a adjacent maleic acid molecule through two forked CH…Cl - It is connected to a berberine hydrochloride CH; at the same time, a maleic acid molecule and a berberine hydrochloride are connected by a CH...O hydrogen bond; CH...O intramolecular hydrogen bonds are formed within the maleic acid molecule and the berberine hydrochloride molecule.

[0018] The second object of the present invention is to provide a method for preparing berberine hydrochloride-maleic acid cocrystal, which is selected from one of the following preparation methods:

[0019] Preparation method 1: berberine hydrochloride and maleic acid are mixed and ground to obtain berberine hydrochloride-maleic acid eutectic;

[0020] Preparation method 2: berberine hydrochloride and maleic acid are mixed and placed in a solvent, and then ground to obtain berberine hydrochloride-maleic acid eutectic;

[0021] Preparation method three: berberine hydrochloride, maleic acid and a solvent are mixed, suspended and then crystallized to obtain berberine hydrochloride-maleic acid eutectic.

[0022] In one embodiment of the present invention, in the preparation method 1, the molar ratio of berberine hydrochloride to maleic acid is 1:0.92-2;

[0023] During the grinding process, the grinding speed is 10-800 r / min, the temperature is 15°C-35°C, and the time is 0.5-8h.

[0024] In one embodiment of the present invention, in the preparation method 2, the molar ratio of berberine hydrochloride to maleic acid is 1:0.92-2;

[0025] The dosage ratio of the mixture of berberine hydrochloride and maleic acid to the solvent is 2 to 12 g / mL;

[0026] During the grinding process, the grinding speed is 10-800 r / min, the temperature is 15°C-35°C, and the time is 0.5-8h.

[0027] In one embodiment of the present invention, in the preparation method 2, the solvent is selected from one or more of methanol, ethanol, isopropanol, n-propanol or acetone.

[0028] In one embodiment of the present invention, in the preparation method three, the molar ratio of berberine hydrochloride to maleic acid is 1:0.92-2;

[0029] The dosage ratio of the mixture of berberine hydrochloride and maleic acid to the solvent is 2 to 12 g / mL;

[0030] The suspension method is selected from stirring or ultrasound;

[0031] During the suspension process, the temperature is 15-35°C and the time is 3-8 hours.

[0032] In one embodiment of the present invention, in the preparation method three, the solvent is selected from one or more of methanol, ethanol, isopropanol, n-propanol or acetone.

[0033] The third object of the present invention is to provide an application of berberine hydrochloride-maleic acid cocrystal in the field of drug preparation.

[0034] The fourth object of the present invention is to provide a drug, which is prepared by the above-mentioned berberine hydrochloride-maleic acid cocrystal.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] The berberine hydrochloride-maleic acid eutectic prepared by the present invention improves the stability of berberine hydrochloride, and the dissolution is basically consistent with that of berberine hydrochloride; the preparation process of the present invention is simple and easy to control, the yield and purity are high, it is suitable for industrial production, and the cost is low. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 Experimental and simulated powder X-ray diffraction analysis spectra of berberine hydrochloride-maleic acid cocrystal.

[0038] Figure 2 Schematic diagram of the asymmetric structural unit of the berberine hydrochloride-maleic acid cocrystal of the present invention.

[0039] Figure 3 Schematic diagram of hydrogen bonding of berberine hydrochloride-maleic acid cocrystal.

[0040] Figure 4 This is the infrared spectrum of berberine hydrochloride-maleic acid cocrystal.

[0041] Figure 5 This is the thermogravimetric analysis diagram of berberine hydrochloride-maleic acid cocrystal.

[0042] Figure 6 This is the differential scanning calorimetry analysis diagram of berberine hydrochloride-maleic acid cocrystal.

[0043] Figure 7 This is the dissolution curve of berberine hydrochloride-maleic acid eutectic and berberine hydrochloride raw material.

[0044] Figure 8 This is the intrinsic dissolution rate curve of berberine hydrochloride-maleic acid cocrystal and berberine hydrochloride raw material. DETAILED DESCRIPTION

[0045] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0046] In the following examples, unless otherwise specified, all reagents used are commercially available reagents, and all monitoring means and methods used are conventional detection means and methods in the art.

[0047] Example 1

[0048] This embodiment provides a method for preparing berberine hydrochloride-maleic acid cocrystal, which specifically comprises the following steps:

[0049] Weigh 200 mg of berberine hydrochloride dihydrate and 57 mg of maleic acid, put them into a clean agate mortar, and grind them at room temperature of 25°C for one hour to obtain berberine hydrochloride-maleic acid eutectic.

[0050] Among them, it should be emphasized that when the preparation process is as follows, berberine hydrochloride-maleic acid eutectic with equivalent performance to that of this embodiment can be prepared;

[0051] The molar ratio of berberine hydrochloride to maleic acid is 1:0.92-2;

[0052] During the grinding process, the grinding speed is 10-800 r / min, the temperature is 15°C-35°C, and the time is 0.5-8h.

[0053] Example 2

[0054] This embodiment provides a method for preparing berberine hydrochloride-maleic acid cocrystal, which specifically comprises the following steps:

[0055] Weigh 200 mg of berberine hydrochloride dihydrate and 57 mg of maleic acid, dissolve them in methanol reagent, transfer them to a clean agate mortar, and grind them at room temperature of 25°C for one hour to obtain berberine hydrochloride-maleic acid eutectic.

[0056] Among them, it should be emphasized that when the preparation process is as follows, berberine hydrochloride-maleic acid eutectic with equivalent performance to that of this embodiment can be prepared;

[0057] The molar ratio of berberine hydrochloride to maleic acid is 1:0.92-2;

[0058] The dosage ratio of the mixture of berberine hydrochloride and maleic acid to the solvent is 2 to 12 g / mL;

[0059] During the grinding process, the grinding speed is 10-800 r / min, the temperature is 15°C-35°C, and the time is 0.5-8h.

[0060] The methanol reagent is replaced by one or more of methanol, ethanol, isopropanol, n-propanol or acetone.

[0061] Example 3

[0062] This embodiment provides a method for preparing berberine hydrochloride-maleic acid cocrystal, which specifically comprises the following steps:

[0063] Weigh 200 mg of berberine hydrochloride dihydrate and 57 mg of maleic acid, put them into a clean glass bottle, then inject 20 mL of a mixture of methanol and chloroform (methanol and chloroform mixed in a volume ratio of 10:1) into it, and perform ultrasonic treatment to completely dissolve it until a transparent solution is obtained, then place it in a fume hood for slow evaporation, and crystals can be observed within 3 to 4 hours. The resulting crystals are berberine hydrochloride-maleic acid eutectics.

[0064] Among them, it should be emphasized that when the preparation process is as follows, berberine hydrochloride-maleic acid eutectic with equivalent performance to that of this embodiment can be prepared;

[0065] The molar ratio of berberine hydrochloride to maleic acid is 1:0.92-2;

[0066] The dosage ratio of the mixture of berberine hydrochloride and maleic acid to the solvent is 2 to 12 g / mL;

[0067] During the suspension process, the temperature is 15-35°C and the time is 3-8h;

[0068] Or, ultrasound treatment can be replaced with stirring treatment;

[0069] During the stirring process, the temperature is 15-35°C and the time is 3-8 hours.

[0070] The mixed solution of methanol and chloroform is replaced with one or more of methanol, ethanol, isopropanol, n-propanol or acetone.

[0071] The berberine hydrochloride-maleic acid cocrystal prepared in Example 1 above was characterized by powder X-ray diffraction analysis (PXRD), infrared analysis (IR), and thermogravimetric and differential scanning calorimetry (TG-DSC). The specific process is as follows:

[0072] (1) PXRD Identification of Berberine Hydrochloride-Maleic Acid Cocrystal

[0073] Instrument: X-ray diffractometer (BRUKER, Germany, model D8);

[0074] Detection conditions: Cu-Ka target, tube voltage 30 kV, tube current 10 mA, scanning range θ 5° to 45°, scanning speed 8° / min, step width 0.015.

[0075] A powder XRD diffraction experiment was performed on the berberine hydrochloride-maleic acid eutectic powder prepared in Example 1 according to the above-mentioned detection conditions.

[0076] The PXRD spectra of the berberine hydrochloride-maleic acid eutectic, the berberine hydrochloride and maleic acid blend (molar ratio 1:1), and the berberine hydrochloride and maleic acid prepared in Example 1 are as follows: Figure 1 As shown, the berberine hydrochloride-maleic acid cocrystal prepared in Example 1 has characteristic peaks at diffraction angles 2θ of 8.0°±0.2, 10.5°±0.2, 13.6°±0.2, 17.5°±0.2, 18.2°±0.2, 24.6°±0.2, 25.6°±0.2, and 27.4°±0.2; berberine hydrochloride has characteristic peaks at diffraction angles 2θ of 6.7°±0.2, 9.0°±0.2, 13.7°±0.2, 16.2°±0.2, 25.3°±0.2, 26.2°±0.2, 28.1°±0.2, and 32.1°±0.2; maleic acid has a characteristic peak mainly at a diffraction angle 2θ of 28.1°±0.2.

[0077] The characteristic peaks of berberine hydrochloride at 6.7°, 16.2°, 28.1°, and 32.1° and the characteristic peak of maleic acid at 28.7° have all disappeared in the eutectic, and new diffraction peaks appear at 8.0°, 17.5°, and 18.3° in the berberine hydrochloride-maleic acid eutectic. The results show that the PXRD spectrum of berberine hydrochloride-maleic acid eutectic is significantly different from that of berberine hydrochloride and maleic acid, indicating that a new crystal phase has been formed between berberine hydrochloride and maleic acid molecules; and the PXRD diffraction pattern of berberine hydrochloride-maleic acid eutectic is superimposed and compared with the diffraction pattern obtained by single crystal calculation simulation, and the two are consistent; indicating that the molecular structure of the prepared berberine hydrochloride-maleic acid eutectic powder is consistent with the single crystal structure.

[0078] The characteristic peaks of diffraction angle 2θ, crystal structure and unit cell parameters of the berberine hydrochloride-maleic acid cocrystals prepared in Examples 2 and 3 by PXRD identification are the same as those in Example 1. This indicates that the dry grinding method (Example 1), the wet grinding method (Example 2) and the saturated liquid suspension method (Example 3) also promote the reaction between berberine hydrochloride and maleic acid to generate a new phase.

[0079] (2) Unit cell parameter test of berberine hydrochloride-maleic acid eutectic

[0080] The powder sample obtained by dry grinding in Example 1 was subjected to a single crystal X-ray diffraction experiment. The eutectic structure was determined by a single crystal X-ray diffractometer (Bruker SMART Apex II diffractometer), with Mo-Ka scanning at 293K; the schematic diagram of the asymmetric structural unit of berberine hydrochloride-maleic acid eutectic is shown in Figure 2 shown.

[0081] The crystallographic data of the berberine hydrochloride-maleic acid cocrystal prepared in Example 1 are shown in Table 1:

[0082] Table 1 Crystallographic data of berberine hydrochloride-maleic acid cocrystal

[0083]

[0084] The hydrogen bond (blue) connection mode of the berberine hydrochloride-maleic acid cocrystal prepared in Example 1 is as follows Figure 3As shown, the quaternary ammonium cations of berberine hydrochloride are stacked along the a-axis to form columns, and interact with the adjacent chloride anions of berberine hydrochloride to maintain charge neutrality; there is a layer of maleic acid molecules between two berberine hydrochloride columnar layers; each chloride anion of berberine hydrochloride is connected to the OH in an adjacent maleic acid molecule through two OH...Cl- hydrogen bond interactions, and is connected to a berberine hydrochloride CH through two forked CH...Cl-; at the same time, a maleic acid molecule and a berberine hydrochloride are connected by CH...O hydrogen bonds; CH...O intramolecular hydrogen bonds are formed within the maleic acid molecule and the berberine hydrochloride molecule.

[0085] (3) Infrared characterization of berberine hydrochloride-maleic acid cocrystal

[0086] Instrument: Fourier transform infrared spectrometer (BRUKER, Germany, Equinox 55);

[0087] Detection conditions: scanning band is 4000~400cm -1 , the sample is KBr solid pellet, resolution: 1cm -1 .

[0088] The berberine hydrochloride-maleic acid eutectic powder prepared in the above example was subjected to infrared spectroscopy scanning according to the above detection conditions.

[0089] The infrared spectrum of berberine hydrochloride-maleic acid cocrystal prepared in Example 1 is as follows Figure 4 As shown, at least at about 2860cm -1 、1590cm -1 、1690cm -1 There are characteristic peaks.

[0090] (4) TG-DSC (Differential Scanning Calorimetry / Thermogravimetry) Test of Berberine Hydrochloride-Maleic Acid Cocrystal

[0091] TG-DSC (Differential Scanning Calorimetry / Thermogravimetry) Test of Berberine Hydrochloride-Maleic Acid Cocrystal

[0092] Instrument: TG-DSCA Synchronous Thermal Analyzer SDT-Q600 (TA Instruments, USA)

[0093] Detection conditions: nitrogen atmosphere, gas flow rate: 10 mL / min, heating rate: 10 °C / min, test temperature range: room temperature ~ 250 °C.

[0094] The TG spectra of the berberine hydrochloride-maleic acid cocrystal and berberine hydrochloride prepared in Example 1 are as follows: Figure 5As shown in Figure 1, the thermal behavior of the eutectic was studied using TG-DSC. In the temperature range of room temperature to 100°C, berberine hydrochloride has a mass loss of 8.67%, which is equivalent to the theoretical content of berberine hydrochloride dihydrate (8.8%). Berberine hydrochloride has an endothermic peak at 87.1°C, which is caused by the dehydration of berberine hydrochloride; there is a sharp endothermic peak at 191.1°C. At this temperature, the TG curve shows an obvious weight loss, which corresponds to the melting decomposition behavior of berberine hydrochloride.

[0095] The DSC spectra of berberine hydrochloride-maleic acid cocrystal and berberine hydrochloride are as follows: Figure 6 As shown. Figure 6 It can be seen that in the temperature range of room temperature to 100°C, the mass loss of berberine hydrochloride-maleic acid eutectic is 0.52%. Figure 5 There is no endothermic peak between room temperature and 100°C, which indicates that the adsorbed water is lost. The endothermic peak at 192.8°C is the melting endothermic peak formed by the melting of berberine hydrochloride-maleic acid eutectic, indicating that the stability of berberine hydrochloride is improved after the eutectic is formed.

[0096] The TG-DSC test results of the berberine hydrochloride-maleic acid co-crystals prepared in Examples 2 and 3 were the same as those in Example 1.

[0097] (5) Dissolution Determination of Berberine Hydrochloride-Maleic Acid Cocrystal

[0098] 1) Determination of the optimal absorption wavelength

[0099] The dissolution of berberine hydrochloride-maleic acid cocrystal was determined by the standard curve method, instrument: Agilent LC1260 high performance liquid chromatograph; detection conditions: Agilent-C18 chromatographic column (4.6 mm×150 nm, 5 μm), mobile phase: gradient elution of a solution prepared by 0.4% phosphoric acid solution and methanol in a ratio of 60:40, flow rate: 1 mL / min, detection wavelength: 230 nm, column temperature of 30°C, injection volume of 10 μL.

[0100] The ultraviolet absorption spectrum scanning results of berberine hydrochloride saturated aqueous solution in the wavelength range of 200-800nm ​​showed that berberine hydrochloride had a strong absorption peak at 230nm. Therefore, the wavelength of 230nm was selected to determine the solubility and dissolution rate of berberine hydrochloride-maleic acid cocrystal.

[0101] 2) Standard curve drawing

[0102] Accurately weigh appropriate amounts of berberine hydrochloride to prepare 0.0098 mg / mL, 0.0197 mg / mL, 0.0491 mg / mL, 0.0983 mg / mL, 0.1474 mg / mL, and 0.1965 mg / mL standard solutions, respectively. The standard solutions were filtered through a 0.45 μL filter membrane and injected separately. The peak area was determined according to the above-mentioned HPLC detection conditions. The linear equation was Y=38273X, r=0.9999, indicating that the berberine hydrochloride mass concentration had a good linear relationship in the range of 0.0098 to 0.1965 mg / mL.

[0103] 3) Dissolution determination of berberine hydrochloride-maleic acid cocrystal

[0104] The powder dissolution was determined by the slurry method. Berberine hydrochloride dihydrate and the berberine hydrochloride-maleic acid eutectic powder prepared in Example 1 were fully ground and passed through a 100-mesh sieve to control the particle size to be uniform. Based on the amount of berberine hydrochloride contained in each sample of 100 mg, the berberine hydrochloride-maleic acid eutectic powder and berberine hydrochloride powder were respectively put into 900 mL of deionized water. The temperature was 37 ° C, the speed was 50 rpm, and the interval sampling time included 8 time points from 5 min to 120 min, such as: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min. In order to ensure the constancy of the total dissolution medium in the experiment, while taking out 5 mL of solution, 5 mL of fresh deionized water should be added to the dissolution cup. HPLC was used to determine the peak area at a wavelength of 230 nm absorption, and the concentration at different time nodes was calculated according to the standard curve. The measurement was repeated three times.

[0105] The dissolution test results of berberine hydrochloride (API) raw material and berberine hydrochloride-maleic acid eutectic prepared in Example 1 are as follows: Figure 7 As shown in the figure, the dissolution rate of berberine hydrochloride-maleic acid cocrystal is basically the same as that of berberine hydrochloride.

[0106] 4) Determination of intrinsic dissolution rate of berberine hydrochloride-maleic acid cocrystal

[0107] Intrinsic dissolution rate (IDR) refers to the amount of drug dissolved per unit time and per unit area in a specific medium. It is usually expressed in mg / (min·cm 2 The test was performed using a sheet-like solid sample sealed in paraffin with only the drug-releasing surface exposed.

[0108] The intrinsic dissolution rate of the raw material berberine hydrochloride and berberine hydrochloride-maleic acid cocrystal was determined by the paddle method. Berberine hydrochloride and the berberine hydrochloride-maleic acid cocrystal prepared in Example 1 were fully ground and passed through a 100-mesh sieve to control the particle size uniformity. Accurately weigh 250 mg of berberine hydrochloride powder and berberine hydrochloride-maleic acid cocrystal powder, and use an infrared tablet press to prepare the tablets used for the test. The pressure is 15 MPa, the pressing time is 3 minutes, and the tablet radius is 6 mm. The obtained tablets also need to be sealed on one side with solid paraffin to ensure that only one surface is exposed. Put it into 900 mL of deionized water. Temperature 37℃; rotation speed 100rpm; sample sampling intervals include 10 time points from 4min to 60min, such as: 4min, 7min, 10min, 15min, 20min, 25min, 30min, 40min, 50min, 60min. To ensure the constancy of the total dissolution medium in the experiment, 5mL of fresh deionized water should be added to the dissolution cup while taking out 5mL of dissolution medium. Use HPLC to measure the peak area at a wavelength of 230nm, and calculate the concentration at different time points based on the standard curve. Repeat the measurement three times.

[0109] As an important physicochemical parameter, intrinsic dissolution rate can predict the dissolution behavior of drug preparations to a certain extent, and provide necessary reference for studying drug preparation technology. Figure 8 As shown in Figure 2, the IDR values ​​of berberine hydrochloride and berberine hydrochloride-maleic acid cocrystal are 0.20626±0.0472 mg·cm -2 ·min -1 and 0.20511±0.0332mg·cm -2 ·min -1 From the IDR experimental results, it can be observed that the intrinsic dissolution rate of berberine hydrochloride-maleic acid cocrystal is basically the same as that of berberine hydrochloride.

[0110] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the explanation of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A berberine hydrochloride-maleic acid eutectic, characterized in that: The berberine hydrochloride-maleic acid cocrystal has berberine hydrochloride as the active pharmaceutical ingredient and maleic acid as the cocrystal former. The crystal formed is a monoclinic system with a space group of P-2. 1 / c , the unit cell parameters are: α / °=90, β / °=94.793(3), γ / °=90, 2. The berberine hydrochloride-maleic acid eutectic according to claim 1, characterized in that: The berberine hydrochloride-maleic acid cocrystal has characteristic peaks at diffraction angles 2θ of 8.0°±0.2, 10.5°±0.2, 13.6°±0.2, 17.5°±0.2, 18.2°±0.2, 24.6°±0.2, 25.6°±0.2, and 27.4°±0.

2.

3. The berberine hydrochloride-maleic acid eutectic according to claim 1, characterized in that: The berberine hydrochloride-maleic acid eutectic is at 2860±5cm -1 、1590±5cm -1 、1690±5cm -1 There are characteristic peaks.

4. The berberine hydrochloride-maleic acid cocrystal according to claim 1, characterized in that: The hydrogen atom in the berberine hydrochloride molecule acts as a hydrogen bond acceptor, and the oxygen atom of the carboxyl group in the maleic acid molecule acts as a hydrogen bond donor to form intermolecular hydrogen bonds.

5. A method for preparing berberine hydrochloride-maleic acid cocrystal according to any one of claims 1 to 4, characterized in that: Select one of the following preparation methods: Preparation method 1: berberine hydrochloride and maleic acid are mixed and ground to obtain berberine hydrochloride-maleic acid eutectic; Preparation method 2: berberine hydrochloride and maleic acid are mixed and placed in a solvent, and then ground to obtain berberine hydrochloride-maleic acid eutectic; Preparation method three: berberine hydrochloride, maleic acid and a solvent are mixed, suspended and then crystallized to obtain berberine hydrochloride-maleic acid eutectic.

6. The method for preparing a berberine hydrochloride-maleic acid cocrystal according to claim 5, characterized in that: In the preparation method 1, the molar ratio of berberine hydrochloride to maleic acid is 1:0.92-2; During the grinding process, the grinding speed is 10-800 r / min, the temperature is 15°C-35°C, and the time is 0.5-8h.

7. The method for preparing berberine hydrochloride-maleic acid cocrystal according to claim 5, characterized in that: In the second preparation method, the molar ratio of berberine hydrochloride to maleic acid is 1:0.92-2; The dosage ratio of the mixture of berberine hydrochloride and maleic acid to the solvent is 2 to 12 g / mL; During the grinding process, the grinding speed is 10-800 r / min, the temperature is 15°C-35°C, and the time is 0.5-8h.

8. The method for preparing berberine hydrochloride-maleic acid cocrystal according to claim 5, characterized in that: In the preparation method 3, the molar ratio of berberine hydrochloride to maleic acid is 1:0.92-2; The dosage ratio of the mixture of berberine hydrochloride and maleic acid to the solvent is 2 to 12 g / mL; The suspension method is selected from stirring or ultrasound; During the suspension process, the temperature is 15-35°C and the time is 3-8 hours.

9. Use of the berberine hydrochloride-maleic acid cocrystal according to any one of claims 1 to 4 in the field of drug preparation.

10. A drug, characterized in that The drug is prepared by the berberine hydrochloride-maleic acid cocrystal according to any one of claims 1 to 4.

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