CN109400598B - Eutectic crystal of berberine hydrochloride and lactic acid, preparation method and application thereof - Google Patents

Eutectic crystal of berberine hydrochloride and lactic acid, preparation method and application thereof Download PDF

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CN109400598B
CN109400598B CN201811325235.2A CN201811325235A CN109400598B CN 109400598 B CN109400598 B CN 109400598B CN 201811325235 A CN201811325235 A CN 201811325235A CN 109400598 B CN109400598 B CN 109400598B
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刘书妤
卢琪
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Abstract

The invention belongs to the field of pharmaceutical co-crystals, and particularly relates to a berberine hydrochloride and lactic acid co-crystal, and a preparation method and application thereof. The invention adopts berberine hydrochloride and lactic acid eutectic crystal prepared by dry grinding method, liquid adding auxiliary grinding method or suspension method, one molecule of berberine hydrochloride, one molecule of lactic acid and one molecule of water form basic structural unit of berberine hydrochloride and lactic acid eutectic crystal through halogen bond and hydrogen bond, and halogen bond is respectively formed between berberine hydrochloride molecule and lactic acid molecule and between berberine hydrochloride molecule and water molecule; hydrogen bonds are formed between the lactic acid molecules and water molecules. The berberine hydrochloride and lactic acid eutectic crystal prepared by the invention can reduce the hygroscopicity of the berberine hydrochloride, improve the solubility and dissolution rate of the berberine hydrochloride and improve the bioavailability of the berberine hydrochloride; improving the pharmacy and medical application of berberine hydrochloride. The preparation process is simple and easy to control, high in yield and purity, suitable for industrial production and low in cost.

Description

Eutectic crystal of berberine hydrochloride and lactic acid, preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical co-crystals, and particularly relates to a berberine hydrochloride and lactic acid co-crystal, and a preparation method and application thereof.
Background
In the process of drug development, the problems of poor solubility, poor dispersibility, low bioavailability, stability and the like of Active Pharmaceutical Ingredients (API) still plague the development of the pharmaceutical industry, and further restrict the development and clinical application of drugs. The problem that the bioavailability of the drug is reduced due to the low dissolution rate of the drug is particularly obvious for solid dosage form drugs, so that the improvement of the dissolution rate of the insoluble drug is still a problem which needs to be solved urgently in drug development, is a problem which is paid more and more attention by drug developers, and is an important aspect in the development of API new solid drugs.
Berberine hydrochloride C20H18ClNO4The isoquinoline alkaloid (formula I) is an isoquinoline alkaloid usually existing in the form of dihydrate, and is mainly used for treating gastroenteritis, bacillary dysentery and other intestinal infections, conjunctivitis, suppurative otitis media and the like, and also has the effect of blocking alpha receptor antiarrhythmic effect. Because berberine hydrochloride has poor water solubility, the bioavailability is low, thereby greatly limiting the clinical drug development. Therefore, the improvement of the water solubility and the dissolution rate of the berberine hydrochloride still remains the problem to be solved in the berberine hydrochloride pharmaceutical preparation.
Figure BDA0001858554000000011
In recent years, the preparation of pharmaceutical co-crystals using supramolecular chemistry and crystal engineering has become a research hotspot in the chemical and pharmaceutical fields, and pharmaceutical co-crystals are favored due to their unique physicochemical properties. Pharmaceutical co-crystals are crystals formed by combining a pharmaceutically active ingredient (API) with a co-crystal former (CCF) such as other physiologically acceptable acids, bases or non-ionic compounds through non-covalent forces such as hydrogen bonds, van der waals forces, pi-pi stacking effects, halogen bonds, and the like.
Disclosure of Invention
The invention aims to provide a new solid form of berberine hydrochloride, namely a eutectic compound formed by taking one molecule of berberine hydrochloride, one molecule of lactic acid and one molecule of water as basic structural units, wherein the eutectic compound can obviously reduce the hygroscopicity of the berberine hydrochloride, improve the solubility and dissolution rate of the berberine hydrochloride and enhance the pharmaceutical and medical applications of the berberine hydrochloride.
The invention also provides a preparation method of the berberine hydrochloride and lactic acid eutectic, and the preparation method is simple and easy to control, is suitable for industrial production and has low cost.
In order to achieve the purpose, the technical scheme of the invention is as follows: the berberine hydrochloride and lactic acid are eutectic, the berberine hydrochloride is used as an active pharmaceutical ingredient, and the lactic acid is used as a precursor to form the eutectic; is a triclinic system, the space group is P-1, and the unit cell parameters are:
Figure BDA0001858554000000021
α＝70.047(7)°，β＝74.868(7)°，γ＝84.194(7)°，
Figure BDA0001858554000000022
Z＝2。
the PXRD of the berberine hydrochloride and lactic acid eutectic has characteristic peaks at diffraction angles 2 theta of 8.43 degrees +/-0.2, 14.82 degrees +/-0.2, 15.26 degrees +/-0.2, 18.86 degrees +/-0.2, 19.99 degrees +/-0.2, 24.93 degrees +/-0.2, 25.71 degrees +/-0.2 and 26.33 degrees +/-0.2.
The infrared spectrogram of the co-crystal of berberine hydrochloride and lactic acid is 1029 + -5 cm-1、1279±5cm-1、1585±5cm-1、1711±5cm-1、3301±5cm-1Has characteristic peaks.
The structural formula of the co-crystal of berberine hydrochloride and lactic acid is C20H18ClNO4·C3H6O3·H2O, forming a basic structural unit of the berberine hydrochloride and lactic acid eutectic by one molecule of berberine hydrochloride, one molecule of lactic acid and one molecule of water through halogen bonds and hydrogen bonds, wherein chlorine atoms of berberine hydrochloride molecules are respectively combined with hydroxyl hydrogen atoms of lactic acid molecules and hydrogen atoms of water molecules through non-covalent bonds, and halogen bonds are respectively formed between the berberine hydrochloride molecules and the lactic acid molecules and between the berberine hydrochloride molecules and the water molecules; the carboxyl oxygen atom in the lactic acid molecule is used as a hydrogen bond donor, the oxygen atom in the water molecule is used as a hydrogen bond acceptor, and a hydrogen bond is formed between the lactic acid molecule and the water molecule.
The invention adopts a grinding method or a suspension method to prepare the pharmaceutical co-crystal of berberine hydrochloride and lactic acid. The grinding method generates halogen bonds, hydrogen bonds or other intermolecular forces among compound molecules to form eutectic crystals through mechanical forces, and comprises a dry grinding method and a liquid-adding auxiliary grinding method. The suspension method is that the active pharmaceutical ingredient and the eutectic formation substance or the precursor are mixed in a solvent, and then the mixture is fully suspended to enable the molecules of the compound to generate halogen bonds, hydrogen bonds or other intermolecular forces to form the eutectic.
The preparation method of the berberine hydrochloride and lactic acid eutectic crystal comprises the steps of blending, grinding and crystallizing berberine hydrochloride and lactic acid.
The molar ratio of the berberine hydrochloride to the lactic acid is 1: 0.9-3, preferably 1:1 to 1.5, more preferably 1: 1.
the grinding method comprises hand grinding, ball grinding or mechanical grinding.
The polishing speed is 10 to 800r/min, preferably 200 to 400 r/min.
The temperature for the grinding is 15 ℃ to 35 ℃, preferably room temperature.
Alternatively, the preparation method further comprises: before blending and grinding, adding a solvent into the berberine hydrochloride and the lactic acid, namely, the solvent is used for auxiliary grinding.
When the solvent is used for auxiliary grinding, the ratio of the total mass of the berberine hydrochloride and the lactic acid to the dosage of the solvent is 2-15 g/ml, preferably 5-7 g/ml, and more preferably 6 g/ml. The solvent includes methanol, ethanol, isopropanol, n-propanol or acetone, etc. When the eutectic crystal is formed by grinding, the solvents such as methanol, ethanol, isopropanol, n-propanol or acetone and the like are volatilized, which is beneficial to the precipitation of the eutectic crystal.
And the method also comprises the step of standing and crystallizing after grinding, wherein in the standing and crystallizing process, solvents such as methanol, ethanol, isopropanol, n-propanol or acetone and the like are volatilized, and eutectic is easy to be saturated and separated out. The temperature for standing and crystallizing is 15-35 ℃, and the preferred temperature is room temperature.
Alternatively, the preparation method can also comprise the following steps: adding berberine hydrochloride into lactic acid until saturation, or mixing berberine hydrochloride and lactic acid until saturation, and suspending and crystallizing.
Specifically, berberine hydrochloride and lactic acid are added into methanol until both reach saturation, so as to form a mixed solution in which berberine hydrochloride and lactic acid both reach saturation.
Suspension acting force (mechanical acting force such as stirring or physical acting force such as sound wave) enables acting force such as halogen bond, hydrogen bond and the like to be generated between berberine hydrochloride and lactic acid to form eutectic, and solvent is volatilized simultaneously in the suspension process, so that the eutectic is favorably saturated and separated out.
The suspension crystallization mode is stirring or ultrasonic and the like.
The temperature for suspension crystallization is 15-35 ℃, and room temperature is preferred.
The suspension crystallization time is 3-8 hours, preferably 4-8 hours, and more preferably 6 hours.
The berberine hydrochloride and lactic acid eutectic crystal prepared by the invention reduces the hygroscopicity of the berberine hydrochloride, is convenient for controlling environmental parameters, process steps and process parameters in the preparation forming process, is beneficial to preparation forming and improves the stability of the preparation after forming.
The berberine hydrochloride and lactic acid eutectic crystal prepared by the invention can be used for preparing a medicinal preparation, and the medicinal preparation contains berberine hydrochloride and lactic acid eutectic active ingredients.
The pharmaceutical preparation also contains any one or more pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials comprise a carrier, an excipient, a disintegrating agent, a flavoring agent, a lubricant, an adhesive and the like.
The pharmaceutical preparation can be prepared into any pharmaceutically acceptable dosage form with prevention and/or treatment effects according to the needs. The pharmaceutically acceptable dosage form includes liquid preparation, solid preparation or semisolid preparation, etc. Solid formulations include, but are not limited to, granules, capsules, tablets or powders; liquid formulations include, but are not limited to, injection solutions, suspensions, or granules; tablets include, but are not limited to, sugar-coated tablets, film-coated tablets, or enteric-coated tablets; capsules include, but are not limited to, hard and soft capsules.
Compared with the prior art, the invention has the beneficial effects that:
(1) the berberine hydrochloride and lactic acid eutectic crystal prepared by the invention can reduce the hygroscopicity of the berberine hydrochloride and enhance the stability of the berberine hydrochloride; the solubility and the dissolution rate of the berberine hydrochloride are improved, the bioavailability and the hygroscopicity of the berberine hydrochloride are improved, and the formability and the stability of the berberine hydrochloride preparation are improved; improving the pharmaceutical and medical application of berberine hydrochloride.
(2) The preparation process of the berberine hydrochloride eutectic is simple and easy to control, the yield is up to 90-93%, the purity is up to 91-96%, the yield and the purity are high, the cost is low, and the berberine hydrochloride eutectic is suitable for industrial production.
Drawings
FIG. 1 is a schematic view of the molecular structure of the eutectic compound of berberine hydrochloride and lactic acid of the present invention.
FIG. 2 is a PXRD spectrogram of a berberine hydrochloride and lactic acid eutectic compound, a berberine hydrochloride and lactic acid eutectic simulation powder, and a berberine hydrochloride dihydrate compound.
FIG. 3 is an infrared spectrum of berberine hydrochloride dihydrate (a) and the co-crystal of berberine hydrochloride and lactic acid (b) prepared in example 1.
FIG. 4 is a TGA graph of berberine hydrochloride dihydrate (a) and the co-crystal of berberine hydrochloride and lactic acid (b) prepared in example 1.
FIG. 5 is the DSC curve chart of berberine hydrochloride dihydrate (a) and the co-crystal of berberine hydrochloride and lactic acid (b) prepared in example 1.
FIG. 6 is a dissolution curve of the co-crystal of berberine hydrochloride and lactic acid and berberine hydrochloride dihydrate (API) prepared in example 1.
Fig. 7 shows a dynamic moisture adsorption curve (a) of berberine hydrochloride dihydrate (API), a dynamic moisture desorption curve (b) of berberine hydrochloride dihydrate (API), a dynamic moisture adsorption curve (c) of the co-crystal of berberine hydrochloride and lactic acid prepared in example 1, and a dynamic moisture desorption curve (d) of the co-crystal of berberine hydrochloride and lactic acid prepared in example 1.
Detailed Description
The invention respectively adopts a grinding method and a suspension method to prepare the pharmaceutical co-crystal of berberine hydrochloride and lactic acid under the condition of room temperature, the molecular structure diagram is shown in figure 1, the berberine hydrochloride is used as a pharmaceutical active ingredient (API), the lactic acid (formula II) is used as a precursor, and a molecule of berberine hydrochloride, a molecule of lactic acid and a molecule of water are combined together through intermolecular halogen bonds and hydrogen bonds to form a crystallography asymmetric unit of the pharmaceutical co-crystal of the berberine hydrochloride and the lactic acid, wherein chlorine atoms in berberine hydrochloride molecules respectively form halogen bonds with hydroxyl hydrogen atoms of lactic acid molecules and hydrogen atoms of water molecules through noncovalent interaction between berberine hydrochloride molecules and lactic acid molecules and between berberine hydrochloride molecules and water molecules; the carboxyl oxygen atom of the lactic acid molecule is used as a hydrogen bond donor, the oxygen atom in the water molecule is used as a hydrogen bond acceptor, and a hydrogen bond is formed between the lactic acid molecule and the water molecule. The specific implementation mode is as follows:
Figure BDA0001858554000000041
example 1
And (3) solution auxiliary grinding: accurately weighing 408mg of berberine hydrochloride dihydrate (1mmol) and 100mg of lactic acid (the mass concentration is 90% and 1mmol), feeding the materials according to the molar ratio of 1:1, putting the materials into an agate mortar, then dropwise adding 1-2 drops of ethanol (about 0.05-0.1 mL) into the berberine hydrochloride dihydrate and the lactic acid, and fully grinding the mixture at room temperature to prepare the eutectic solid powder of the berberine hydrochloride and the lactic acid, wherein the yield is 90.5% and the purity is 96.2%. In the process, the auxiliary solution is volatilized, so that eutectic precipitation is facilitated. The auxiliary solution added dropwise during the grinding can be methanol, n-propanol, acetone or isopropanol, besides ethanol.
Example 2
A suspension method comprises the following steps: 408mg of berberine hydrochloride dihydrate (1mmol) is accurately weighed and dissolved in 10mL of lactic acid (with the mass concentration of 90 percent) to prepare supersaturated berberine hydrochloride lactic acid solution, and the solution is fully stirred for 6 hours until light yellow solid is precipitated to form the eutectic of berberine hydrochloride and lactic acid.
Example 3
Dry milling method: 408mg of berberine hydrochloride dihydrate (about 1mmol) and 100mg of lactic acid (90% mass concentration and 1mmol) are accurately weighed, the materials are put into an agate mortar according to the molar ratio of 1:1, and the materials are fully ground under the room temperature condition to prepare the eutectic solid powder of the berberine hydrochloride and the lactic acid, wherein the yield is 90% and the purity is 93%.
Example 4
Adding 100mg of lactic acid (with the mass concentration of 90 percent and 1mmol) and 408mg of berberine hydrochloride dihydrate (with the mass concentration of 1mmol) into 10mL of methanol at room temperature to obtain a mixed solution with saturated lactic acid and berberine hydrochloride, and stirring at room temperature until berberine hydrochloride and lactic acid eutectic are separated out, wherein the yield is 93 percent and the purity is 91 percent.
The berberine hydrochloride and lactic acid eutectic prepared in the above embodiment are characterized by PXRD through respective diffraction patterns, are subjected to respective single crystal structure analysis through infrared, DSC/TG and DVS, and are respectively subjected to solubility determination of different solutions (water, methanol and ethanol) and dissolution determination in water. The specific process is as follows:
(1) PXRD (powder X-ray diffraction method) identification of berberine hydrochloride and lactic acid eutectic
The instrument comprises the following steps: x-ray diffractometer (BRUKER, germany, model D2);
detection conditions are as follows: the tube voltage of the Cu-Ka target is 30kV, the tube current is 10mA, the scanning range theta is 5-45 degrees, the scanning speed is 8 degrees/min, and the step width is 0.015.
PXRD spectrogram of the co-crystal of berberine hydrochloride and lactic acid, the simulated powder of the co-crystal of berberine hydrochloride and lactic acid and the dihydrate of berberine hydrochloride prepared in example 1 is shown in figure 2, and the co-crystal of berberine hydrochloride and lactic acid prepared in example 1 has characteristic peaks at diffraction angles 2 theta of 8.43 degrees +/-0.2, 14.82 degrees +/-0.2, 15.26 degrees +/-0.2, 18.86 degrees +/-0.2, 19.99 degrees +/-0.2, 24.93 degrees +/-0.2, 25.71 degrees +/-0.2 and 26.33 degrees +/-0.2. The berberine hydrochloride dihydrate has characteristic peaks at diffraction angles 2 theta of 8.64 degrees +/-0.2, 9.09 degrees +/-0.2, 12.98 degrees +/-0.2, 16.31 degrees +/-0.2, 25.40 degrees +/-0.2, 26.26 degrees +/-0.2, 26.86 degrees +/-0.2 and 30.20 degrees +/-0.2.
As can be seen from FIG. 2, the characteristic diffraction peak and diffraction peak intensity of the co-crystal of berberine hydrochloride and lactic acid are significantly changed relative to berberine hydrochloride dihydrate, which indicates that the reaction between berberine hydrochloride and lactic acid generates a new phase and the characteristic peak of the co-crystal of berberine hydrochloride and lactic acid appears at 25.71 deg.
The characteristic peaks of PXRD diffraction angle 2 theta of the berberine hydrochloride and lactic acid co-crystals prepared in examples 2 to 4 are the same as those of example 1. The dry grinding method and the suspension method can promote the reaction between the berberine hydrochloride and the lactic acid to generate a new phase.
(2) Test of crystal cell parameters of berberine hydrochloride and lactic acid eutectic
The eutectic structure was measured by an X-ray single crystal diffractometer (Bruker SMART Apex IIdiffractometer) and Mo-Ka was scanned at a temperature of 173K.
The crystal structure of the co-crystal of berberine hydrochloride and lactic acid prepared in example 1 is a triclinic crystal system, the space group is P-1, and the unit cell parameters are as follows:
Figure BDA0001858554000000061
α＝70.047(7)°，β＝74.868(7)°，γ＝84.194(7)°，
Figure BDA0001858554000000062
Z＝2。
the unit cell parameters of the berberine hydrochloride and lactic acid co-crystals prepared in examples 2 to 4 are the same as those of example 1.
(3) Infrared characterization of co-crystal of berberine hydrochloride and lactic acid
The instrument comprises the following steps: fourier transform infrared spectrometer (BRUKER, germany, model Equinox 55);
detection conditions are as follows: the scanning wave band is 4000-400 cm-1The sample adopts KBr solid tablet, and the resolution ratio is as follows: 1cm-1。
The infrared spectra of berberine hydrochloride dihydrate (a) and co-crystal (b) of berberine hydrochloride and lactic acid prepared in example 1 are shown in FIG. 3, wherein the berberine hydrochloride dihydrate is at least about 3421cm-1、1621cm-1、1504cm-1、1028cm-1Has characteristic peak, and the eutectic crystal of berberine hydrochloride and lactic acid is at least about 3301cm-1、1711cm-1、1585cm-1、1279cm-1、1029cm-1Has characteristic peaks. As can be seen from FIG. 3, the infrared characteristic peak of the co-crystal of berberine hydrochloride and lactic acid has changed significantly compared to berberine hydrochloride dihydrate, indicating that the reaction between berberine hydrochloride and lactic acid has occurred and a new phase has been generated.
The characteristic peaks of the infrared spectrums of the berberine hydrochloride and lactic acid co-crystals prepared in the examples 2 to 4 are the same as those of the example 1.
(4) DSC/TG (differential scanning calorimetry/thermogravimetry) test of berberine hydrochloride and lactic acid eutectic
The instrument comprises the following steps: DSC/TGA synchronous thermal analyzer (SDT-600Q series DSC/TGA/DTA synchronous thermal analyzer);
detection conditions are as follows: nitrogen atmosphere, gas flow rate: 10mL/min, the heating rate is 10 ℃/min, the test temperature interval is as follows: room temperature to 250 ℃.
The TGA spectra of berberine hydrochloride dihydrate (a) and berberine hydrochloride and lactic acid co-crystal (b) prepared in example 1 are shown in FIG. 4. The loss mass of the berberine hydrochloride dihydrate (a) at 99.6 ℃ is 8.9 percent and is matched with the theoretical mass of two molecules of water in the berberine hydrochloride dihydrate by 8.8 percent, which indicates that the used raw material berberine hydrochloride is the dihydrate; at 67.1 ℃, the berberine hydrochloride and lactic acid eutectic (b) has 3.9 percent of mass loss which is consistent with a theoretically calculated water molecule content (3.8 percent), which indicates that the berberine hydrochloride-lactic acid eutectic contains a crystal water.
The DSC spectra of berberine hydrochloride dihydrate (a) and berberine hydrochloride and lactic acid co-crystal (b) prepared in example 1 are shown in figure 5. The berberine hydrochloride and lactic acid eutectic crystal (b) has an absorption peak at 67.1 ℃, which indicates that the berberine hydrochloride-lactic acid eutectic crystal contains water; there is a sharp exothermic peak at 210 c corresponding to the thermal decomposition temperature of the eutectic compound.
The DSC/TG test results of the co-crystals of berberine hydrochloride and lactic acid prepared in examples 2 to 4 are the same as those of example 1.
(5) Solubility determination of berberine hydrochloride and lactic acid eutectic
Determination of the optimum absorption wavelength
The solubility of the berberine hydrochloride and lactic acid eutectic is measured by adopting a standard curve method and an instrument: Agilent-1260S high performance liquid chromatograph; detection conditions are as follows: Agilent-C18Column (4.6mm × 150nm, 5 μm), mobile phase: methanol-0.4% phosphoric acid solution gradient elution, flow rate: 1ml/min, detection wavelength: 230nm, the column temperature is 30 ℃, and the sample injection amount is 10 mu L.
The berberine hydrochloride dihydrate has a strong absorption peak at 230nm, so that the solubility and dissolution rate of the co-crystal of the berberine hydrochloride and the lactic acid are determined at the wavelength of 230 nm.
Elution procedure for HPLC
Figure BDA0001858554000000071
III, drawing a standard curve
Precisely weighing appropriate amount of berberine hydrochloride dihydrate, respectively preparing 0.0196mg/ml, 0.0492mg/ml, 0.0983mg/ml, 0.1966mg/ml, 0.2949mg/ml, 0.3932mg/ml, 0.4915mg/ml and 0.5898mg/ml standard solutions, filtering the standard solutions by 0.45 mu L filter membrane, respectively injecting samples, and measuring peak area according to the HPLC detection conditions, wherein the linear equation is that Y is 40044X +20.191, and related R is2＝1>0.995, which shows that the linear relation of the berberine hydrochloride mass concentration is good within the range of 0.0196-0.5898 mg/ml.
IV, measuring solubility of berberine hydrochloride and lactic acid eutectic
The results of measuring the solubilities of berberine hydrochloride dihydrate (API) and the co-crystal of berberine hydrochloride and lactic acid prepared in example 1 at 25 ℃ and 37 ℃ are shown in Table 1 and Table 2, respectively.
TABLE 125 deg.C berberine hydrochloride dihydrate (API), berberine hydrochloride and lactic acid eutectic solubility results (in mg/ml)
Figure BDA0001858554000000081
TABLE 237 deg.C Berberine hydrochloride dihydrate (API), Berberine hydrochloride and lactic acid Co-crystal solubility results (in mg/ml)
Figure BDA0001858554000000082
From the results in tables 1 and 2, it can be seen that the solubility of berberine hydrochloride, co-crystal of berberine hydrochloride and lactic acid in the solvent (water, methanol and ethanol) increases with the increase of temperature, and the solubility of co-crystal of berberine hydrochloride and lactic acid is higher than that of berberine hydrochloride under the same temperature and same solvent (water, methanol and ethanol). Berberis vulgaris hydrochlorideThe solubilities of the alkali, the berberine hydrochloride and the lactic acid eutectic crystal in water, methanol and ethanol are in the same order as follows: sMethanol>SWater (W)>SEthanol。
The solubility test results of the berberine hydrochloride and lactic acid co-crystals prepared in examples 2 to 4 are similar to those of example 1.
V. determination of dissolution rate of berberine hydrochloride and lactic acid eutectic
Weighing berberine hydrochloride dihydrate 109mg (containing berberine hydrochloride 100mg) and berberine hydrochloride and lactic acid eutectic 129mg (wherein the berberine hydrochloride amount is 100mg), determining dissolution rate and release degree, using 900mL water as dissolution medium, adopting slurry method, setting rotation speed at 50r/min, measuring temperature at 37 deg.C, starting timing at 5min, 10min, 15min, 20min, 30min, 45min, 60min, 90min, 120min until all raw materials are dissolved completely, taking the same volume of dissolution medium, i.e. 5mL, supplementing the same volume of dissolution medium after each taking, filtering the taken dissolution medium with water system filter membrane, transferring filtrate into liquid phase vial, determining content according to the HPLC detection conditions, and the cumulative dissolution rate curve of berberine hydrochloride and lactic acid eutectic is shown in FIG. 6.
As shown in FIG. 6, when the berberine hydrochloride dihydrate (API) is completely dissolved in water, the time taken for the berberine hydrochloride dihydrate (API) is 90min, the time taken for the co-crystal of the berberine hydrochloride and the lactic acid prepared in example 1 is 30min, and the dissolution rate of the berberine hydrochloride is greatly improved after the co-crystal of the berberine hydrochloride and the lactic acid is formed.
Dissolution test results of the berberine hydrochloride and lactic acid co-crystals prepared in examples 2 to 4 are similar to those of example 1.
(6) Dynamic vapor adsorption method (DVS) determination of berberine hydrochloride and lactic acid eutectic
DVS experiments were performed on an SMS DVS instrument (surface measurement system, uk). First, berberine hydrochloride dihydrate powder, berberine hydrochloride and lactic acid eutectic powder are dried in nitrogen flow for several hours to establish equilibrium dry weight, the relative humidity range is 0% -95% -0%, and 10% RH increment is added, the temperature is kept unchanged at 25 ℃, and dynamic water absorption/desorption test is carried out.
The berberine hydrochloride dihydrate (API) contains two molecules of water in the molecule, and the dynamic water adsorption curve and desorption curve are shown in figure 7. In the dynamic water adsorption process, the relative mass change of the berberine hydrochloride dihydrate is small and basically kept stable within the range of 10-70 percent of relative humidity; when the relative humidity rises to more than 70 percent, the berberine hydrochloride begins to absorb water; when the relative humidity reaches 95%, two more molecules of water are added into the berberine hydrochloride molecules, and at the moment, the berberine hydrochloride contains four molecules of water. The berberine hydrochloride containing the four molecules of water is relatively stable, the berberine hydrochloride containing the four molecules of water begins to lose water only when the relative humidity is less than 20 percent in the dynamic water desorption process, and the water content in the berberine hydrochloride is only about 1 percent when the relative humidity is reduced to 0 percent.
As can be seen from the dynamic moisture absorption/desorption curve of the berberine hydrochloride dihydrate shown in FIG. 7, the berberine hydrochloride dihydrate has a moisture absorption hysteresis loop in the range of 10% -95% of the relative humidity, the berberine hydrochloride dihydrate has moisture absorption hysteresis, and the berberine hydrochloride dihydrate has strong affinity with water molecules and high moisture absorption.
The eutectic molecule of berberine hydrochloride and lactic acid contains a molecule of water, and the dynamic water adsorption curve and desorption curve of the eutectic of berberine hydrochloride and lactic acid prepared in example 1 are shown in fig. 7. In the dynamic water adsorption process, the co-crystal of berberine hydrochloride and lactic acid slowly absorbs water along with the increase of humidity, and when the relative humidity rises to 70 percent, the co-crystal of berberine hydrochloride and lactic acid gradually absorbs water to a great extent; when the humidity reaches 95%, the eutectic molecules of berberine hydrochloride and lactic acid absorb 8% of water again. In the dynamic water decomposition and adsorption process, in the process that the relative humidity is reduced from 95% to 70%, the berberine hydrochloride and lactic acid eutectic rapidly lose two molecules of water; when the relative humidity is reduced to below 20% from 70%, the relative mass of the berberine hydrochloride and lactic acid eutectic is slowly changed, and the water content in the berberine hydrochloride and lactic acid eutectic is basically kept unchanged; when the relative humidity drops below 20%, water is rapidly lost again. As can be seen from the dynamic water absorption/desorption curve of the co-crystal of berberine hydrochloride and lactic acid in FIG. 7, it is demonstrated that the affinity of the co-crystal of berberine hydrochloride and lactic acid with water molecules is significantly weakened and the hygroscopicity is significantly reduced.
After the berberine hydrochloride and the lactic acid are combined in a eutectic form, the hygroscopicity of the berberine hydrochloride or the berberine hydrochloride dihydrate is obviously improved, the control of environmental parameters, process steps and process parameters in the preparation forming process is convenient, and the stability and the bioavailability of the preparation after forming are improved.
The results of the dynamic steam absorption/desorption test of the co-crystal of berberine hydrochloride and lactic acid prepared in examples 2 to 4 are similar to those of example 1.
The embodiments described above are intended to facilitate the understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (3)

1. The berberine hydrochloride and lactic acid eutectic crystal is characterized in that berberine hydrochloride is used as an active pharmaceutical ingredient, and lactic acid is used as a precursor to form a crystal; is a triclinic system, the space group is P-1, and the unit cell parameters are:
Figure FDA0002599481530000011
Figure FDA0002599481530000012
α＝70.047(7)°，β＝74.868(7)°，γ＝84.194(7)°，
Figure FDA0002599481530000013
Z＝2；
wherein, one molecule of berberine hydrochloride, one molecule of lactic acid and one molecule of water form a basic structural unit of the berberine hydrochloride and lactic acid eutectic through halogen bonds and hydrogen bonds, chlorine atoms of berberine hydrochloride molecules are respectively combined with hydroxyl hydrogen atoms of lactic acid molecules and hydrogen atoms of water molecules through non-covalent bonds, and halogen bonds are respectively formed between the berberine hydrochloride molecules and the lactic acid molecules and between the berberine hydrochloride molecules and the water molecules; the oxygen atom of carboxyl group in the lactic acid molecule is used as hydrogen bond donor, the oxygen atom in the water molecule is used as hydrogen bond acceptor, and hydrogen bond is formed between the lactic acid molecule and the water molecule;
PXRD has characteristic peaks at diffraction angle 2 theta of 8.43 degrees +/-0.2, 14.82 degrees +/-0.2, 15.26 degrees +/-0.2, 18.86 degrees +/-0.2, 19.99 degrees +/-0.2, 24.93 degrees +/-0.2, 25.71 degrees +/-0.2 and 26.33 degrees +/-0.2; the infrared spectrum is 1029 +/-5 cm-1、1279±5cm-1、1585±5cm-1、1711±5cm-1、3301±5cm-1Has characteristic peaks.
2. The method for preparing the co-crystal of berberine hydrochloride and lactic acid as claimed in claim 1, wherein berberine hydrochloride and lactic acid are blended, ground and crystallized; or adding berberine hydrochloride into lactic acid to supersaturate, suspending and crystallizing; or suspension crystallization is carried out on the mixed solution of berberine hydrochloride and lactic acid which are both saturated;
in the blending and grinding system, the molar ratio of berberine hydrochloride to lactic acid is 1: 0.9-3 ℃, wherein the grinding temperature is 15-35 ℃;
before blending and grinding, adding a solvent into the berberine hydrochloride and the lactic acid, wherein the ratio of the total mass of the berberine hydrochloride and the lactic acid to the using amount of the solvent is 2-15 g/ml, and the solvent comprises methanol, ethanol, isopropanol, n-propanol or acetone;
in a suspension crystallization system in which berberine hydrochloride and lactic acid are saturated, the solvent is methanol;
the suspension crystallization mode is stirring or ultrasonic, and the suspension crystallization temperature is 15-35 ℃.
3. A pharmaceutical preparation comprising the berberine hydrochloride of claim 1 in co-crystal with lactic acid.
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