CN110016022B - Palmatine hydrochloride-naringenin pharmaceutical co-crystal with slow release effect - Google Patents
Palmatine hydrochloride-naringenin pharmaceutical co-crystal with slow release effect Download PDFInfo
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Abstract
The invention discloses a hydrochloric acid bar with a slow release effectA maleic hydrazide-naringenin pharmaceutical co-crystal belongs to the technical field of pharmaceutical crystallization. The structural unit of the pharmaceutical co-crystal comprises palmatine hydrochloride molecules and naringenin molecules, the molar ratio of the palmatine hydrochloride molecules to the naringenin molecules is 1:1, and the molecular formula is [ C ]21H22ClNO4]·[C15H12O5]. The palmatine hydrochloride pharmaceutical co-crystal is prepared by mixing palmatine hydrochloride and naringenin in proportion, and performing solvent evaporation, stirring or grinding processing. The preparation method is simple and easy to implement, and the eutectic yield is high; the prepared palmatine hydrochloride-naringenin pharmaceutical co-crystal has no hygroscopicity, high thermal stability and high light stability, has a slow release effect on palmatine hydrochloride, and can be used for developing the application of the palmatine hydrochloride slow release preparation.
Description
Technical Field
The invention belongs to the technical field of drug crystallization, and particularly relates to a palmatine hydrochloride-naringenin pharmaceutical co-crystal with a slow release effect.
Background
Palmatine hydrochloride (fibrauretine) is an important isocalamine alkaloid, is an effective component in traditional Chinese medicine fibrauretine, has anti-inflammatory and broad-spectrum antibacterial effects, and is known as "natural plant antibiotic". Clinically, palmatine hydrochloride is mainly used for treating enteritis, bacillary dysentery, respiratory tract and urinary tract infection, gynecological inflammation, surgical infection, conjunctivitis and the like. Recent studies show that palmatine hydrochloride also has significant pharmacological activities such as anti-tumor, anti-depression and anti-Alzheimer's disease (BBA-Gen. Subjects,2018, 1862, 1565-1575.). Although the medicinal value of the palmatine hydrochloride is high, the medicinal property of the palmatine hydrochloride is limited due to some defects of the palmatine hydrochloride. Firstly, palmatine hydrochloride has strong hygroscopicity, and the number of crystal water in molecules can be changed under different humidities, so that the humidity stability of the palmatine hydrochloride is poor. Secondly, palmatine hydrochloride, although having good water solubility, does not easily permeate biological membranes, so that it has poor gastrointestinal absorption and low oral bioavailability. In addition, pharmacokinetic data show that the in vivo half-life period of the palmatine hydrochloride is short, and the fluctuation of the blood concentration is large. Therefore, the development of a novel palmatine hydrochloride solid preparation with low hygroscopicity, easy absorption and sustained release function becomes a research and development hotspot.
Naringenin is flavanone compound, and has antiinflammatory, antibacterial, antioxidant, blood lipid reducing, antitussive, liver function protecting, aortic dissection preventing and treating, platelet aggregation resisting, anti-tumor, brain injury protecting, and Alzheimer disease resisting effects. But the water solubility and the fat solubility are poor, so that the absorption in vivo is poor, and the oral bioavailability is low, thereby limiting the clinical application of the medicine.
The pharmaceutical co-crystal is a novel pharmaceutical solid form, and is a crystal formed by the active pharmaceutical ingredient and other physiologically acceptable co-crystal formers through non-covalent bond actions such as hydrogen bond and the like according to a certain stoichiometric ratio. The pharmaceutical co-crystal can improve the physical and chemical properties of the drug such as solubility, dissolution rate, bioavailability and stability without changing the molecular structure of the drug, and has a very positive effect on the development of oral pharmaceutical preparations (chem. Commun. 2016, 52, 8342-8360.).
In conclusion, co-crystallizing the palmatine hydrochloride with better water solubility and the naringenin which is difficult to dissolve in water is expected to balance the water solubility of the palmatine hydrochloride and the naringenin, namely, the solubility and the dissolution rate of the naringenin are improved while the solubility and the dissolution rate of the palmatine hydrochloride are reduced to achieve a slow release effect. By utilizing the characteristic of no hygroscopicity of naringenin, the hygroscopicity of palmatine hydrochloride is expected to be reduced, and the humidity stability of palmatine hydrochloride is improved. In addition, because the palmatine hydrochloride and the naringenin have a plurality of similar pharmacological activities, the drug-drug cocrystal formed by the palmatine hydrochloride and the naringenin has important clinical application value from the perspective of the synergistic effect of drug combination.
At present, no public report of drug-drug cocrystal of palmatine hydrochloride and naringenin exists.
Disclosure of Invention
The invention aims to provide a palmatine hydrochloride-naringenin pharmaceutical co-crystal with a slow release effect. The pharmaceutical co-crystal of the palmatine hydrochloride has a definite crystal structure, contains two pharmaceutical active ingredients of palmatine hydrochloride and naringenin, and has high thermal stability, light stability and humidity stability. The dissolution rate of the palmatine hydrochloride in the eutectic is obviously reduced compared with that of pure palmatine hydrochloride, and the sustained-release effect is obvious. In order to achieve the purpose, the invention adopts the following technical scheme:
a palmatine hydrochloride-naringenin pharmaceutical co-crystal with a slow release effect is characterized in that the X-ray powder diffraction (Cu K α radiation) pattern is in a diffraction angle of 2θDegree ± 0.2 is: characteristic diffraction peaks exist at 6.1, 7.7, 10.0, 12.4, 12.9, 13.6, 14.7, 15.3, 15.8, 16.7, 17.2, 17.9, 18.2, 19.0, 19.7, 19.8, 20.2, 20.6, 21.2, 21.3, 22.3, 22.8, 23.1, 23.4, 23.9, 24.2, 24.7, 25.5, 26.2, 27.6, 29.9, 30.6, 31.2, 31.6, 32.0, 34.0, 36.0 and 36.9.
The palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect comprises a structural unit of palmatine hydrochloride molecules and naringenin molecules, wherein the molar ratio of the palmatine hydrochloride molecules to the naringenin molecules is 1: 1. The eutectic belongs to a triclinic system, P-1 space group, and the unit cell parameters are as follows:a= 7.8611(4) Å，b =14.3547(6) Å，c= 14.4770(6) Å，α =74.534(4)º，β =86.337(4)º，γ =74.321(4)º，V= 1515.84(12) Å3，Z = 2，D c = 1.446 g/cm3the molecular formula is [ C ]21H22ClNO4]·[C15H12O5]。
In the palmatine hydrochloride pharmaceutical co-crystal with the slow release effect, the palmatine hydrochloride and naringenin molecules are combined together through the hydrogen bond action between the hydroxyl of naringenin and the chloride ions of palmatine hydrochloride. The naringenin molecules and chloride ions in the palmatine hydrochloride are assembled into a supermolecular layered structure, and the palmatine cations are uniformly distributed between supermolecular layers formed by the naringenin molecules and the chloride ions.
The palmatine hydrochloride-naringenin pharmaceutical cocrystal with the slow release effect has orange crystal color; measured by differential scanning calorimetry, it has a melting peak between 210 ℃ and 240 ℃, and the peak temperature is 227 ℃; the weight percentage of the adsorbed water was 0.4% at 25 ℃ and 95% RH.
A preparation method of the palmatine hydrochloride-naringenin pharmaceutical co-crystal with a slow release effect comprises the following steps: completely dissolving palmatine hydrochloride and naringenin in an organic solvent at a molar ratio of 1:1 to prepare a mixed solution, and evaporating the mixed solution to dryness to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect; or mixing the palmatine hydrochloride and the naringenin in the molar ratio of 1:1 in an organic solvent, sealing, stirring at room temperature, filtering, washing and airing the obtained precipitate to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect; or mixing the palmatine hydrochloride and the naringenin in a molar ratio of 1:1, placing the mixture into a grinding tank, adding an organic solvent, and grinding to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect.
In the preparation method, the organic solvent is one or a mixture of more of ethanol, methanol, acetone, ethyl acetate and acetonitrile.
A pharmaceutical co-crystal of palmatine hydrochloride-naringenin with sustained release effect has sustained release effect on palmatine hydrochloride in simulated gastric juice and simulated intestinal juice.
A palmatine hydrochloride-naringenin pharmaceutical co-crystal with sustained release effect is applied in palmatine hydrochloride sustained release preparation.
The invention has the following remarkable advantages:
(1) the method for preparing the palmatine hydrochloride-naringenin pharmaceutical co-crystal for the first time is simple and easy to implement, has a clear crystal structure, and simultaneously contains two pharmaceutical active ingredients of palmatine hydrochloride and naringenin.
(2) In the palmatine hydrochloride-naringenin pharmaceutical eutectic, palmatine hydrochloride molecules and naringenin molecules are combined together through the hydrogen bond action between hydroxyl of naringenin and chloride ions of palmatine hydrochloride. The naringenin molecules and chloride ions in the palmatine hydrochloride are assembled into a supermolecular layered structure, the palmatine cations are uniformly distributed between supermolecular layers formed by the naringenin molecules and the chloride ions, and the special structure ensures that the weight percentage of adsorbed moisture of the eutectic is only 0.4 percent at 25 ℃ and 95 percent RH, namely the eutectic has no hygroscopicity. The eutectic crystal is stored for 20 days at 60 ℃ (60% RH without light), 20 days at 90% RH (at 25 ℃ without light) and 10 days at 6000 Lx (at 40 ℃ and 75% RH), and does not have crystal transformation, which indicates that the eutectic crystal has excellent thermal stability, light stability and humidity stability.
(3) The palmatine hydrochloride-naringenin pharmaceutical eutectic has a special crystal structure, so that the dissolution rate of the palmatine hydrochloride is obviously reduced, namely the naringenin plays a role of a slow release carrier.
Drawings
Fig. 1 is an X-ray powder diffraction (XRD) pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1.
Fig. 2 shows the crystal structure unit of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1.
Fig. 3 shows the accumulation mode of palmatine hydrochloride molecules and naringenin molecules in unit cells in the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1.
Fig. 4 is a Differential Scanning Calorimetry (DSC) chart of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1.
Fig. 5 is a dynamic water vapor sorption (DVS) diagram of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1 at 25 ℃.
Fig. 6 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1 after storage for 20 days at 60 ℃ (60% RH without light).
Fig. 7 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1 after storage for 20 days at 90% RH (temperature 25 ℃, no light).
Fig. 8 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1 after storage at 6000 Lx light intensity (temperature 40 ℃, humidity 75%) for 10 days.
Fig. 9 is a dissolution profile of palmatine hydrochloride, naringenin and palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1 in simulated gastric fluid (pH = 1.2 hydrochloric acid solution).
Fig. 10 is a dissolution profile of palmatine hydrochloride, naringenin, and palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 1 in simulated intestinal fluid (pH =6.8 phosphate solution).
Fig. 11 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 2.
Fig. 12 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 3.
Fig. 13 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 4.
Fig. 14 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 5.
Fig. 15 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 6.
Fig. 16 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in example 7.
Detailed Description
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
Example 1
Completely dissolving 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin in 200 mL of absolute ethyl alcohol to prepare a mixed solution; and naturally volatilizing and airing the mixed solution at room temperature to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect.
Fig. 1 is an XRD chart of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. As shown in FIG. 1, the prepared pharmaceutical co-crystal has a diffraction angle of 2θDegree ± 0.2 is: characteristic diffraction peaks exist at 6.1, 7.7, 10.0, 12.4, 12.9, 13.6, 14.7, 15.3, 15.8, 16.7, 17.2, 17.9, 18.2, 19.0, 19.7, 19.8, 20.2, 20.6, 21.2, 21.3, 22.3, 22.8, 23.1, 23.4, 23.9, 24.2, 24.7, 25.5, 26.2, 27.6, 29.9, 30.6, 31.2, 31.6, 32.0, 34.0, 36.0 and 36.9.
Fig. 2 shows a crystal structure unit of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. As shown in figure 2, the structural unit of the prepared pharmaceutical co-crystal comprises palmatine cations, chloride ions and naringenin neutral molecules, and the molar ratio of the palmatine cations to the chloride ions to the naringenin neutral molecules is 1:1: 1. The palmatine hydrochloride and the naringenin are combined together through the hydrogen bond action between the hydroxyl of the naringenin and chloride ions.
Fig. 3 shows the accumulation mode of palmatine hydrochloride molecules and naringenin molecules in unit cells in the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. As shown in fig. 3, the chloride ions in the naringenin molecules and palmatine hydrochloride assemble into a supramolecular layered structure, and the palmatine cations are uniformly distributed between the supramolecular layers formed by the naringenin molecules and the chloride ions.
Fig. 4 is a DSC chart of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. As shown in FIG. 4, the palmatine hydrochloride-naringenin pharmaceutical co-crystal has a melting peak at the temperature of between 210 ℃ and 240 ℃, and the peak temperature is 227 ℃.
Fig. 5 is a DVS diagram of palmatine hydrochloride and palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example at 25 ℃. As shown in fig. 5, the water content absorbed by the palmatine hydrochloride-naringenin pharmaceutical co-crystal is only 0.4% by weight, i.e., no hygroscopicity exists.
Fig. 6 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example after storage at 60 ℃ (60% RH without light) for 20 days. Fig. 6 shows that all diffraction peak angles of the palmatine hydrochloride-naringenin pharmaceutical co-crystal remain unchanged after 20 days at 60 ℃, indicating that the co-crystal has excellent thermal stability.
Fig. 7 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example after storage for 20 days at 90% RH relative humidity (temperature 25 ℃, no light). As shown in fig. 7, after being stored for 20 days at 90% RH, all diffraction peak angles of the palmatine hydrochloride-naringenin pharmaceutical co-crystal remain unchanged, indicating that the co-crystal has excellent humidity stability.
Fig. 8 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example after being stored for 10 days at 6000 Lx light intensity (temperature 40 ℃, humidity 75%). Fig. 8 shows that after the pharmaceutical co-crystal is stored for 10 days at 6000 Lx light intensity, all diffraction peak angles of the palmatine hydrochloride-naringenin pharmaceutical co-crystal remain unchanged, indicating that the co-crystal has excellent light stability.
Fig. 9 is a dissolution profile of palmatine hydrochloride, naringenin and palmatine hydrochloride-naringenin pharmaceutical co-crystal in simulated gastric fluid (pH = 1.2 hydrochloric acid solution). As shown in fig. 9, compared with palmatine hydrochloride, the dissolution rate of palmatine hydrochloride in the palmatine hydrochloride-naringenin pharmaceutical cocrystal in simulated gastric fluid is significantly reduced, and the dissolution rate reaches 97% after 6 hours, which indicates that naringenin plays a role in controlling the sustained release of palmatine hydrochloride. This is related to the structure of paumatin encapsulated by supramolecular layer formed by naringenin molecule and chloride ion shown in fig. 3. As can also be seen from fig. 9, compared to naringenin, the dissolution rate of naringenin in the palmatine hydrochloride-naringenin pharmaceutical co-crystal is significantly increased, which is also related to the layered accumulation structure of palmatine hydrochloride and naringenin shown in fig. 3, i.e., the introduction of palmatine reduces the density of naringenin molecular accumulation.
Fig. 10 is a dissolution profile of palmatine hydrochloride, naringenin, and palmatine hydrochloride-naringenin pharmaceutical co-crystals in simulated intestinal fluid (pH =6.8 phosphate solution). As shown in fig. 10, compared with palmatine hydrochloride, the dissolution rate of palmatine hydrochloride in the palmatine hydrochloride-naringenin pharmaceutical cocrystal in intestinal fluid is also obviously reduced, and the dissolution rate reaches 62% after 24 hours, which indicates that naringenin also has a sustained release effect on the sustained release of palmatine hydrochloride in simulated intestinal fluid.
Example 2
And (3) putting 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin into 5 mL of absolute ethanol for mixing, sealing a beaker containing the mixture, stirring at room temperature for 48 hours, filtering the obtained precipitate, washing with a small amount of ethanol, and airing to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect.
Fig. 11 is an XRD chart of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. Fig. 11 shows that the pharmaceutical co-crystal of palmatine hydrochloride and naringenin prepared in this example peaks at the same 2 θ angle as that of example 1, indicating that the crystal structures of the two are the same.
Example 3
And (3) putting 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin into 5 mL of methanol for mixing, sealing a beaker containing the mixture, stirring at room temperature for 48 hours, filtering the obtained precipitate, washing with a small amount of methanol, and airing to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect.
Fig. 12 is an XRD chart of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. Fig. 12 shows that the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example and example 1 peak at the same 2 θ angle, indicating that the crystal structures of the two are the same.
Example 4
And (3) putting 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin into 5 mL of acetone for mixing, sealing a beaker containing the mixture, stirring at room temperature for 48 hours, filtering the obtained precipitate, washing with a small amount of acetone, and drying in the air to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect.
Fig. 13 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. Fig. 13 shows that the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example and example 1 peak at the same 2 θ angle, indicating that the crystal structures of the two are the same.
Example 5
And (3) mixing 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin in 5 mL of ethyl acetate, sealing a beaker containing the mixture, stirring at room temperature for 48 hours, filtering the obtained precipitate, washing with a small amount of ethyl acetate, and airing to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect.
Fig. 14 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. Fig. 14 shows that the pharmaceutical co-crystal of palmatine hydrochloride and naringenin prepared in this example peaks at the same 2 θ angle as that of example 1, indicating that the crystal structures of the two are the same.
Example 6
And (3) putting 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin into 5 mL of acetonitrile for mixing, sealing a beaker containing the mixture, stirring at room temperature for 48 hours, filtering the obtained precipitate, washing with a small amount of acetonitrile, and airing to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect.
Fig. 15 is an XRD pattern of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. Fig. 15 shows that the pharmaceutical co-crystal of palmatine hydrochloride and naringenin prepared in this example peaks at the same 2 θ angle as that of example 1, indicating that the crystal structures of the two are the same.
Example 7
And (3) placing 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin into a grinding tank, adding 100 mu L of absolute ethyl alcohol, and grinding for 30 minutes to obtain the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the slow release effect.
Fig. 16 is an XRD chart of the palmatine hydrochloride-naringenin pharmaceutical co-crystal prepared in this example. Fig. 16 shows that the pharmaceutical co-crystal of palmatine hydrochloride and naringenin prepared in this example peaks at the same 2 θ angle as that of example 1, indicating that the crystal structures of the two are the same.
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (7)
1. A palmatine hydrochloride-naringenin pharmaceutical co-crystal with a slow release effect is characterized in that: its X-ray powder diffraction pattern at diffraction angle 2θDegree ± 0.2 is: characteristic diffraction peaks exist at 6.1, 7.7, 10.0, 12.4, 12.9, 13.6, 14.7, 15.3, 15.8, 16.7, 17.2, 17.9, 18.2, 19.0, 19.7, 19.8, 20.2, 20.6, 21.2, 21.3, 22.3, 22.8, 23.1, 23.4, 23.9, 24.2, 24.7, 25.5, 26.2, 27.6, 29.9, 30.6, 31.2, 31.6, 32.0, 34.0, 36.0 and 36.9;
the palmatine hydrochloride-naringenin pharmaceutical co-crystal comprises a structural unit comprising palmatine hydrochloride molecules and naringenin molecules, wherein the molar ratio of the palmatine hydrochloride molecules to the naringenin molecules is 1: 1; the eutectic belongs to a triclinic system, P-1 space group, and the unit cell parameters are as follows:a= 7.8611(4) Å，b =14.3547(6) Å，c= 14.4770(6) Å，α =74.534(4)º，β =86.337(4)º，γ =74.321(4)º，V= 1515.84(12) Å3，Z = 2，D c = 1.446 g/cm3the molecular formula is [ C ]21H22ClNO4]·[C15H12O5]。
2. The palmatine hydrochloride-naringenin pharmaceutical co-crystal with sustained release effect according to claim 1, which is characterized in that: the palmatine hydrochloride molecules and the naringenin molecules are combined together through hydrogen bonding between hydroxyl of the naringenin and chloride ions of the palmatine hydrochloride, the naringenin molecules and the chloride ions in the palmatine hydrochloride form a supermolecular layered structure, and the palmatine cations are uniformly distributed between supermolecular layers formed by the naringenin molecules and the chloride ions.
3. The palmatine hydrochloride-naringenin pharmaceutical co-crystal with sustained release effect according to claim 1, which is characterized in that: the color of the pharmaceutical eutectic crystal is orange yellow; a melting peak exists between 210 ℃ and 240 ℃, and the peak temperature is 227 ℃; the water content of the adsorbent is 0.4% by weight under the conditions of 25 ℃ and 95% relative humidity.
4. The preparation method of the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the sustained release effect as claimed in claim 1, is characterized in that: completely dissolving palmatine hydrochloride and naringenin in an organic solvent at a molar ratio of 1:1 to prepare a mixed solution; evaporating the mixed solution to dryness to obtain a palmatine hydrochloride-naringenin pharmaceutical co-crystal; the organic solvent is one or a mixture of more of ethanol, methanol, acetone, ethyl acetate and acetonitrile.
5. The preparation method of the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the sustained release effect as claimed in claim 1, is characterized in that: mixing the palmatine hydrochloride and the naringenin in an organic solvent according to a molar ratio of 1:1, sealing, stirring at room temperature, filtering, washing and airing the obtained precipitate to obtain a palmatine hydrochloride-naringenin pharmaceutical eutectic; the organic solvent is one or a mixture of more of ethanol, methanol, acetone, ethyl acetate and acetonitrile.
6. The preparation method of the palmatine hydrochloride-naringenin pharmaceutical co-crystal with the sustained release effect as claimed in claim 1, is characterized in that: mixing the palmatine hydrochloride and the naringenin in a molar ratio of 1:1, placing the mixture into a grinding tank, adding an organic solvent, and grinding to obtain a palmatine hydrochloride-naringenin pharmaceutical eutectic; the organic solvent is one or a mixture of more of ethanol, methanol, acetone, ethyl acetate and acetonitrile.
7. The use of the palmatine hydrochloride-naringenin pharmaceutical co-crystal with sustained release effect of claim 1 in a palmatine hydrochloride sustained release preparation.
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