CN110627793B - Penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal and preparation method thereof - Google Patents
Penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal and preparation method thereof Download PDFInfo
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Abstract
The invention discloses penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal and a preparation method thereof. In the penciclovir eutectic with 3, 5-dihydroxy-benzoic acid, the molar ratio of penciclovir to 3, 5-dihydroxy-benzoic acid is 1: 1. The preparation method of the penciclovir eutectic with 3, 5-dihydroxy-benzoic acid has the advantages of simple process, easy control of crystallization process, good reproducibility and suitability for industrial production. The penciclovir and 3, 5-dihydroxy benzoic acid eutectic has higher dissolution rate and larger apparent solubility than penciclovir, is beneficial to improving the bioavailability of penciclovir, and provides a material basis for successfully developing oral preparations and liquid preparations of penciclovir.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to penciclovir and 3, 5-dihydroxy benzoic acid eutectic and a preparation method thereof.
Background
The pharmaceutically active ingredient is usually present in crystalline forms, such as polymorphs, hydrates, solvates, salts, co-crystals and the like. Different crystalline forms have different physicochemical properties for the same pharmaceutically active ingredient. Therefore, obtaining a suitable crystalline form of a drug is of great importance in the pharmaceutical industry. The drug exists in a eutectic form, and has remarkable advantages in the aspects of improving the stability, solubility, permeability and the like of active ingredients of the drug. Therefore, pharmaceutical co-crystals are generally an effective means for improving the physicochemical properties of the active ingredients of drugs.
Penciclovir (Penciclovir) has the chemical name of 9- [ 4-hydroxy-3- (hydroxymethyl) -butyl]-guanine, of the formula:
penciclovir is a nucleoside broad-spectrum antiviral drug, and has inhibitory effect on HSV-I, HSV-II, HBV, EBV, CMV and other viruses. Penciclovir is poor in water solubility, difficult to be absorbed by oral administration, and difficult to be prepared into liquid preparations such as injection, eye drops and the like for use, and most of the current dosage forms sold at home and abroad are ointments. The lyophilized powder injection of penciclovir sodium salt has been developed abroad, although the solubility of penciclovir sodium salt in water can be obviously improved by preparing the lyophilized powder injection into penciclovir sodium salt, the pH value of the aqueous solution of penciclovir sodium salt reaches 11, the penciclovir sodium salt has large irritation to human bodies and is easy to cause phlebitis, so that the clinical application of penciclovir sodium salt is limited.
Therefore, how to improve the solubility of penciclovir under the premise of ensuring the drug effect and patient compliance of penciclovir is of particular significance for developing oral preparations and liquid preparations of penciclovir.
Disclosure of Invention
In order to overcome the problem of solubility of penciclovir in the prior art, the invention aims to provide a penciclovir eutectic with 3, 5-dihydroxy-benzoic acid; the second purpose of the invention is to provide a preparation method of the penciclovir eutectic with 3, 5-dihydroxy-benzoic acid; the invention also aims to provide application of the penciclovir eutectic crystal and 3, 5-dihydroxy benzoic acid.
The inventor of the invention has tried a screening experiment of co-crystal of penciclovir and various acids, including vanillic acid, orotic acid, nicotinic acid, isonicotinic acid, benzoic acid, ferulic acid, p-hydroxybenzoic acid, p-hydroxyphenylacetic acid, gallic acid, 3, 5-dihydroxybenzoic acid and mandelic acid. Finally, the penciclovir eutectic is successfully found, and the dissolution property of penciclovir can be effectively improved. The penciclovir eutectic crystal and 3, 5-dihydroxy benzoic acid have obvious advantages in the aspect of dissolution property of the medicine, and provide a material basis for successfully developing oral preparations and liquid preparations of penciclovir.
The technical scheme adopted by the invention is as follows:
the invention provides a penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
An eutectic crystal of penciclovir and 3, 5-dihydroxy benzoic acid is shown in a formula (I):
in the eutectic, the molar ratio of penciclovir to 3, 5-dihydroxy-benzoic acid is 1: 1.
The penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal has characteristic peaks at diffraction angles 2 theta of 7.0 +/-0.2 degrees, 9.9 +/-0.2 degrees, 15.7 +/-0.2 degrees, 17.9 +/-0.2 degrees and 20.5 +/-0.2 degrees by X-ray powder diffraction measured by Cu Kalpha rays.
Preferably, the penciclovir eutectic with 3, 5-dihydroxy benzoic acid has the X-ray powder diffraction and also has characteristic peaks at one or more of diffraction angles 2 theta of 16.4 +/-0.2 degrees, 16.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.3 +/-0.2 degrees and 29.4 +/-0.2 degrees.
Preferably, the penciclovir eutectic crystal and 3, 5-dihydroxy benzoic acid eutectic crystal are monoclinic system, and the space group is P21C, unit cell parameter of
α -90 deg., β -93.5 + -0.2 deg., and gamma-90 deg., and in some preferred embodiments, the penciclovir eutectic crystal with 3, 5-dihydroxybenzoic acid has unit cell parameters of
α＝90°，β＝93.474(2)°，γ＝90°。
The invention provides a preparation method of penciclovir and 3, 5-dihydroxy-benzoic acid.
A preparation method of penciclovir and 3, 5-dihydroxy-benzoic acid eutectic crystal comprises the following steps: penciclovir, 3, 5-dihydroxy benzoic acid and a solvent are mixed, and then the mixture is stirred, subjected to ultrasonic treatment, volatilized or subjected to cooling crystallization to obtain the eutectic crystal.
Preferably, in the preparation method of the eutectic, the ratio of the total mass of penciclovir and 3, 5-dihydroxy-benzoic acid to the dosage of the solvent is (50-500) mg: 1 mL; further preferably, the ratio of the total mass of penciclovir and 3, 5-dihydroxy benzoic acid to the dosage of the solvent is (80-400) mg: 1 mL; still further preferably, the ratio of the total mass of penciclovir and 3, 5-dihydroxy benzoic acid to the amount of the solvent is (100-380) mg: 1 mL.
Preferably, in the preparation method of the eutectic, the feeding molar ratio of penciclovir to 3, 5-dihydroxy benzoic acid is 1: (1-8).
Preferably, in the method for preparing the co-crystal, the solvent is at least one selected from water, alcohol solvents, ester solvents, ketone solvents, ether solvents, nitrile solvents and halogenated hydrocarbon solvents; wherein, the alcohol solvent includes but is not limited to methanol, ethanol, isopropanol; ester solvents include, but are not limited to, methyl acetate, ethyl acetate, isopropyl acetate, ethyl formate; ketone solvents include, but are not limited to, acetone; ether solvents include, but are not limited to, diethyl ether, tetrahydrofuran; nitrile solvents include, but are not limited to, acetonitrile; haloalkane solvents include, but are not limited to, dichloromethane, trichloromethane; further preferably, the solvent is selected from one or more of methanol, ethanol aqueous solution, isopropanol, ethyl acetate, isopropyl acetate, ethyl formate, acetonitrile, acetone, tetrahydrofuran and dichloromethane; when the solvent is ethanol water solution, the volume percentage of ethanol in the ethanol water solution is 0-60%, preferably 50%.
In some preferred embodiments of the present invention, the preparation method of the eutectic is specifically as follows: and mixing penciclovir, 3, 5-dihydroxy benzoic acid and a solvent, stirring, filtering, and drying the obtained solid product to obtain the eutectic crystal.
In other preferred embodiments of the present invention, the preparation method of the eutectic is specifically: mixing penciclovir, 3, 5-dihydroxy benzoic acid and a solvent, then carrying out ultrasonic treatment, filtering, standing and volatilizing the filtrate to obtain the eutectic crystal.
Preferably, in the preparation method of the eutectic crystal, stirring is performed at room temperature for 2-24 hours.
Preferably, in the preparation method of the eutectic crystal, the volatilization is performed at room temperature for 3-5 days.
The invention provides a pharmaceutical composition, which comprises the penciclovir eutectic crystal with 3, 5-dihydroxy-benzoic acid and pharmaceutically acceptable excipient.
In the present invention, the pharmaceutically acceptable excipient refers to a pharmaceutically acceptable material, mixture or solvent related to the consistency of the administration form or pharmaceutical composition. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition.
Preferably, the pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers.
The invention also provides application of the penciclovir eutectic and 3, 5-dihydroxy-benzoic acid in preparation of a medicament for treating diseases caused by herpes viruses and/or hepatitis B viruses.
Preferably, in application, the diseases caused by the herpes virus comprise herpetic gingival stomatitis, herpetic vulvovaginitis, inoculated herpes simplex, herpetic eczema, disseminated herpes simplex and neonatal herpes; diseases caused by hepatitis B virus include hepatitis B.
The invention has the beneficial effects that:
the penciclovir and 3, 5-dihydroxy-benzoic acid eutectic has higher dissolution rate and larger apparent solubility than penciclovir, is beneficial to improving the bioavailability of penciclovir, and provides a material basis for successfully developing oral preparations and liquid preparations of penciclovir.
The preparation method of the penciclovir eutectic with 3, 5-dihydroxy-benzoic acid disclosed by the invention is simple in process, easy to control the crystallization process, good in reproducibility and suitable for industrial production.
The penciclovir eutectic crystal and 3, 5-dihydroxy-benzoic acid has wide application prospect in preparing medicaments for treating diseases caused by herpes viruses or hepatitis B viruses.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of a penciclovir eutectic with 3, 5-dihydroxybenzoic acid;
FIG. 2 is a differential scanning calorimetry plot of penciclovir eutectic with 3, 5-dihydroxybenzoic acid;
FIG. 3 is a thermogravimetric analysis of penciclovir eutectic with 3, 5-dihydroxybenzoic acid;
FIG. 4 is a Fourier transform infrared spectrum of a penciclovir eutectic with 3, 5-dihydroxybenzoic acid;
FIG. 5 is a schematic diagram of a single crystal asymmetric unit of penciclovir eutectic with 3, 5-dihydroxybenzoic acid;
FIG. 6 is a schematic diagram of a unit cell structure of penciclovir eutectic with 3, 5-dihydroxybenzoic acid;
figure 7 is a powder dissolution profile of penciclovir and penciclovir series co-crystals.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The starting materials used in the examples are, unless otherwise specified, commercially available from conventional sources.
Example 1
Weighing 63.3mg penciclovir and 308.2mg 3, 5-dihydroxybenzoic acid, adding 1mL 50% ethanol (the volume ratio of ethanol to water is 1:1) to obtain a suspension, placing the suspension at room temperature, stirring for 24h, carrying out suction filtration, washing the obtained white solid with a proper amount of 50% ethanol, and then drying at 40 ℃ for 48h to obtain a solid sample of penciclovir and 3, 5-dihydroxybenzoic acid eutectic.
Example 2
Weighing 63.3mg of penciclovir and 231.2mg of 3, 5-dihydroxy benzoic acid, adding the penciclovir and 231.2mg of 3, 5-dihydroxy benzoic acid into 1mL of ethanol to obtain a suspension, placing the suspension at room temperature, stirring for 2h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 3
Weighing 63.3mg of penciclovir and 231.2mg of 3, 5-dihydroxy benzoic acid, adding the penciclovir and the 3, 5-dihydroxy benzoic acid into 1mL of methanol to obtain a suspension, placing the suspension at room temperature, stirring for 12h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 4
Weighing 63.3mg of penciclovir and 231.2mg of 3, 5-dihydroxy benzoic acid, adding into 1mL of isopropanol to obtain a suspension, placing the suspension at room temperature, stirring for 12h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 5
Weighing 63.3mg of penciclovir and 38.5mg of 3, 5-dihydroxy benzoic acid, adding the penciclovir and 38.5mg of 3, 5-dihydroxy benzoic acid into 1mL of ethyl acetate to obtain a suspension, placing the suspension at room temperature, stirring for 12h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 6
Weighing 63.3mg of penciclovir and 38.5mg of 3, 5-dihydroxy benzoic acid, adding the penciclovir and 38.5mg of 3, 5-dihydroxy benzoic acid into 1mL of methyl acetate to obtain a suspension, placing the suspension at room temperature, stirring for 12h, and drying the obtained white solid in the suction filtration process to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 7
Weighing 63.3mg of penciclovir and 38.5mg of 3, 5-dihydroxy benzoic acid, adding into 1mL of isopropyl acetate to obtain a suspension, placing the suspension at room temperature, stirring for 12h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 8
Weighing 63.3mg of penciclovir and 38.5mg of 3, 5-dihydroxy benzoic acid, adding the penciclovir and 38.5mg of 3, 5-dihydroxy benzoic acid into 1mL of ethyl formate to obtain a suspension, placing the suspension at room temperature, stirring for 12h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 9
Weighing 63.3mg of penciclovir and 154.1mg of 3, 5-dihydroxy benzoic acid, adding the penciclovir and 154.1mg of 3, 5-dihydroxy benzoic acid into 1mL of acetonitrile to obtain a suspension, placing the suspension at room temperature, stirring for 12h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 10
Weighing 63.3mg of penciclovir and 231.2mg of 3, 5-dihydroxy benzoic acid, adding the penciclovir and the 3, 5-dihydroxy benzoic acid into 1mL of acetone to obtain a suspension, placing the suspension at room temperature, stirring for 12h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 11
Weighing 63.3mg of penciclovir and 231.2mg of 3, 5-dihydroxy benzoic acid, adding the penciclovir and the 3, 5-dihydroxy benzoic acid into 1mL of tetrahydrofuran to obtain a suspension, placing the suspension at room temperature, stirring for 12h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Example 12
Weighing 31.7mg of penciclovir and 77.1mg of 3, 5-dihydroxy benzoic acid, adding the penciclovir and 77.1mg of 3, 5-dihydroxy benzoic acid into 1mL of dichloromethane to obtain a suspension, placing the suspension at room temperature, stirring for 12h, carrying out suction filtration, and drying the obtained white solid to obtain a solid sample of penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal.
Characterization analysis
The penciclovir and 3, 5-dihydroxy benzoic acid eutectic provided by the invention is characterized by methods such as X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC) analysis, Thermogravimetry (TG) analysis, Fourier transform infrared spectroscopy (IR) and the like.
The solid sample of the penciclovir eutectic with 3, 5-dihydroxy benzoic acid prepared in example 1 was subjected to X-ray powder diffraction analysis, which employed a bruker d2PHASER type diffractometer manufactured by bruker instruments ltd, germany, with a Cu K α ray, a voltage of 30 kv, a current of 10 ma, a step size of 0.01 °, a scanning speed of 6 °/min, a scanning range of 5.0 to 40.0 °, and a test temperature of room temperature. The analysis results are shown in X-ray powder diffraction (XRPD) chart of figure 1, and the X-ray powder diffraction data is shown in Table 1.
TABLE 1 Co-crystal X-ray powder diffraction data of penciclovir and 3, 5-dihydroxybenzoic acid
It is well known to those skilled in the art that crystalline materials can be characterized by X-ray diffraction techniques, but the X-ray diffraction patterns typically vary with the test conditions of the instrument. It is particularly noted that the relative intensities of the X-ray diffraction patterns may vary with the experimental conditions, so that the relative intensity order of the X-ray diffraction peaks cannot be the sole or determining factor in the characterization of crystalline material. In addition, the peak angle is usually allowed to have an error of ± 0.2 °, and due to the influence of experimental factors such as sample height and test temperature, the peak angle is shifted as a whole, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of the penciclovir eutectic with 3, 5-dihydroxybenzoic acid according to the present invention does not need to be identical to the X-ray diffraction pattern in the present example, and any situation having the same or similar characteristic peaks in this pattern is within the scope of the present invention. One skilled in the art can compare the profile listed in the present invention with a profile of an unknown substance to confirm whether the unknown substance is or is not penciclovir with 3, 5-dihydroxybenzoic acid cocrystals as described herein.
Differential scanning calorimetry was performed on a solid sample of the penciclovir eutectic with 3, 5-dihydroxybenzoic acid prepared in example 1, which was detected by a DSC 214 differential calorimeter of German Ascendens scientific instruments, Inc., under nitrogen atmosphere and at a temperature rise rate of 10 ℃/min. The analysis result is shown in the Differential Scanning Calorimetry (DSC) analysis chart of figure 2. The DSC curve shows that no significant endotherm or exotherm was observed before thermal decomposition of penciclovir cocrystals with 3, 5-dihydroxybenzoic acid.
The solid sample of penciclovir eutectic with 3, 5-dihydroxy benzoic acid obtained in example 1 was subjected to thermogravimetric analysis using a Perkinelmer STA 6000 thermogravimetric analyzer under nitrogen atmosphere at a temperature rise rate of 10 ℃/min. The analysis result is shown in the Thermogravimetric (TG) analysis chart of FIG. 3. The TG curve shows that penciclovir eutectic with 3, 5-dihydroxybenzoic acid starts to decompose when heated to around 228 ℃ and there is no weight loss before this temperature.
Infrared spectrum analysis is carried out on the penciclovir and 3, 5-dihydroxy benzoic acid eutectic sample prepared in the example 1, a Fourier transform infrared spectrometer of Perkin Elmer company is adopted for detection, and the detection range is 4000-400 cm-1The analysis result is shown in the Fourier transform Infrared (IR) spectrum of figure 4. As can be seen from FIG. 4, the characteristic peak position of the infrared spectrum is (cm)-1)：3481、3437、3393、3336、3266、3146、3020、2956、2818、2697、2608、2508、1686、1623、1597、1515、1477、1452、1389、1332、1275、1218、1174、1111、1066、1041、978、933、871、845、820、801、782、731、706、668、630、580、529、478、440。
Single crystal research of penciclovir and 3, 5-dihydroxy benzoic acid eutectic
Taking 4mL of 50% ethanol, adding 63.3mg of penciclovir and 308.2mg of 3, 5-dihydroxy benzoic acid, carrying out ultrasonic treatment until the penciclovir and the 308.2mg of 3, 5-dihydroxy benzoic acid are completely dissolved, filtering, standing the filtrate at room temperature, and slowly volatilizing for 3-5 days to obtain a light yellow transparent block crystal.
The model of the X-ray single crystal diffractometer is as follows: XtaLAB Pro MM003 Cu/Mo;
wavelength Cu K α
And (3) testing temperature: 150K;
computer program for structure resolution: olex2, Shelxtl;
the experimental general formula is as follows: c17H21N5O7；
Molecular weight: 407.39, respectively;
crystal system: monoclinic system;
space group: p21/c；
Unit cell parameters:
α＝90°；
β＝93.474(2)°；
γ＝90°；
unit cell volume:
z (number of experimental formulae contained in unit cell): 4;
calculating the density: 1.509g/cm3。
Structural description: single crystal diffraction and structure analysis show that the asymmetric structural unit of the single crystal contains a penciclovir molecule and a 3, 5-dihydroxy benzoic acid molecule; the unit cell of the crystal contains four penciclovir molecules and four 3, 5-dihydroxy benzoic acid molecules. The schematic diagram of asymmetric structural units of the penciclovir eutectic crystal with 3, 5-dihydroxy benzoic acid is shown in figure 5, and the schematic diagram of unit cell structure is shown in figure 6.
Evaluation of solubility
And carrying out comparative study on powder dissolution curves of penciclovir eutectic and 3, 5-dihydroxy benzoic acid and penciclovir.
The source of the test sample is: the penciclovir eutectic crystal and 3, 5-dihydroxy benzoic acid are prepared by the method provided by the embodiment 1 of the invention; penciclovir was purchased from Shanghai Shengde pharmaceutical science and technology, Inc. at 99% purity.
The experimental method comprises the following steps: grinding penciclovir, 3, 5-dihydroxy benzoic acid eutectic and penciclovir, and then respectively sieving the grinded powder with 100-200 meshes of sieve, wherein the particle size of the powder is controlled to be 75-150 mu m. 500mg penciclovir, 804.2mg penciclovir and 3, 5-dihydroxy benzoic acid eutectic are respectively weighed, added into 50mL of dissolution medium, 0.2mL of solution is taken at intervals, filtered by a 0.22 mu m microporous membrane and diluted to proper times, the concentration of the solution at each time point is monitored by high performance liquid chromatography, and finally the penciclovir and 3, 5-dihydroxy benzoic acid eutectic and the powder dissolution curve of penciclovir are obtained.
Dissolution conditions:
dissolution medium: 0.2M phosphate buffer pH 7.4;
stirring speed: 150 revolutions per minute;
dissolution temperature: 37 plus or minus 0.5 ℃;
sampling time: 0.25, 0.5, 1, 2, 3,5, 10, 20, 30, 60, 120, 180, 240, 300, 360, 480, 600 minutes;
liquid phase conditions:
the instrument comprises the following steps: SHIMADZU LC-2030C 3D;
a chromatographic column: ODS Hypersil C18 column (4.6 mm. times.150 mm, 5 μm);
ultraviolet detection wavelength: 253 nm;
mobile phase: methanol: 0.05M pH 7.0KH2PO4NaOH solution 90: 10;
column temperature: 25 ℃;
flow rate: 1 mL/min;
sample introduction amount: 10 μ L.
The results are shown in the powder dissolution profile of figure 7. The dissolution rate of penciclovir is slow, the maximum apparent solubility in 30 minutes is 3.5 +/-0.4 mg/mL, the dissolution rate of penciclovir and 3, 5-dihydroxy benzoic acid eutectic provided by the invention is fast, and the maximum apparent solubility in 30 minutes is 7.1 +/-0.6 mg/mL which is more than 2 times that of penciclovir.
At the same time, the solubility of penciclovir with p-hydroxybenzoic acid in the form of a eutectic (molar ratio 1:1), penciclovir, 3, 5-dihydroxybenzoic acid in the form of a eutectic hydrate (molar ratio 1:7:8), penciclovir with gallic acid in the form of a eutectic (molar ratio 1:1), and penciclovir with gallic acid in the form of a eutectic hydrate (molar ratio 1:1:1) was also evaluated in the same manner. The results of the experiment are shown in FIG. 7. As can be seen from fig. 7, it was found that the solubility of penciclovir was increased significantly only when the anhydrous co-crystal of the present invention was formed with 3, 5-dihydroxybenzoic acid at a molar ratio of 1:1, and the solubility of other co-crystals was not increased significantly. And the solubility of the eutectic hydrate formed by penciclovir and 3, 5-dihydroxy-benzoic acid according to the ratio of 1:7:8 is reduced, and the solubility increase of the anhydrous eutectic formed by penciclovir and 3, 5-dihydroxy-benzoic acid is not obvious.
The penciclovir and 3, 5-dihydroxy-benzoic acid eutectic provided by the invention can be applied to preparation of medicaments for treating diseases caused by herpes viruses and/or hepatitis B viruses, and has wide application prospects.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (7)
1. An eutectic crystal of penciclovir and 3, 5-dihydroxy benzoic acid is characterized in that: the structural formula of the eutectic is shown as the formula (I):
in the eutectic, the molar ratio of penciclovir to 3, 5-dihydroxy benzoic acid is 1: 1;
the eutectic has characteristic peaks at diffraction angles 2 theta of 7.0 +/-0.2 degrees, 9.9 +/-0.2 degrees, 15.7 +/-0.2 degrees, 17.9 +/-0.2 degrees and 20.5 +/-0.2 degrees by X-ray powder diffraction measured by Cu Kalpha rays.
2. The penciclovir eutectic with 3, 5-dihydroxybenzoic acid as claimed in claim 1, wherein: the X-ray powder diffraction of the eutectic also has characteristic peaks at one or more of diffraction angles 2 theta of 16.4 +/-0.2 degrees, 16.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.3 +/-0.2 degrees and 29.4 +/-0.2 degrees.
3. Penciclovir cocrystal with 3, 5-dihydroxybenzoic acid according to claim 1 or 2 characterized in that: the eutectic is monoclinic system, and the space group is P21C, unit cell parameter of
α＝90°，β＝93.5±0.2°，γ＝90°。
4. A method for preparing the penciclovir eutectic with 3, 5-dihydroxy benzoic acid according to any one of claims 1-3, wherein: the method comprises the following steps: mixing penciclovir, 3, 5-dihydroxy benzoic acid and a solvent, and then stirring, performing ultrasonic treatment, volatilizing or cooling for crystallization to obtain eutectic;
the ratio of the total mass of penciclovir and 3, 5-dihydroxy benzoic acid to the dosage of the solvent is (50-500) mg: 1 mL;
the solvent is at least one selected from water, alcohol solvents, ester solvents, ketone solvents, ether solvents, nitrile solvents and halogenated hydrocarbon solvents.
5. The method of claim 4, wherein: the feeding molar ratio of penciclovir to 3, 5-dihydroxy benzoic acid is 1: (1-8).
6. A pharmaceutical composition characterized by: the penciclovir eutectic crystal and 3, 5-dihydroxy benzoic acid eutectic crystal and a pharmaceutically acceptable excipient are included in any one of claims 1-3.
7. Use of penciclovir with 3, 5-dihydroxybenzoic acid cocrystal according to any one of claims 1-3 in preparation of a medicament for treating diseases caused by herpes virus and/or hepatitis B virus.
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