CN113149946A - Michellac dimethylamine lactone-m-hydroxybenzoate and preparation method and application thereof - Google Patents
Michellac dimethylamine lactone-m-hydroxybenzoate and preparation method and application thereof Download PDFInfo
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- lactone
- michelia
- hydroxybenzoate
- michelia lactone
- dimethylamine
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- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides michelia lactone-m-hydroxybenzoate as well as a preparation method and application thereof, wherein the crystallographic characteristics of the michelia lactone-m-hydroxybenzoate as dimethylamine comprise: space group is P212121Cell parameter of
α is 90 °, β is 90 °, γ is 90 °, and unit cell volume is
The michelia lactone-m-hydroxybenzoate prepared by the method has good hygroscopicity and physical and chemical stability, and has good drug development prospect; the preparation method has the advantages of simple operation, mild condition, good repeatability, environmental protection, low toxicity and safety, and is convenient for large-scale production and application.
Description
Technical Field
The invention belongs to the technical field of medical crystallization, and particularly relates to michelia lactone-m-hydroxybenzoate dimethylamine and a preparation method and application thereof.
Background
Cancer seriously harms human life health, has high morbidity, high mortality and low cure rate, and becomes a public health problem which draws attention in the world. According to the recent report of the World Health Organization (WHO), the incidence of cancer and the death of cancer are rapidly increasing worldwide, and the cancer is expected to become the leading cause of death in the 21 st century.
At present, the popular field of cancer drug development at home and abroad is mainly to obtain effective anticancer active ingredients from natural products. According to statistics, about 1/4 in 2015-2016, the most popular medicine in the world comes from natural products and derivatives thereof. In recent years, sesquiterpenes have also become one of the most active areas in natural product chemistry.
The michelia lactone belongs to sesquiterpene lactone compounds, but has poor water solubility, and greatly limits the development of medicines. Dimethylamine michelia lactone with molecular formula C17H27NO3It is white powdery solid. Compared with michelia lactone, the dimethylamine michelia lactone has a certain degree of improvement on water solubility, but can be degraded after being placed for a long time, and has poor stability. Based on the crystal engineering angle, the compounds with poor water solubility and stability are designed and synthesized into multi-component crystals such as eutectic crystals, salts and the like, so that the product performance can be effectively improved.
WO2015006893a1 discloses a method for preparing michelia lactone dimethylamine hydrochloride and fumarate by using a dichloromethane solvent, but dichloromethane belongs to two types of organic solvents, has certain toxicity and carcinogenicity, has a very low boiling point, has anesthetic property by steam, can cause acute poisoning by large-amount inhalation, causes symptoms such as headache, vomiting, impaired hematopoietic function and the like, and brings certain potential safety hazard for industrial mass production.
CN104876899A indicates that the dimethylamine michelia lactone hydrochloride has serious moisture absorption and can be seriously degraded under the conditions of high temperature and high humidity. A series of patents CN103724307B, CN111303097A, CN111303100A, CN111303098A and CN111303099A successively disclose 6 different crystal forms of michelia dimpled lactone fumarate and a preparation method thereof, but experimental studies find that the different crystal forms of michelia dimpled lactone fumarate are mutually transformed under certain conditions of solvent, temperature, humidity and the like, and the existence of the polycrystalline forms makes the quality stability of the michelia dimpled lactone fumarate difficult to control in the production process. Different crystal forms of the same drug have obvious differences in the aspects of solubility, melting point, dissolution behavior, fluidity, bioavailability and the like, so that the stability, bioavailability and curative effect of the drug are influenced.
The currently disclosed michelia lactone hydrochloride and michelia lactone fumarate do not have obvious advantages in the aspects of hygroscopicity, physical and chemical stability, controllability of product quality and the like, and the properties are crucial to the research and development and scale-up production of medicaments.
Therefore, the development of new salt forms of michelia dimethylamine lactone enables the new salt forms to have more excellent characteristics, including production safety, product stability, good post-processing property, lower hygroscopicity and the like, and is very important for realizing effective application of medicaments.
Disclosure of Invention
The invention provides a michelia lactone-m-hydroxybenzoate dimethylamine and a preparation method thereof, aiming at solving the technical problems of high hygroscopicity, poor stability, easy mutual transformation of crystal forms, complex preparation process, strong toxicity of used solvents, poor controllability of process and product quality and the like in the existing michelia lactone salt form of dimethylamine and the preparation method thereof. The michelia lactone-m-hydroxybenzoate provided by the invention has the advantages of low hygroscopicity, high physical and chemical stability, safe preparation process, low toxicity of the used solvent, small dosage, good repeatability, strong operability and mild conditions, and is beneficial to industrial production and subsequent drug development.
One of the purposes of the invention is to provide michelia lactone-m-hydroxybenzoate, wherein the molecular formula of the michelia lactone-m-hydroxybenzoate is C24H33NO6And has the following structure:
the crystallography characteristics of the michelia lactone-m-hydroxybenzoate salt of dimethylamine comprise: space group is P2 12121Cell parameter of
α is 90 °, β is 90 °, γ is 90 °, and unit cell volume is
In the invention, in an X-ray powder diffraction spectrum of the michelia lactone-m-hydroxybenzoate, the diffraction angle 2 theta has peaks at 7.9 +/-0.2 °, 10.6 +/-0.2 °, 11.2 +/-0.2 °, 12.1 +/-0.2 °, 12.5 +/-0.2 °, 13.1 +/-0.2 °, 14.3 +/-0.2 °, 15.4 +/-0.2 °, 16.0 +/-0.2 °, 17.0 +/-0.2 °, 18.7 +/-0.2 °, 19.3 +/-0.2 °, 19.6 +/-0.2 °, 20.1 +/-0.2 °, 21.1 +/-0.2 °, 22.2 +/-0.2 °, 23.0 +/-0.2 °, 23.5 +/-0.2 °, 24.2 +/-0.2 °, 24.6 +/-0.2 °, 25.2 +/-0.2 °, 26.0 +/-0.2 °, 26.6 +/-0.2 ° and 27.5 +/-0.2 °.
In the invention, the differential scanning calorimetry analysis spectrum of the michelia lactone-m-hydroxybenzoate has a characteristic melting peak at 177 +/-2 ℃.
The product purity of the michelia lactone-m-hydroxybenzoate provided by the invention can reach more than 99%, the product yield is more than 90%, and the crystal habit is massive.
The water content of the michelia lactone-m-hydroxybenzoate sample provided by the invention is only 0.41% +/-0.01% when the ambient temperature is 25 ℃ and the relative humidity reaches 95%. In an accelerated stability experiment in which the temperature is controlled to be 40 ℃ and the humidity is 75% for 12 weeks, the melting point of the michelia lactone-m-hydroxybenzoate sample provided by the invention is not obviously changed compared with that of an initial sample, and the weight loss before decomposition is less than 0.06%, which indicates that the michelia lactone-m-hydroxybenzoate sample provided by the invention has higher stability and lower hygroscopicity. In a buffer solution simulating the pH value of human intestinal juice to be 6.8, the michelia lactone-m-hydroxybenzoate dimethylamine sample provided by the invention has no crystal form conversion or degradation in the suspension experiment process for 5 hours.
The second purpose of the invention is to provide a preparation method of the michelia lactone-m-hydroxybenzoate as defined in the first purpose, which comprises the following steps:
(1) reacting michelia lactone dimethylamine with m-hydroxybenzoic acid in an organic solvent to obtain a mixture;
(2) and (2) cooling and crystallizing the mixture obtained by the reaction in the step (1) to obtain the michelia lactone-m-hydroxybenzoate.
Compared with other preparation processes, the preparation method of the michelia lactone-m-hydroxybenzoate of dimethylamine provided by the invention has the advantages of simple operation, mild conditions, easy preparation, good repeatability, environment-friendly, low-toxicity and safety, and is suitable for large-scale production, and the selected solvents are three solvents.
In the present invention, the reaction in step (1) comprises a reaction in an organic solvent.
In the present invention, the molar ratio of the michelia lactone dimethylamine to the m-hydroxybenzoic acid is 1 (0.8-1.5), for example, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.
In the present invention, the amount of the organic solvent added in step (1) is 1mL, based on the amount of 20 to 80mg (for example, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, etc.) of the michelia lactone added.
In the present invention, the organic solvent in step (1) includes any one of methanol, ethanol, acetone or isopropyl acetate or a combination of at least two thereof.
In the present invention, the reaction temperature in step (1) is 40-60 deg.C, such as 40 deg.C, 42 deg.C, 45 deg.C, 47 deg.C, 50 deg.C, 52 deg.C, 55 deg.C, 57 deg.C, 60 deg.C, etc., and the reaction time is 10-30min, such as 10min, 12min, 15min, 17min, 20min, 22min, 25min, 27min, 30min, etc.
In the invention, the cooling rate of the cooling crystallization in the step (2) is 10-15 ℃/h, such as 10 ℃/h, 11 ℃/h, 12 ℃/h, 13 ℃/h, 14 ℃/h, 15 ℃/h and the like.
In the present invention, the cooling end point of the cooling crystallization in the step (2) is 0 to 10 ℃, for example, 0 ℃, 1 ℃, 2 ℃, 3 ℃,4 ℃, 5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃, 10 ℃ and the like.
In the present invention, the step (2) further comprises sequentially performing solid-liquid separation, washing and drying on the crystal obtained after cooling crystallization.
Preferably, the solid-liquid separation mode is filtration.
Preferably, the drying is carried out under atmospheric conditions at a temperature of 25-40 deg.C, such as 25 deg.C, 28 deg.C, 30 deg.C, 32 deg.C, 35 deg.C, 37 deg.C, 40 deg.C, etc., for a time of 3-6h, such as 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, etc.
The third object of the present invention is to provide a method for preparing michelia lactone-m-hydroxybenzoate as defined in the first object, which comprises the following steps:
grinding and mixing the michelia lactone dimethylamine and m-hydroxybenzoic acid for reaction to obtain the michelia lactone-m-hydroxybenzoate.
In the present invention, the molar ratio of the michelia lactone dimethylamine to the m-hydroxybenzoic acid is 1 (1-1.1), for example, 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.1, etc.
In the present invention, the grinding apparatus includes a ball mill or an agate mortar.
In the present invention, the polishing is carried out in a solvent, and the volume of the solvent added is 0.683 to 1.365. mu.L, for example, 0.683. mu.L, 0.7. mu.L, 0.8. mu.L, 0.9. mu.L, 1. mu.L, 1.1. mu.L, 1.2. mu.L, 1.3. mu.L, 1.365. mu.L, based on 1mg of the added amount of the michelia lactone.
In the present invention, the solvent includes any one of ethanol, acetone, acetonitrile, 1, 4-dioxane or methyl acetate or a combination of at least two thereof.
In the present invention, the frequency of the grinding is 20 to 30Hz, such as 20Hz, 21Hz, 22Hz, 23Hz, 24Hz, 25Hz, 26Hz, 27Hz, 28Hz, 29Hz, 30Hz, etc., and the grinding time is 5 to 30min, such as 5min, 8min, 10min, 12min, 15min, 18min, 20min, 22min, 25min, 28min, 30min, etc.
The fourth purpose of the invention is to provide an application of the michelia lactone-m-hydroxybenzoate as one of the purposes in antirheumatic drugs or anticancer drugs.
Compared with the prior art, the invention has the following beneficial effects:
the michelia lactone-m-hydroxybenzoate provided by the invention has lower hygroscopicity and higher physical and chemical stability, and is easy to store and transport; the preparation method of the michelia lactone-m-hydroxybenzoate of dimethylamine is simple, the raw materials are easy to obtain, the price is low, the safety and the low toxicity are realized, and the industrial large-scale production and application are facilitated; the michelia lactone-m-hydroxybenzoate provides a new choice for preparation of medicaments, has important significance for development of medicaments, and is better used for clinical treatment.
Drawings
FIG. 1 is a crystal structure diagram of michelia lactone-m-hydroxybenzoate salt of dimethylamine prepared in example 1.
FIG. 2 is an X-ray diffraction Pattern (PXRD) of michelia lactone-m-hydroxybenzoate salt of dimethylamine prepared in example 1.
FIG. 3 is a Differential Scanning Calorimetry (DSC) chart of the michelia lactone-m-hydroxybenzoate salt of dimethylamine prepared in example 1.
FIG. 4 is a photomicrograph (50X magnification) of the michelia lactone-m-hydroxybenzoate salt of dimethylamine prepared in example 1.
FIG. 5 is a graph showing the dynamic water absorption of the michelia lactone-m-hydroxybenzoate salt of dimethylamine prepared in example 1.
Figure 6 is a graph showing the dynamic water uptake of michelia lactone fumarate.
FIG. 7 is an X-ray diffraction pattern of michelia lactone-m-hydroxybenzoate salt of dimethylamine prepared in example 1, after dynamic moisture adsorption.
FIG. 8 is an X-ray diffraction pattern of michelia lactone fumarate before and after dynamic moisture adsorption.
Fig. 9 is a comparison of experimental stability spectra of michelia lactone-m-hydroxybenzoate of dimethylamine prepared in example 1, wherein the PXRD spectra are sequentially from bottom to top for 0 day, 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks.
Fig. 10 is a comparison of PXRD patterns of dimethylamine michelia lactone-m-hydroxybenzoate, dimethylamine michelia lactone fumarate and dimethylamine michelia lactone prepared in example 1 suspended in a phosphate buffer solution with a pH of 6.8 for 5 hours, wherein the PXRD patterns are the PXRD pattern of dimethylamine michelia lactone-m-hydroxybenzoate before suspension, the PXRD pattern of dimethylamine michelia lactone-m-hydroxybenzoate after suspension, the PXRD pattern of dimethylamine michelia lactone fumarate before suspension, the PXRD pattern of dimethylamine michelia lactone fumarate after suspension, the PXRD pattern of dimethylamine michelia lactone before suspension and the PXRD pattern of dimethylamine michelia lactone after suspension in sequence from bottom to top.
Detailed Description
The foregoing and other objects of the present invention will be more fully understood from the following detailed description of the embodiments, taken in conjunction with the accompanying drawings, which are included to illustrate, but are not to be construed as the limit of the invention. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
It is noted that in X-ray powder diffraction spectroscopy, the diffraction pattern obtained from a crystalline compound tends to be characteristic for a particular crystalline form, where the relative intensities of characteristic peaks may vary due to the dominant orientation effect resulting from differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question. When judging whether the crystal form is the same as the known crystal form, the relative positions of the peaks rather than the relative intensities are more important. Furthermore, for any given crystalline compound, the position of the peaks may vary somewhat due to equipment and operating conditions, and characteristic peaks within error may be considered to be one and the same, as is also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, sample movement, calibration of the instrument, or the like, and the measurement error of the 2 θ value is sometimes about ± 0.2 °. Therefore, this error should be taken into account when determining each crystal structure. For the same crystal form of the same compound, the peak positions of PXRD spectrums have similarity on the whole, and the relative intensity error is likely to be larger.
(1) PXRD test instrument: x-ray powder diffractometer
The instrument model is as follows: rigaku D/max-2500, Japan;
the test method comprises the following steps: Cu-Kalpha radiation of copper target
The voltage is 40kV, the current is 100mA, the test angle is 2-40 degrees, the step length is 8 degrees/min, the exposure time is 0.2s, the test temperature is room temperature (25 ℃), the width of the light tube slit is 1mm, and the width of the detector slit is 2.7 mm.
(2) DSC instrument: differential calorimetric scanner
The instrument model is as follows: mettler Toledo DSC1/500 from Mettler Toledo company;
the test method comprises the following steps: the sample amount is 5-10mg, the heating rate is 10 ℃/min, and the flow rate of protective gas nitrogen is 50 mL/min.
(3) Instrument for SCXRD testing: single crystal X-ray diffractometer
The instrument model is as follows: rigaku Saturn model 70 single crystal diffractometer, Japan;
the test method comprises the following steps: CCD Detector (graphite monochromator), molybdenum target Mo-Ka ray
The temperature 113K was collected.
(4) DVS dynamic water adsorption instrument: dynamic steam adsorption instrument
The instrument model is as follows: VTI-SA + type dynamic moisture adsorption apparatus (TA instruments, USA);
the test method comprises the following steps: the sample amount is 5-20mg, the temperature is constant at 25 ℃, and the relative humidity is from 1-95%.
Example 1
Weighing 29.3mg of michelia lactone dimethylamine solid and 13.8mg of m-hydroxybenzoic acid solid, adding 20 mu L of ethanol, carrying out ball milling for 30min at the frequency of 20Hz, and drying at room temperature for a period of time to obtain a michelia lactone dimethylamine-m-hydroxybenzoate solid sample.
FIG. 1 shows the crystallographic characteristics of the solid sample prepared in example 1, as can be seen from FIG. 1: space group is P2 12121Cell parameter of
α is 90 °, β is 90 °, γ is 90 °, and unit cell volume is
FIG. 2 is a powder X-ray diffraction pattern of a solid sample prepared in example 1, and it can be seen from FIG. 2 that characteristic peaks are shown at 7.9 °, 10.6 °, 11.2 °, 12.1 °, 12.5 °, 13.1 °, 14.3 °, 15.4 °, 16.0 °, 17.0 °, 18.7 °, 19.3 °, 19.6 °, 20.1 °, 21.1 °, 22.2 °, 23.0 °, 23.5 °, 24.2 °, 24.6 °, 25.2 °, 26.0 °, 26.6 °, and 27.5 ° with diffraction angles 2 θ.
FIG. 3 is a DSC of a solid sample prepared in example 1, and it can be seen from FIG. 3 that the solid sample has a characteristic melting peak at 177 ℃.
FIG. 4 is a microscope photograph (50 times magnified) of a solid sample prepared in example 1, and it can be seen from FIG. 4 that the solid sample is a bulk crystal habit.
The following performance tests were carried out on the solid samples obtained in example 1:
(1) and (3) conventional performance test:
example 1 gave a solid product with a purity (HPLC) of 99.4% and a yield of 96%.
(2) Moisture wicking test:
test objects: the solid product obtained in example 1 and michelia lactone fumarate dimethylamine (CN 111303097A);
testing an instrument: VTI-SA+Type dynamic moisture adsorbers (TA instruments, usa);
the test method comprises the following steps: placing a 5mg sample in a moisture adsorption instrument, keeping the temperature constant at 25 ℃, keeping the relative humidity from 1-95%, and observing the change of the water content of the sample;
and (3) testing results: the product prepared in example 1 had a moisture content varying from only 0.01% to 0.42% (see fig. 5), whereas the dimethylamine sphaelactone fumarate (CN111303097A) had a moisture content varying from 0.01% to 4.3% (see fig. 6), as indicated by the comparison: the product obtained in example 1 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
test objects: the product obtained in example 1 after the end of the hygroscopicity test and dimethylamine michelia lactone fumarate (CN 111303097A);
testing an instrument: an X-ray diffractometer;
and (3) testing results: after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak (see fig. 7) compared with that of fig. 2, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the michelia lactone-m-hydroxybenzoate salt of dimethylamine prepared in example 1 has better stability.
After the water adsorption experiment is finished, new characteristic peaks (shown in figure 8) appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN111303097A), and the X-ray powder diffraction pattern of a sample is obviously changed.
In conclusion, the michelia lactone-m-hydroxybenzoate prepared in the embodiment 1 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
test objects: the product obtained in example 1;
the test method comprises the following steps: uniformly spreading a michelia lactone-m-hydroxybenzoate dimethylamine sample in an open culture dish, wherein the thickness of the sample is less than 5mm, sealing the sample in a dryer, placing the sample for 12 weeks, controlling the temperature at 40 ℃ and the humidity at 75%, then respectively carrying out PXRD, TGA and DSC detection on the samples placed for 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks, and comparing the detection result with the detection result of the day 0;
and (3) testing results: PXRD spectrum is shown in figure 9, and TGA and DSC specific data are shown in table 1;
TABLE 1
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| Weight loss (%) TGA before decomposition | 0.01 | 0.01 | 0.03 | 0.02 | 0.06 | 0.05 |
| Tonset(℃)DSC | 177.20 | 177.19 | 176.85 | 176.11 | 176.11 | 175.86 |
As can be seen from fig. 9 and table 1: the PXRD spectrum, the weight loss amount of TGA and the melting point on DSC of the michelia lactone-m-hydroxybenzoate sample are not obviously changed, and the results prove that no crystal form transformation occurs in the michelia lactone-m-hydroxybenzoate sample, and the stability is good.
And (3) testing the stability:
test objects: the product prepared in example 1, a sample of michelia dimethylamine fumarate (CN111303097A), a sample of michelia dimethylamine (CN 102234259B);
the test method comprises the following steps: adding the three samples into 3 penicillin bottles containing 15mL phosphate buffer solution (PH is 6.8), placing the penicillin bottles on a constant-temperature heating stirrer at 37 ℃, performing a suspension experiment at a stirring speed of 300r/min, centrifuging and filtering the suspension after 5 hours, drying the suspension at room temperature for 3 hours to obtain corresponding solid samples, and performing PXRD characterization on 3 groups of solid samples;
and (3) testing results: the specific comparison map of PXRD is shown in fig. 10, and it can be seen from fig. 10 that: only the solid sample of the michelia lactone-m-hydroxybenzoate of the invention has no obvious change, but the PXRD spectra of the solid samples corresponding to the michelia lactone and the michelia lactone fumarate have obvious new diffraction peaks, which shows that a new phase is generated, and proves that the michelia lactone-m-hydroxybenzoate of the dimethylamine solves the problems of poor stability and easy degradation of the michelia lactone, and simultaneously overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia lactone fumarate is easy to generate crystal form conversion.
Example 2
Weighing 58.6mg of michelia lactone dimethylamine solid and 29.0mg of m-hydroxybenzoic acid solid, adding 50 mu L of acetone, carrying out ball milling at the frequency of 30Hz for 5min, and drying at room temperature for a period of time to obtain a michelia lactone dimethylamine-m-hydroxybenzoic acid solid sample.
The product obtained in example 2 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 2 was subjected to PXRD test, which revealed that: the characteristic peaks are shown at diffraction angles 2 theta at 8.1 DEG, 10.8 DEG, 11.4 DEG, 12.3 DEG, 12.7 DEG, 13.3 DEG, 14.5 DEG, 15.6 DEG, 16.2 DEG, 17.2 DEG, 18.9 DEG, 19.5 DEG, 19.8 DEG, 20.3 DEG, 21.3 DEG, 22.4 DEG, 23.2 DEG, 23.7 DEG, 24.4 DEG, 24.8 DEG, 25.4 DEG, 26.2 DEG, 26.8 DEG, and 27.7 deg.
The DSC test of example 2 revealed that: the product has an endothermic peak at 176.9 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 2:
(1) and (3) conventional performance test:
the purity of the product obtained in example 2 was 99.5%, the yield of the product was 98%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 2 had a moisture content varying from only 0.01% to 0.40% and the dimethylamine sphaelactone fumarate (CN111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by comparison: the product obtained in example 2 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 2, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the dimethylamine michelia lactone-m-hydroxybenzoate prepared in the embodiment of the invention has better stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia lactone-m-hydroxybenzoate prepared in the embodiment 2 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-m-hydroxybenzoate sample prepared in example 2 do not change significantly, which proves that no crystal transformation occurs in the michelia lactone-m-hydroxybenzoate, and the stability is good.
And (3) testing the stability:
the solid sample of the michelia dimpled lactone-m-hydroxybenzoate prepared in the embodiment 2 is not obviously changed, but the PXRD patterns of the solid samples corresponding to the michelia dimpled lactone and the michelia dimpled lactone fumarate have obvious new diffraction peaks, which indicates that a new phase is generated, and the new phase proves that the michelia dimpled lactone-m-hydroxybenzoate solves the problems of poor stability and easy degradation of the michelia dimpled lactone, and overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia dimpled lactone fumarate is easy to generate crystal form conversion.
Example 3
Weighing 146.5mg of michelia lactone dimethylamine solid and 69mg of m-hydroxybenzoic acid solid, adding 200 mu L of methyl acetate, carrying out ball milling at the frequency of 25Hz for 20min, and drying at room temperature for a period of time to obtain a michelia lactone-m-hydroxybenzoate dimethylamine solid sample.
The product obtained in example 3 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 3 was subjected to PXRD test, which revealed that: the characteristic peaks expressed by the diffraction angle 2 theta at 7.7 DEG, 10.4 DEG, 11.0 DEG, 12.0 DEG, 12.4 DEG, 12.9 DEG, 14.1 DEG, 15.2 DEG, 15.8 DEG, 16.8 DEG, 18.5 DEG, 19.1 DEG, 19.4 DEG, 20.0 DEG, 20.9 DEG, 22.0 DEG, 22.8 DEG, 23.3 DEG, 24.0 DEG, 24.4 DEG, 25.0 DEG, 25.8 DEG, 26.4 DEG, and 27.3 deg.
The DSC test of example 3 revealed that: the product has an endothermic peak at 177.3 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 3:
(1) and (3) conventional performance test:
the purity of the product obtained in example 3 was 99.7%, the yield of the product was 98%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 3 had a moisture content varying from only 0.01% to 0.42% and the dimethylamine sphaelactone fumarate (CN111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by the comparison: the product obtained in example 3 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 2, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the dimethylamine michelia lactone-m-hydroxybenzoate prepared in the embodiment of the invention has better stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia lactone-m-hydroxybenzoate prepared in the embodiment 3 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-m-hydroxybenzoate sample prepared in example 3 do not change significantly, which proves that no crystal transformation occurs in the michelia lactone-m-hydroxybenzoate, and the stability is good.
And (3) testing the stability:
the solid sample of the michelia figo lactone-m-hydroxybenzoate prepared in the embodiment 3 has no obvious change, and the PXRD pattern of the solid sample corresponding to the michelia figo lactone and the michelia figo lactone fumarate has obvious new diffraction peak, which indicates that a new phase is generated, and proves that the michelia figo lactone-m-hydroxybenzoate solves the problems of poor stability and easy degradation of the michelia figo lactone, and simultaneously overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal form conversion.
Example 4
Weighing 29.3mg of michelia lactone dimethylamine solid and 15.2mg of m-hydroxybenzoic acid solid, putting into an agate mortar, adding 20 mu L of 1, 4-dioxane, grinding for 5min, and drying at room temperature for a period of time to obtain a michelia lactone dimethylamine-m-hydroxybenzoate solid sample.
The product obtained in example 4 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 4 was subjected to PXRD test, which revealed that: the characteristic peaks are shown at diffraction angles 2 theta at 7.8 °, 10.5 °, 11.1 °, 12.0 °, 12.4 °, 13.0 °, 14.2 °, 15.3 °, 15.9 °, 16.9 °, 18.6 °, 19.2 °, 19.5 °, 20.0 °, 21.0 °, 22.1 °, 22.9 °, 23.4 °, 24.1 °, 24.5 °, 25.1 °, 25.9 °, 26.5 °, and 27.4 °.
The DSC test of example 4 revealed that: the product has an endothermic peak at 178.0 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 4:
(1) and (3) conventional performance test:
the purity of the product obtained in example 4 was 99%, the yield of the product was 98.5%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 4 had a moisture content varying from only 0.01% to 0.41% and the dimethylamine sphaelactone fumarate (CN111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by comparison: the product obtained in example 4 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 2, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the dimethylamine michelia lactone-m-hydroxybenzoate prepared in example 4 has better stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia lactone-m-hydroxybenzoate prepared in the embodiment 4 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-m-hydroxybenzoate sample prepared in example 4 do not change significantly, which proves that the michelia lactone-m-hydroxybenzoate does not undergo crystal transformation and has good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-m-hydroxybenzoate prepared in the embodiment 4 has no obvious change, and the PXRD pattern of the solid sample corresponding to the michelia figo lactone and the michelia figo lactone fumarate has obvious new diffraction peak, which indicates that a new phase is generated, and proves that the michelia figo lactone-m-hydroxybenzoate solves the problems of poor stability and easy degradation of the michelia figo lactone, and simultaneously overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal form conversion.
Example 5
Weighing 58.6mg of michelia lactone dimethylamine solid and 27.6mg of m-hydroxybenzoic acid solid, adding 40 mu L of acetonitrile, carrying out ball milling at the frequency of 20Hz for 20min, and drying at room temperature for a period of time to obtain a michelia lactone-m-hydroxybenzoate dimethylamine solid sample.
The product obtained in example 5 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 5 was subjected to PXRD test, which revealed that: the characteristic peaks are shown at diffraction angles 2 theta at 8.0 °, 10.7 °, 11.3 °, 12.2 °, 12.6 °, 13.2 °, 14.4 °, 15.5 °, 16.1 °, 17.1 °, 18.8 °, 19.4 °, 19.7 °, 20.2 °, 21.2 °, 22.3 °, 23.1 °, 23.6 °, 24.3 °, 24.7 °, 25.3 °, 26.1 °, 26.7 °, and 27.6 °.
The DSC test of example 5 revealed that: the product has an endothermic peak at 176.8 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 5:
(1) and (3) conventional performance test:
the purity of the product obtained in example 5 was 99.3%, the yield of the product was 97%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 5 had a moisture content varying from only 0.01% to 0.42% and the dimethylamine sphaelactone fumarate (CN111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by comparison: the product obtained in example 5 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 2, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the dimethylamine michelia lactone-m-hydroxybenzoate prepared in example 5 has better stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia lactone-m-hydroxybenzoate prepared in the embodiment 5 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-m-hydroxybenzoate sample prepared in example 5 do not change significantly, which proves that the michelia lactone-m-hydroxybenzoate does not undergo crystal transformation and has good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-m-hydroxybenzoate prepared in the embodiment 5 has no obvious change, and the PXRD pattern of the solid sample corresponding to the michelia figo lactone and the michelia figo lactone fumarate has obvious new diffraction peak, which indicates that a new phase is generated, and proves that the michelia figo lactone-m-hydroxybenzoate solves the problems of poor stability and easy degradation of the michelia figo lactone, and simultaneously overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal form conversion.
Example 6
1.5g of michelia lactone dimethylamine solid, 0.706g of m-hydroxybenzoic acid solid and 75mL of isopropyl acetate are added into a reaction bottle, heated to 60 ℃, and stirred for 30min to ensure that the raw materials are fully reacted. Cooling to 10 ℃ at the speed of 10 ℃/h, filtering the obtained product, and then drying at the temperature of 25 ℃ for 6h under normal pressure to obtain the dimethylamine michelia lactone-m-hydroxybenzoate.
The product obtained in example 6 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 6 was subjected to PXRD test, which revealed that: the characteristic peaks expressed by the diffraction angle 2 theta at 7.9 degrees, 10.5 degrees, 11.1 degrees, 12.0 degrees, 12.4 degrees, 13.1 degrees, 14.1 degrees, 15.2 degrees, 15.9 degrees, 17.0 degrees, 18.7 degrees, 19.3 degrees, 19.7 degrees, 20.2 degrees, 21.1 degrees, 22.2 degrees, 23.0 degrees, 23.5 degrees, 24.2 degrees, 24.6 degrees, 25.2 degrees, 26.0 degrees, 26.6 degrees and 27.5 degrees.
The DSC test of example 6 revealed that: the product has an endothermic peak at 177.2 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 6:
(1) and (3) conventional performance test:
the purity of the product obtained in example 6 was 99.7%, the yield of the product was 96%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 6 had a moisture content varying from only 0.01% to 0.41% and the dimethylamine sphaelactone fumarate (CN111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by comparison: the product obtained in example 6 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 2, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the dimethylamine michelia lactone-m-hydroxybenzoate prepared in example 6 has better stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia lactone-m-hydroxybenzoate prepared in the embodiment 6 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-m-hydroxybenzoate sample prepared in example 6 do not change significantly, which proves that the michelia lactone-m-hydroxybenzoate does not undergo crystal transformation and has good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-m-hydroxybenzoate prepared in the embodiment 6 has no obvious change, and the PXRD pattern of the solid sample corresponding to the michelia figo lactone and the michelia figo lactone fumarate has obvious new diffraction peak, which indicates that a new phase is generated, and proves that the michelia figo lactone-m-hydroxybenzoate solves the problems of poor stability and easy degradation of the michelia figo lactone, and simultaneously overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal form conversion.
Example 7
3g of michelia lactone dimethylamine solid, 1.1304g of m-hydroxybenzoic acid solid and 37.5mL of methanol are added into a reaction bottle, heated to 55 ℃, and stirred for 10min to ensure that the raw materials are fully reacted. Cooling to 5 ℃ at the speed of 15 ℃/h, filtering the obtained product, and then drying at 30 ℃ for 3h under normal pressure to obtain the dimethylamine michelia lactone-m-hydroxybenzoate.
The product obtained in example 7 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 7 was subjected to PXRD test, which revealed that: the characteristic peaks expressed by the diffraction angle 2 theta at 7.9 degrees, 10.6 degrees, 11.2 degrees, 12.1 degrees, 12.5 degrees, 13.1 degrees, 14.3 degrees, 15.4 degrees, 16.0 degrees, 17.0 degrees, 18.7 degrees, 19.3 degrees, 19.6 degrees, 20.1 degrees, 21.1 degrees, 22.2 degrees, 23.0 degrees, 23.5 degrees, 24.2 degrees, 24.6 degrees, 25.2 degrees, 26.0 degrees, 26.6 degrees and 27.5 degrees.
The DSC test of example 7 revealed that: the product has an endothermic peak at 178.3 ℃.
The following performance tests were carried out by the same method as in example 1 on the product obtained in example 7:
(1) and (3) conventional performance test:
example 7 gave a product with a purity of 99.6% and a yield of 95.5%, the crystal habit of the product being bulk.
(2) Moisture wicking test:
the product prepared in example 7 had a moisture content varying from only 0.01% to 0.40% and the dimethylamine sphaelactone fumarate (CN111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by comparison: the product obtained in example 7 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 2, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the michelia lactone-m-hydroxybenzoate dimethylamine prepared in example 7 has better stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia lactone-m-hydroxybenzoate prepared in the embodiment 7 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA, and the melting point on DSC of the michelia lactone-m-hydroxybenzoate sample prepared in example 7 did not change significantly, which proves that the michelia lactone-m-hydroxybenzoate has no crystal transformation and good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-m-hydroxybenzoate prepared in the embodiment 7 has no obvious change, and the PXRD pattern of the solid sample corresponding to the michelia figo lactone and the michelia figo lactone fumarate has an obvious new diffraction peak, which indicates that a new phase is generated, and proves that the michelia figo lactone-m-hydroxybenzoate solves the problems of poor stability and easy degradation of the michelia figo lactone, and simultaneously overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal form conversion.
Example 8
Adding 6g of michelia lactone dimethylamine solid, 4.234g of m-hydroxybenzoic acid solid and 120mL of acetone into a reaction bottle, heating to 50 ℃, and stirring for 20min to ensure that the raw materials are fully reacted. Cooling to 0 ℃ at the speed of 12 ℃/h, filtering the obtained product, and then drying at 40 ℃ for 4h under normal pressure to obtain the dimethylamine michelia lactone-m-hydroxybenzoate.
The product obtained in example 8 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 8 was subjected to PXRD test, which revealed that: the characteristic peaks expressed by the diffraction angle 2 theta at 7.9 degrees, 10.5 degrees, 11.1 degrees, 12.0 degrees, 12.6 degrees, 13.2 degrees, 14.4 degrees, 15.5 degrees, 16.2 degrees, 17.2 degrees, 18.8 degrees, 19.4 degrees, 19.7 degrees, 20.2 degrees, 21.2 degrees, 22.3 degrees, 23.1 degrees, 23.6 degrees, 24.3 degrees, 24.7 degrees, 25.3 degrees, 26.1 degrees, 26.7 degrees and 27.6 degrees.
The DSC test of example 8 revealed that: the product has an endothermic peak at 177.1 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 8:
(1) and (3) conventional performance test:
the purity of the product obtained in example 8 was 99.6%, the yield of the product was 97%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 8 had a moisture content varying from only 0.01% to 0.41% and the dimethylamine sphaelactone fumarate (CN111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by comparison: the product obtained in example 8 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 2, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the michelia lactone-m-hydroxybenzoate dimethylamine prepared by the method disclosed by the invention has better stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia lactone-m-hydroxybenzoate prepared in the embodiment 8 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA, and the melting point on DSC of the michelia lactone-m-hydroxybenzoate sample prepared in example 8 did not change significantly, which proves that the michelia lactone-m-hydroxybenzoate has no crystal transformation and good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-m-hydroxybenzoate prepared in the embodiment 8 has no obvious change, and the PXRD pattern of the solid sample corresponding to the michelia figo lactone and the michelia figo lactone fumarate has an obvious new diffraction peak, which indicates that a new phase is generated, and proves that the michelia figo lactone-m-hydroxybenzoate solves the problems of poor stability and easy degradation of the michelia figo lactone, and simultaneously overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal form conversion.
Example 9
3g of michelia lactone dimethylamine solid, 1.696g of m-hydroxybenzoic acid solid and 45mL of ethanol are added into a reaction bottle, heated to 40 ℃, and stirred for 20min, so that the raw materials are fully reacted. Cooling to 0 ℃ at the speed of 10 ℃/h, filtering the obtained product, and then drying at 40 ℃ for 3h under normal pressure to obtain the dimethylamine michelia lactone-m-hydroxybenzoate.
The product obtained in example 9 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 9 was subjected to PXRD test, which revealed that: the characteristic peaks are shown at diffraction angles 2 theta at 8.0 °, 10.8 °, 11.3 °, 12.3 °, 12.7 °, 13.3 °, 14.5 °, 15.6 °, 16.2 °, 17.2 °, 18.9 °, 19.5 °, 19.8 °, 20.3 °, 21.2 °, 22.3 °, 23.2 °, 23.7 °, 24.4 °, 24.7 °, 25.3 °, 26.1 °, 26.7 °, and 27.7 °.
DSC test was performed on example 9, and it was found that: the product has an endothermic peak at 178.6 ℃.
The following performance tests were carried out by the same method as in example 1 on the product obtained in example 9:
(1) and (3) conventional performance test:
the purity of the product obtained in example 9 was 99.6%, the yield of the product was 92%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 9 had a moisture content varying from only 0.01% to 0.42% and the dimethylamine sphaelactone fumarate (CN111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by comparison: the product obtained in example 9 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 2, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the michelia lactone-m-hydroxybenzoate dimethylamine prepared in example 9 has better stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia lactone-m-hydroxybenzoate prepared in the embodiment 9 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA, and the melting point on DSC of the michelia lactone-m-hydroxybenzoate sample prepared in example 9 did not change significantly, which proves that the michelia lactone-m-hydroxybenzoate has no crystal transformation and good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-m-hydroxybenzoate prepared in the example 9 is not obviously changed, but the PXRD patterns of the solid samples corresponding to the michelia figo lactone and the michelia figo lactone fumarate have obvious new diffraction peaks, which indicates that a new phase is generated, and the new phase proves that the michelia figo lactone-m-hydroxybenzoate solves the problems of poor stability and easy degradation of the michelia figo lactone, and overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal form conversion.
The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be understood by those skilled in the art that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are within the scope and disclosure of the present invention.
Claims (10)
1. A michelia lactone-m-hydroxybenzoate salt as an active ingredient, wherein the michelia lactone-m-hydroxybenzoate salt is prepared from sodium-dimethyl-amineThe molecular formula of the hydroxybenzoate is C24H33NO6And has the following structure:
the crystallography characteristics of the michelia lactone-m-hydroxybenzoate salt of dimethylamine comprise: space group is P212121Cell parameter of
α is 90 °, β is 90 °, γ is 90 °, and unit cell volume is
2. The michelia lactone-m-hydroxybenzoate salt as claimed in claim 1, wherein the michelia lactone-m-hydroxybenzoate salt has an X-ray powder diffraction pattern having peaks at 2 Θ diffraction angles of 7.9 ± 0.2 °, 10.6 ± 0.2 °, 11.2 ± 0.2 °, 12.1 ± 0.2 °, 12.5 ± 0.2 °, 13.1 ± 0.2 °, 14.3 ± 0.2 °, 15.4 ± 0.2 °, 16.0 ± 0.2 °, 17.0 ± 0.2 °, 18.7 ± 0.2 °, 19.3 ± 0.2 °, 19.6 ± 0.2 °, 20.1 ± 0.2 °, 21.1 ± 0.2 °, 22.2 ± 0.2 °, 23.0 ± 0.2 °, 23.5 ± 0.2 °, 24.2 ± 0.2 °, 24.6 ± 0.2 °, 25.2 ± 0.26.2 ± 0.26 ± 0.2 °, 27.2 °.
3. The michelia lactone-m-hydroxybenzoate salt as claimed in claim 1, wherein the differential scanning calorimetry analysis of the michelia lactone-m-hydroxybenzoate salt has a characteristic melting peak at 177 ± 2 ℃.
4. The method of producing michelia lactone-m-hydroxybenzoate as claimed in any one of claims 1 to 3, wherein the method comprises the steps of:
(1) reacting michelia lactone dimethylamine with m-hydroxybenzoic acid in an organic solvent to obtain a mixture;
(2) and (2) cooling and crystallizing the mixture obtained by the reaction in the step (1) to obtain the michelia lactone-m-hydroxybenzoate.
5. The method according to claim 4, wherein the molar ratio of the michelia lactone and the m-hydroxybenzoic acid in the dimethylamine in the step (1) is 1 (0.8-1.5);
preferably, the addition amount of the organic solvent in the step (1) is 1mL, wherein the addition amount of the michelia lactone is 20-80 mg;
preferably, the organic solvent in step (1) comprises any one of methanol, ethanol, acetone or isopropyl acetate or a combination of at least two of the above.
6. The preparation method according to claim 4, wherein the reaction temperature in the step (1) is 40-60 ℃, and the reaction time is 10-30 min;
preferably, the cooling rate of the cooling crystallization in the step (2) is 10-15 ℃/h;
preferably, the cooling crystallization of the step (2) has a cooling end point of 0-10 ℃.
7. The preparation method according to claim 4, wherein the step (2) further comprises sequentially subjecting the crystal obtained after cooling crystallization to solid-liquid separation, washing and drying;
preferably, the solid-liquid separation mode is filtration;
preferably, the drying is carried out under normal pressure, the drying temperature is 25-40 ℃, and the drying time is 3-6 h.
8. The method of producing michelia lactone-m-hydroxybenzoate as claimed in any one of claims 1 to 3, wherein the method comprises the steps of:
grinding and mixing the michelia lactone dimethylamine and m-hydroxybenzoic acid for reaction to obtain the michelia lactone-m-hydroxybenzoate.
9. The method according to claim 8, wherein the molar ratio of the michelia lactone to the m-hydroxybenzoic acid is 1 (1-1.1);
preferably, the apparatus for grinding comprises a ball mill or an agate mortar;
preferably, the grinding is carried out in a solvent, and the adding volume of the solvent is 0.683-1.365 mu L based on the adding amount of the michelia lactone of dimethylamine as 1 mg;
preferably, the solvent comprises any one of ethanol, acetone, acetonitrile, 1, 4-dioxane or methyl acetate or a combination of at least two of the above;
preferably, the frequency of the grinding is 20-30Hz, and the grinding time is 5-30 min.
10. The use of michelia lactone-m-hydroxybenzoate according to any one of claims 1 to 3, as an antirheumatic or anticancer agent.
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