CN113200949B - Dimethylamine michelia lactone-salicylate and preparation method and application thereof - Google Patents
Dimethylamine michelia lactone-salicylate and preparation method and application thereof Download PDFInfo
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 title claims abstract description 264
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- C07C65/05—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 o-Hydroxy carboxylic acids
- C07C65/10—Salicylic acid
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention relates to michelia dimctum lactone-salicylate and a preparation method and application thereof, wherein the molecular formula of the michelia dimctum lactone-salicylate is C 24 H 33 NO 6 The crystallography characteristics of the michelia lactone-salicylate of dimethylamine comprise that the space group is P2 1 2 1 2 1 With cell parameters of
α =90 °, β =90 °, γ =90 °, cell volume of
Compared with the michelia lactone fumarate and the michelia lactone hydrochloride, the michelia lactone salicylate provided by the invention has better hygroscopicity and stability. The preparation method is simple to operate, mild in condition, good in repeatability, green, environment-friendly, low in toxicity and safe, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of medical crystallization, and particularly relates to michelia lactone-salicylate dimethylamine and a preparation method and application thereof.
Background
The sesquiterpenoids are mainly a compound group which is composed of 3 isoprene units and contains 15 carbon atoms, are typical NF-kB inhibitors, have wide significance in cancer treatment, and have good treatment effects on diseases such as liver cancer, lung cancer, pancreatic cancer, breast cancer, brain glioma, acute lymphocytic leukemia and the like through in vivo and in vitro experiments, and can selectively kill tumor cells without damaging normal cells. Meanwhile, the compounds are widely distributed, so that the cost can be reduced, and the life quality of cancer patients can be improved.
The michelia lactone of dimethylamine belongs to sesquiterpene lactone compounds, and the molecular formula is C 17 H 27 NO 3 The product is a white powdery solid with poor water solubility and can be degraded after being placed for a long time, and the problems influence the development of a drug product, the design of a process and the prospect of curative effect of treating diseases to a great extent.
WO2015006893A1 discloses application of sesquiterpene lactone compounds containing michelia dimethylamine lactone and derivatives thereof in treating rheumatoid arthritis, inhibiting cancer stem cells and further treating cancer, and provides preparation methods of michelia dimethylamine lactone hydrochloride and fumarate. Dissolving the michelia lactone dimethylamine in dichloromethane, adding a dilute hydrochloric acid solution while stirring, monitoring the pH value of the solution in real time during stirring, stopping dropwise adding the dilute hydrochloric acid when the pH value of the solution is controlled to be 4-5, collecting the solution, and freeze-drying to obtain the michelia lactone dimethylamine hydrochloride; the michelia lactone fumarate is prepared by dissolving michelia lactone in dichloromethane, adding fumaric acid into the solution, concentrating and drying. The dichloromethane belongs to two types of organic solvents, has certain toxicity and carcinogenicity, has extremely low boiling point, has anesthetic property of steam, can cause acute poisoning by mass inhalation, has symptoms of headache, vomit, impaired hematopoietic function and the like, and brings certain potential safety hazard for industrial mass production.
CN104876899A indicates that dimethylamine michelia lactone hydrochloride can improve water solubility, but has serious moisture absorption, and the color of the powder product is changed from white to gray and dark brown in high-temperature and high-humidity tests, and the content of active substances is reduced from 99% to 60%, which indicates that the dimethylamine michelia lactone hydrochloride is seriously degraded. The defects of high hygroscopicity and poor physicochemical stability further limit the research and development of the dimethylamine michelia lactone hydrochloride medicament. Compared with the dimethylamine smilacin hydrochloride, the dimethylamine smilacin fumarate improves the hygroscopicity to a certain extent, but still does not solve the problem that the product is easy to degrade and deteriorate.
A series of patents CN103724307B, CN111303097A, CN111303100A, CN111303098A and CN111303099A successively disclose 6 different crystal forms of dimethylamine michelia lactone fumarate and a preparation method thereof. Due to the existence of the polymorphism, the quality stability of the michelia lactone fumarate is difficult to control in the production process, because experimental researches find that different crystal forms of the michelia lactone fumarate are mutually converted under the conditions of certain solvent, temperature, humidity and the like. 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 crystal form has important influence on the properties and use of the drug product, and a stable preparation process with high reproducibility is urgently needed to ensure the effective crystal form of the product.
In conclusion, 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-salicylate dimethylamine and a preparation method and application thereof, aiming at solving the technical problems of high hygroscopicity, poor stability, easy mutual transformation of crystal forms, complex process, strong toxicity of used solvents, poor controllability of process and product quality and the like in the existing michelia lactone dimethylamine salt and the preparation method thereof. The dimethylamine michelia lactone salicylate provided by the invention has the advantages of low hygroscopicity, high physical and chemical stability, safe and low-toxicity preparation process, less used solvent, 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 salicylate, and the molecular formula of the michelia lactone salicylate is C 24 H 33 NO 6 And has the following structure:
the crystallography characteristics of the michelia dimethylamine lactone-salicylate comprise that the space group is P2 1 2 1 2 1 Cell parameter of
α =90 °, β =90 °, γ =90 °, cell volume of
In the invention, in the X-ray powder diffraction spectrum of the michelia lactone-salicylate, the characteristic peaks exist at the 2 theta diffraction angles of 7.6 +/-0.2 degrees, 10.2 +/-0.2 degrees, 11.4 +/-0.2 degrees, 11.9 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.2 +/-0.2 degrees, 14.9 +/-0.2 degrees, 16.0 +/-0.2 degrees, 16.5 +/-0.2 degrees, 17.8 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.2 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.1 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.0 +/-0.2 degrees, 24.0 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.1 +/-0.2 degrees and 27.4 +/-0.2 degrees.
In the invention, the differential scanning calorimetry analysis spectrum of the michelia lactone-salicylate has a characteristic melting peak at 172 +/-2 ℃.
The product purity of the michelia lactone salicylate of dimethylamine 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 dimethylamine michelia lactone salicylate sample is only 0.6% +/-0.03% 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 salicylate 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 0.1%, which shows that the michelia lactone salicylate sample provided by the invention has higher stability and lower hygroscopicity. In a buffer solution with the pH =6.8 and simulating the intestinal juice of a human body, the dimethylamine smilacin salicylate sample provided by the invention has no crystal form transformation and degradation in the suspension experiment process for 5 hours.
Another object of the present invention is to provide a method for preparing michelia lactone-salicylate, the method comprising the steps of:
grinding and mixing the michelia lactone dimethylamine and salicylic acid to obtain the michelia lactone salicylate.
Compared with other preparation processes, the solvent auxiliary grinding method of the dimethylamine michelia lactone salicylate provided by the invention is simple to operate, mild in condition, easy to prepare, good in repeatability, green, environment-friendly, low in toxicity and safe, and the selected solvent is three solvents, so that the method is suitable for large-scale production.
In the present invention, the molar ratio of dimethylamine michelia lactone and salicylic acid is 1 (0.8-1.2), such as 1.
In the present invention, the grinding apparatus includes a ball mill or an agate mortar.
In the present invention, the grinding is carried out in a solvent, and the addition volume of the solvent is 0.512 to 0.853. Mu.L, for example, 0.512. Mu.L, 0.55. Mu.L, 0.6. Mu.L, 0.65. Mu.L, 0.7. Mu.L, 0.75. Mu.L, 0.8. Mu.L, 0.853. Mu.L, etc., based on 1mg of added dimethylamine michelia lactone.
In the present invention, the solvent includes any one of methanol, ethanol, n-propanol, acetone, acetonitrile, 1, 4-dioxane, ethyl acetate, or isopropyl acetate, or a combination of at least two thereof.
In the present invention, the frequency of the grinding is 15 to 30Hz, such as 15Hz, 18Hz, 20Hz, 22Hz, 25Hz, 28Hz, 30Hz, etc., and the grinding time is 5 to 60min, such as 5min, 10min, 15min, 20min, 25min, 30min, 35min, 40min, 45min, 50min, 55min, 60min, etc.
The third object of the present invention is to provide a method for preparing michelia lactone-salicylate, which comprises the following steps:
(1) Reacting michelia lactone dimethylamine with salicylic 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 dimethylamine michelia lactone-salicylate.
Compared with other preparation processes, the cooling crystallization preparation method of the dimethylamine michelia lactone salicylate provided by the invention is simple to operate, mild in condition, easy to prepare, good in repeatability, green, environment-friendly, low in toxicity and safe, and the selected solvents are three solvents, so that the method is suitable for large-scale production.
In the present invention, the molar ratio of dimethylamine michelia lactone to salicylic acid in step (1) is 1 (0.9-1.5), for example, 1.
In the present invention, the amount of the organic solvent added in step (1) is 1mL, based on the amount of 15 to 60mg (for example, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, etc.) of the michelia lactone added.
In the present invention, the organic solvent in step (1) includes any one of ethanol, acetone, acetonitrile, 1, 4-dioxane, ethyl acetate 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 30-60min, such as 30min, 35min, 40min, 45min, 50min, 55min, 60min, etc.
In the invention, the cooling rate of the cooling crystallization in the step (2) is 5-10 ℃/h, such as 5 ℃/h, 6 ℃/h, 7 ℃/h, 8 ℃/h, 9 ℃/h, 10 ℃/h and the like.
In the present invention, the end point of the cooling of the cooled crystals in step (2) is 10 to 20 ℃, for example, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃,20 ℃ 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.
In the present invention, the solid-liquid separation method is filtration.
In the present invention, the drying is performed under normal pressure conditions, the drying temperature is 25 to 40 ℃, such as 25 ℃, 28 ℃, 30 ℃, 32 ℃, 35 ℃, 37 ℃,40 ℃ and the like, and the drying time is 3 to 6 hours, such as 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours and the like.
The fourth purpose of the invention is to provide the application of the dimethylamine michelia lactone-salicylate in an antirheumatic drug or an anticancer drug.
Compared with the prior art, the invention has the following beneficial effects:
the michelia lactone salicylate 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-salicylate 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 convenient; the michelia lactone-salicylate 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 the minocycline salicylate prepared in example 1.
FIG. 2 is an X-ray diffraction Pattern (PXRD) of the dimethylamine michelia lactone salicylate prepared in example 1.
FIG. 3 is a Differential Scanning Calorimetry (DSC) chart of the dimethylamine michelia lactone salicylate prepared in example 1.
FIG. 4 is a graph showing the dynamic water uptake of the minocycline salicylate prepared in example 1.
Figure 5 is a drawing of the dynamic water uptake of michelia lactone fumarate.
FIG. 6 is an X-ray diffraction pattern of the salt of michelia lactone salicylate of dimethylamine prepared in example 1 before and after dynamic moisture adsorption.
FIG. 7 is an X-ray diffraction pattern of michelia lactone fumarate before and after dynamic moisture adsorption.
Fig. 8 is a graph comparing the stability tests of the salicylates of michelia lactone of dimethylamine prepared in example 1, wherein the PXRD graphs are from bottom to top for 0 day, 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks.
Fig. 9 is a comparison of PXRD patterns of dimethylamine michelia lactone salicylate, dimethylamine michelia lactone fumarate, and dimethylamine michelia lactone in a phosphate buffer solution with pH =6.8 suspended for 5h prepared in example 1, wherein the PXRD pattern of dimethylamine michelia lactone salicylate before suspension, the PXRD pattern of dimethylamine michelia lactone salicylate 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 are sequentially arranged 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 the characteristic peaks within the error range 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, movement of the sample, 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 2.7mm.
(2) DSC instrument: differential calorimetric scanner
The instrument model is as follows: mettler-Tollido Corp Mettler Toledo DSC1/500;
the test method comprises the following steps: the sample amount is 5-10mg, the heating rate is 10 ℃/min, and the flow rate of the protective gas nitrogen is 50mL/min.
(3) Instrument for SCXRD testing: single crystal X-ray diffractometer
The instrument model is as follows: rigaku Saturn model 70 single crystal diffractometer in 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 apparatus: 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 salicylic acid solid, adding 20 mu L of methanol, carrying out ball milling at the frequency of 30Hz for 30min, and drying at room temperature to obtain a michelia lactone dimethylamine salicylate solid sample.
FIG. 1 shows the crystallographic characteristics of the product prepared in example 1, as can be seen from FIG. 1: space group is P2 1 2 1 2 1 Cell parameter of
α =90 °, β =90 °, γ =90 °, cell volume of
FIG. 2 is a powder X-ray diffraction pattern of the product prepared in example 1, and it can be seen from FIG. 2 that characteristic peaks are shown at 7.6 °, 10.2 °, 11.4 °, 11.9 °, 12.5 °, 13.2 °, 14.9 °, 16.0 °, 16.5 °, 17.8 °, 18.8 °, 19.6 °, 20.2 °, 21.7 °, 22.1 °, 22.4 °, 23.0 °, 24.0 °, 24.7 °, 25.1 °, and 27.4 ° with a diffraction angle 2 θ.
FIG. 3 is a DSC spectrum of the product prepared in example 1, and it can be seen from FIG. 3 that the product has a characteristic melting peak at 172 ℃.
The following performance tests were carried out on the product obtained in example 1:
(1) And (3) conventional performance test:
the purity (HPLC) of the product obtained in example 1 was 99.5%, the yield of the product was 96%, and the crystal habit (scanning electron microscope) of the product was bulk crystal habit.
(2) Moisture wicking test:
test object(s): the product obtained in example 1 and dimethylamine michelia lactone fumarate (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 water content of the product prepared in example 1 varied from only 0.01% to 0.61% (see fig. 4), whereas the water content of michelia lactone fumarate (CN 111303097A) varied from 0.01% to 4.3% (see fig. 5), 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 the 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. 6) 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 dimethylamine michelia lactone-salicylate disclosed by the invention has better stability.
After the water adsorption experiment is finished, new characteristic peaks (shown in figure 7) appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in dimethylamine michelia lactone fumarate (CN 111303097A), and an X-ray powder diffraction pattern of a sample is obviously changed.
In conclusion, the dimethylamine smilacin-salicylate prepared in the embodiment 1 can well overcome the defects of high hygroscopicity and poor stability of the dimethylamine smilacin fumarate, and the quality controllability and the safety of the medicament are improved.
And (5) testing the stability:
test object(s): the product obtained in example 1;
the test method comprises the following steps: uniformly spreading a dimethylamine michelia lactone-salicylate sample in an open culture dish, wherein the thickness of the sample is less than 5mm, sealing and placing in a dryer 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 results with the detection results on the 0 th day;
and (3) testing results: PXRD spectrum is shown in figure 8, TGA and DSC detailed data are shown in table 1;
TABLE 1
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| Weight loss (%) TGA before decomposition | 0.02 | 0.03 | 0.05 | 0.06 | 0.08 | 0.07 |
| T onset (℃)DSC | 172.05 | 172.03 | 172.06 | 172.05 | 172.11 | 172.08 |
As can be seen from fig. 8 and table 1: PXRD atlas, TGA weight loss amount and DSC melting point of the michelia dimoxystrobin-salicylate sample do not change obviously, and therefore the michelia dimoxystrobin-salicylate sample is proved to have no crystal form transformation and good stability.
And (3) testing the stability:
test object(s): the product prepared in example 1, a sample of michelia dimethylamine lactone fumarate (CN 111303097A), a sample of michelia dimethylamine (CN 102234259B);
the test method comprises the following steps: adding the three samples into 3 penicillin bottles containing 15mL of phosphate buffer solution (PH = 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 then performing PXRD characterization on 3 groups of solid samples;
and (3) testing results: the specific comparison map of PXRD is shown in fig. 9, and it can be seen from fig. 9 that: only the solid sample of the dimethylamine smilax lactone-salicylate has no obvious change, but PXRD spectrums of the solid samples corresponding to the dimethylamine smilax lactone and the dimethylamine smilax lactone fumarate have obvious new diffraction peaks, which indicates that a new phase is generated, and the difficulties that the dimethylamine smilax lactone has poor stability and is easy to degrade are solved by the dimethylamine smilax lactone-salicylate again, and the obstacle that the product quality is difficult to control due to the fact that the dimethylamine smilax lactone fumarate is easy to generate crystal form conversion is overcome.
Example 2
Weighing 58.6mg of michelia lactone dimethylamine solid and 33.12mg of salicylic acid solid, adding 50 mu L of acetone, carrying out ball milling at the frequency of 30Hz for 40min, and drying at room temperature to obtain a michelia lactone dimethylamine salicylate 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 diffraction angle 2 theta indicates that the diffraction grating has characteristic peaks at 7.4 DEG, 10.0 DEG, 11.2 DEG, 11.7 DEG, 12.3 DEG, 13.0 DEG, 14.7 DEG, 15.8 DEG, 16.3 DEG, 17.6 DEG, 18.6 DEG, 19.4 DEG, 20.0 DEG, 21.5 DEG, 21.9 DEG, 22.2 DEG, 22.8 DEG, 23.9 DEG, 24.6 DEG, 25.0 DEG and 27.2 deg.
The DSC test of example 2 revealed that: the product has an endothermic peak at 171.5 ℃.
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 99.2%, the yield of the product was 95%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 2 had a water content varying from only 0.01% to 0.60%, whereas dimethylamine michelia lactone fumarate (CN 111303097A) had a water content varying from 0.01% to 4.5%, as indicated by the comparison: the product obtained in example 2 has a low hygroscopicity.
(3) And (3) testing the stability:
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-salicylate prepared in the embodiment of the invention has better stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.9 degrees, 10.6 degrees, 11.2 degrees and 12.7 degrees in the michelia dimpled lactone fumarate (CN 111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the dimethylamine smilacin-salicylate prepared in example 2 can well overcome the defects of high hygroscopicity and poor stability of dimethylamine smilacin fumarate, and improve the quality controllability and safety of the medicament.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-salicylate sample prepared in example 2 did not change significantly, which proves that the michelia lactone-salicylate has no crystal transformation and has good stability.
And (3) testing the stability:
the solid sample of the dimethylamine smilax lactone-salicylate prepared in example 2 is not obviously changed, but PXRD patterns of the solid samples corresponding to dimethylamine smilax lactone (CN 102234259B) and dimethylamine smilax lactone fumarate (CN 111303097A) show obvious new diffraction peaks, which indicates that a new phase is generated, and the solid samples prove that the dimethylamine smilax lactone-salicylate solves the problems of poor stability and easy degradation of dimethylamine smilax lactone, and overcomes the obstacle that the product quality is difficult to control due to the fact that the dimethylamine smilax lactone fumarate is easy to generate crystal form transformation.
Example 3
Weighing 146.5mg of michelia lactone dimethylamine solid and 55.2mg of salicylic acid solid, adding 100 mu L of ethyl acetate, carrying out ball milling at the frequency of 20Hz for 60min, and carrying out forced air drying at 40 ℃ to obtain a solid sample of michelia lactone dimethylamine salicylate.
The product obtained in example 3 was subjected to the crystallographic test, the test results being the same as in example 1.
XRD testing of the product obtained in example 3 revealed that: when the diffraction angle is 2 theta, the characteristic peaks are shown at 2 theta diffraction angles of 7.7 degrees, 10.3 degrees, 11.5 degrees, 11.9 degrees, 12.6 degrees, 13.3 degrees, 14.9 degrees, 16.1 degrees, 16.6 degrees, 17.9 degrees, 18.8 degrees, 19.7 degrees, 20.3 degrees, 21.8 degrees, 22.2 degrees, 22.5 degrees, 23.1 degrees, 24.1 degrees, 24.8 degrees, 25.2 degrees and 27.5 degrees.
The DSC test of example 3 revealed that: the product has an endothermic peak at 170.8 ℃.
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 99.2%, 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 0.61% and the dimethylamine sphaelactone fumarate (CN 111303097A) had a moisture content varying from 0.01% to 4.4%, 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-salicylate 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 (CN 111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the dimethylamine smilacin-salicylate prepared in example 3 can well overcome the defects of high hygroscopicity and poor stability of dimethylamine smilacin fumarate, and improve the quality controllability and safety of the medicament.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-salicylate sample prepared in example 3 did not change significantly, which proves that the michelia lactone-salicylate has no crystal transformation and has good stability.
And (3) testing the stability:
the solid sample of the michelia dimidiata lactone-salicylate prepared in the example 3 has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia dimidiata lactone (CN 102234259B) and the michelia dimidiata lactone fumarate (CN 111303097A) have obvious new diffraction peaks, which indicates that a new phase is generated, and the new phase proves that the michelia dimidiata lactone-salicylate solves the problems of poor stability and easy degradation of the michelia dimidiata lactone, and overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia dimidiata lactone fumarate is easy to generate crystal form conversion.
Example 4
Weighing 29.3mg of michelia diminera lactone solid and 13.8mg of salicylic acid solid, putting the mixture into an agate mortar, adding 20 mu L of 1, 4-dioxane, grinding for 5min, and drying at room temperature to obtain a solid sample of michelia diminera lactone salicylate.
The product obtained in example 4 was subjected to the crystallographic test, the test results being the same as in example 1.
XRD testing of the product obtained in example 4 revealed that: the diffraction angle is 2 theta, and the characteristic peaks are shown at 7.8 degrees, 10.4 degrees, 11.6 degrees, 12.0 degrees, 12.6 degrees, 13.4 degrees, 15.0 degrees, 16.2 degrees, 16.7 degrees, 17.9 degrees, 18.9 degrees, 19.8 degrees, 20.4 degrees, 21.9 degrees, 22.3 degrees, 22.5 degrees, 23.2 degrees, 24.2 degrees, 24.9 degrees, 25.3 degrees and 27.6 degrees.
The DSC test of example 4 revealed that: the product has an endothermic peak at 172.2 ℃.
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 99.2%, 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 4 had a moisture content varying from only 0.01% to 0.62% and the dimethylamine sphaelactone fumarate (CN 111303097A) had a moisture content varying from 0.01% to 4.7%, as indicated by the 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-salicylate 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 (CN 111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia dimctum lactone-salicylate prepared in the embodiment 4 can well overcome the defects of high hygroscopicity and poor stability of the michelia dimctum lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD spectrum, the weight loss amount of TGA and the melting point on DSC of the sample of the michelia lactone salicylate of dimethylamine prepared in example 4 are not obviously changed, which proves that no crystal form transformation occurs in the michelia lactone salicylate of dimethylamine and the stability is good.
And (3) testing the stability:
the solid sample of the michelia dimidiata lactone-salicylate prepared in example 4 has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia dimidiata lactone (CN 102234259B) and the michelia dimidiata lactone fumarate (CN 111303097A) have obvious new diffraction peaks, which indicates that a new phase is generated, and the new phase proves that the michelia dimidiata lactone-salicylate solves the problems of poor stability and easy degradation of the michelia dimidiata lactone, and overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia dimidiata lactone fumarate is easy to generate crystal form conversion.
Example 5
58.6mg of michelia lactone dimethylamine solid and 27.6mg of salicylic acid solid are weighed, 30 mu L of acetonitrile is added, ball milling is carried out at the frequency of 15Hz for 20min, and air blowing drying is carried out at the temperature of 40 ℃, so as to obtain a solid sample of michelia lactone dimethylamine salicylate.
The product obtained in example 5 was subjected to the crystallographic test, the test results being the same as in example 1.
XRD testing was performed on the product obtained in example 5, and it was found that: the diffraction angle 2 theta indicates that the diffraction grating has characteristic peaks at 7.7 DEG, 10.3 DEG, 11.5 DEG, 12.0 DEG, 12.5 DEG, 13.2 DEG, 14.9 DEG, 16.1 DEG, 16.6 DEG, 17.8 DEG, 19.0 DEG, 19.6 DEG, 20.3 DEG, 21.8 DEG, 22.3 DEG, 22.5 DEG, 23.2 DEG, 24.1 DEG, 24.8 DEG, 25.3 DEG and 27.5 deg.
The DSC test of example 5 revealed that: the product has an endothermic peak at 173.1 ℃.
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 99.2%, 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 5 had a moisture content varying from only 0.01% to 0.58% and the dimethylamine sphaelactone fumarate (CN 111303097A) had a moisture content varying from 0.01% to 4.5%, as indicated by the comparison: the product obtained in example 5 has a low hygroscopicity.
(3) And (3) testing the stability:
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-salicylate prepared in example 5 has good 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 (CN 111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the dimethylamine smilacin-salicylate prepared in example 5 can well overcome the defects of high hygroscopicity and poor stability of dimethylamine smilacin fumarate, and improve the quality controllability and safety of the medicament.
And (5) testing the stability:
the PXRD spectrum, the weight loss amount of TGA and the melting point on DSC of the sample of the michelia lactone salicylate of dimethylamine prepared in example 5 are not obviously changed, which proves that no crystal form transformation occurs in the michelia lactone salicylate of dimethylamine and the stability is good.
And (3) testing the stability:
the solid sample of the dimethylamine smilax lactone-salicylate prepared in example 5 has no obvious change, and PXRD patterns of the solid samples corresponding to dimethylamine smilax lactone (CN 102234259B) and dimethylamine smilax lactone fumarate (CN 111303097A) have obvious new diffraction peaks, which indicates that a new phase is generated, and the solid sample of the dimethylamine smilax lactone-salicylate is proved to solve the problems of poor stability and easy degradation of the dimethylamine smilax lactone, and simultaneously overcome the obstacle that the product quality is difficult to control due to the fact that the dimethylamine smilax lactone fumarate is easy to generate crystal form transformation.
Example 6
1.5g of michelia lactone dimethylamine solid, 0.706g of salicylic acid solid and 100mL of ethyl acetate are added into a reaction bottle, heated to 60 ℃, and stirred for 60min to ensure that the raw materials are fully reacted. Cooling to 10 deg.C at a rate of 5 deg.C/h, filtering the obtained product, and drying at 25 deg.C under normal pressure for 6h to obtain dimethylamine michelia lactone salicylate.
The product obtained in example 6 was subjected to the crystallographic test, the test results being the same as in example 1.
XRD testing of the product obtained in example 6 revealed that: the diffraction angle 2 theta indicates that the diffraction grating has characteristic peaks at 7.6 degrees, 10.2 degrees, 11.4 degrees, 11.9 degrees, 12.5 degrees, 13.2 degrees, 14.9 degrees, 16.0 degrees, 16.5 degrees, 17.8 degrees, 18.8 degrees, 19.6 degrees, 20.2 degrees, 21.7 degrees, 22.1 degrees, 22.4 degrees, 23.0 degrees, 24.0 degrees, 24.7 degrees, 25.1 degrees and 27.4 degrees.
The DSC test of example 6 revealed that: the product has an endothermic peak at 172.3 ℃.
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:
example 6 the purity of the product was 99.2%, the yield of the product was 96.5%, 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 0.60% and the dimethylamine sphaelactone fumarate (CN 111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by the 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-salicylate 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 (CN 111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia dimctum lactone-salicylate prepared in the embodiment 6 can well overcome the defects of high hygroscopicity and poor stability of the michelia dimctum 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-salicylate sample prepared in example 6 did not change significantly, which proves that the michelia lactone-salicylate has no crystal transformation and has good stability.
And (5) testing the stability:
the solid sample of the michelia dimidiata lactone-salicylate prepared in example 6 has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia dimidiata lactone (CN 102234259B) and the michelia dimidiata lactone fumarate (CN 111303097A) have obvious new diffraction peaks, which indicates that a new phase is generated, and the new phase proves that the michelia dimidiata lactone-salicylate solves the problems of poor stability and easy degradation of the michelia dimidiata lactone, and overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia dimidiata lactone fumarate is easy to undergo crystal form conversion.
Example 7
Adding 3g of michelia lactone dimethylamine solid, 2.119g of salicylic acid solid and 50mL of ethanol into a reaction bottle, heating to 40 ℃, and stirring for 30min to ensure that the raw materials fully react. Cooling to 10 deg.C at a rate of 10 deg.C/h, filtering the obtained product, and drying at 30 deg.C under normal pressure for 3h to obtain dimethylamine michelia lactone salicylate. The powder X-ray diffraction pattern of the product is consistent with that of figure 1, and the DSC pattern has an endothermic peak at 173.7 ℃.
The product obtained in example 7 was subjected to the crystallographic test, the test results being the same as in example 1.
XRD testing of the product obtained in example 7 revealed that: the diffraction angle is 2 theta, and the characteristic peaks are shown at 7.5 degrees, 10.2 degrees, 11.3 degrees, 11.7 degrees, 12.4 degrees, 13.0 degrees, 14.7 degrees, 15.9 degrees, 16.4 degrees, 17.7 degrees, 18.6 degrees, 19.4 degrees, 20.1 degrees, 21.6 degrees, 22.0 degrees, 22.3 degrees, 22.9 degrees, 23.8 degrees, 24.5 degrees, 24.9 degrees and 27.2 degrees.
DSC test was performed on example 7, and it was found that: the product has an endothermic peak at 173.7 ℃.
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:
the purity of the product obtained in example 7 was 99.2%, the yield of the product was 93%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 7 had a moisture content varying from only 0.01% to 0.61% and the dimethylamine sphaelactone fumarate (CN 111303097A) had a moisture content varying from 0.01% to 4.3%, as indicated by the comparison: the product obtained in example 7 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability testing:
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-salicylate prepared in example 7 has good 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 (CN 111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia dimctum lactone-salicylate prepared in example 7 can well overcome the defects of high hygroscopicity and poor stability of michelia dimctum lactone fumarate, and the controllability and 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-salicylate sample prepared in example 7 did not change significantly, which proves that the michelia lactone-salicylate has no crystal transformation and has good stability.
And (3) testing the stability:
the solid sample of the michelia dimidiata lactone-salicylate prepared in example 7 has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia dimidiata lactone (CN 102234259B) and the michelia dimidiata lactone fumarate (CN 111303097A) have obvious new diffraction peaks, which indicates that a new phase is generated, and the new phase proves that the michelia dimidiata lactone-salicylate solves the problems of poor stability and easy degradation of the michelia dimidiata lactone, and overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia dimidiata lactone fumarate is easy to undergo crystal form conversion.
Example 8
Adding 6g of michelia lactone dimethylamine solid, 2.543g of salicylic acid solid and 120mL of acetonitrile into a reaction bottle, heating to 50 ℃, and stirring for 40min to ensure that the raw materials fully react. Cooling to 20 ℃ at the speed of 8 ℃/h, filtering the obtained product, and then drying for 5h at 40 ℃ under normal pressure to obtain the dimethylamine michelia lactone salicylate.
The product obtained in example 8 was subjected to the crystallographic test, the test results being the same as in example 1.
XRD testing of the product obtained in example 8 revealed that: the diffraction angle 2 theta indicates that the diffraction grating has characteristic peaks at 7.6 degrees, 10.2 degrees, 11.4 degrees, 11.9 degrees, 12.5 degrees, 13.2 degrees, 14.9 degrees, 16.0 degrees, 16.5 degrees, 17.8 degrees, 18.8 degrees, 19.6 degrees, 20.2 degrees, 21.7 degrees, 22.1 degrees, 22.4 degrees, 23.0 degrees, 24.0 degrees, 24.7 degrees, 25.1 degrees and 27.4 degrees.
The DSC test of example 8 revealed that: the product has an endothermic peak at 173.2 ℃.
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 99.2%, the yield of the product was 93.5%, 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 0.60% and the dimethylamine sphaelactone fumarate (CN 111303097A) had a moisture content varying from 0.01% to 4.4%, as indicated by the 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-salicylate prepared in example 8 has good 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 (CN 111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the dimethylamine smilacin-salicylate prepared in example 8 can well overcome the defects of high hygroscopicity and poor stability of dimethylamine smilacin fumarate, and improve the quality controllability and safety of the medicament.
And (5) testing the stability:
the PXRD pattern, the weight loss amount of TGA and the melting point on DSC of the michelia lactone salicylate sample prepared in example 8 did not change significantly, which proves that no crystal form transformation of michelia lactone salicylate occurs and the stability is good.
And (3) testing the stability:
the solid sample of the dimethylamine smilax lactone-salicylate prepared in example 8 has no obvious change, and PXRD patterns of the solid samples corresponding to dimethylamine smilax lactone (CN 102234259B) and dimethylamine smilax lactone fumarate (CN 111303097A) have obvious new diffraction peaks, which indicates that a new phase is generated, and the solid sample of the dimethylamine smilax lactone-salicylate is proved to solve the problems of poor stability and easy degradation of the dimethylamine smilax lactone, and simultaneously overcome the obstacle that the product quality is difficult to control due to the fact that the dimethylamine smilax lactone fumarate is easy to generate crystal form transformation.
Example 9
3g of michelia lactone dimethylamine solid, 1.412g of salicylic acid solid and 75mL of acetone are added into a reaction bottle, heated to 45 ℃, and stirred for 40min to ensure that the raw materials are fully reacted. Cooling to 10 deg.C at a rate of 5 deg.C/h, filtering the obtained product, and drying at 40 deg.C under normal pressure for 3h to obtain dimethylamine michelia lactone salicylate.
The product obtained in example 9 was subjected to the crystallographic test, the test results being the same as in example 1.
XRD testing was performed on the product obtained in example 9, and it was found that: the diffraction angle is 2 theta, and the characteristic peaks are shown at 7.7 degrees, 10.4 degrees, 11.5 degrees, 12.0 degrees, 12.6 degrees, 13.3 degrees, 15.0 degrees, 16.2 degrees, 16.6 degrees, 17.9 degrees, 19.0 degrees, 19.8 degrees, 20.4 degrees, 21.8 degrees, 22.3 degrees, 22.5 degrees, 23.2 degrees, 24.1 degrees, 24.8 degrees, 25.2 degrees and 27.5 degrees.
DSC test was performed on example 9, and it was found that: the product has an endothermic peak at 172 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 9:
(1) And (3) conventional performance test:
the purity of the product obtained in example 9 was 99.2%, the yield of the product was 94%, 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 0.57% and the dimethylamine sphaelactone fumarate (CN 111303097A) had a moisture content varying from 0.01% to 4.8%, as indicated by the comparison: the product obtained in example 9 has a low hygroscopicity. And (3) stability testing:
and (3) stability testing:
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-salicylate 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 (CN 111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia dimctum lactone-salicylate prepared in example 9 can well overcome the defects of high hygroscopicity and poor stability of michelia dimctum lactone fumarate, and the controllability and safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss amount of TGA and the melting point on DSC of the michelia lactone-salicylate sample prepared in example 9 did not change significantly, which proves that no crystal form transformation of michelia lactone-salicylate occurred and that the stability was better.
And (3) testing the stability:
the solid sample of the michelia dimidiata lactone-salicylate prepared in example 9 has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia dimidiata lactone (CN 102234259B) and the michelia dimidiata lactone fumarate (CN 111303097A) have obvious new diffraction peaks, which indicates that a new phase is generated, and the new phase proves that the michelia dimidiata lactone-salicylate solves the problems of poor stability and easy degradation of the michelia dimidiata lactone, and overcomes the obstacle that the product quality is difficult to control due to the fact that the michelia dimidiata lactone fumarate is easy to undergo crystal form conversion.
Example 10
1.5g of dimethylamine michelia lactone solid, 0.706g of salicylic acid solid and 50mL of 1,4 dioxane are added into a reaction bottle, heated to 55 ℃, and stirred for 30min to ensure that the raw materials are fully reacted. Cooling to 15 ℃ at the speed of 8 ℃/h, filtering the obtained product, and then drying at 30 ℃ for 5h under normal pressure to obtain the dimethylamine michelia lactone salicylate.
The product obtained in example 10 was subjected to crystallographic tests, the results of which were identical to those of example 1.
XRD testing of the product obtained in example 10 revealed that: the diffraction angle is 2 theta, and the characteristic peaks are shown at 7.8 degrees, 10.4 degrees, 11.6 degrees, 12.0 degrees, 12.7 degrees, 13.4 degrees, 15.1 degrees, 16.2 degrees, 16.7 degrees, 18.0 degrees, 19.0 degrees, 19.8 degrees, 20.4 degrees, 21.9 degrees, 22.3 degrees, 22.6 degrees, 23.2 degrees, 24.2 degrees, 24.9 degrees, 25.3 degrees and 27.6 degrees.
DSC test was performed on example 10, and it was found that: the product has an endothermic peak at 171.8 ℃.
The following performance tests were carried out by the same method as in example 1 on the product obtained in example 10:
(1) And (3) conventional performance test:
the purity of the product obtained in example 10 was 99.2%, the yield of the product was 94.5%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 10 had a water content varying from only 0.01% to 0.6%, whereas dimethylamine michelia lactone fumarate (CN 111303097A) had a water content varying from 0.01% to 4.7%, as indicated by the comparison: the product obtained in example 10 has a low hygroscopicity. 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-salicylate prepared in example 10 has good 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 (CN 111303097A), and the X-ray powder diffraction pattern of the sample is obviously changed.
In conclusion, the michelia dimctum lactone-salicylate prepared in example 10 can well overcome the defects of high hygroscopicity and poor stability of michelia dimctum lactone fumarate, and the controllability and safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss amount of TGA and the melting point on DSC of the sample of the michelia lactone-salicylate of dimethylamine prepared in example 10 do not change significantly, which proves that no crystal form transformation occurs in the michelia lactone-salicylate of dimethylamine and the stability is good.
And (5) testing the stability:
the solid sample of the dimethylamine smilax lactone-salicylate prepared in example 10 has no obvious change, and PXRD patterns of the solid samples corresponding to dimethylamine smilax lactone (CN 102234259B) and dimethylamine smilax lactone fumarate (CN 111303097A) have obvious new diffraction peaks, which indicates that a new phase is generated, and the solid samples prove that the dimethylamine smilax lactone-salicylate solves the problems of poor stability and easy degradation of dimethylamine smilax lactone, and overcomes the obstacle that the product quality is difficult to control due to the fact that the dimethylamine smilax lactone fumarate is easy to generate crystal form transformation.
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 (8)
1. The michelia lactone-salicylate is characterized in that the molecular formula of the michelia lactone-salicylate is C 24 H 33 NO 6 And has the following structure:
the crystallography characteristics of the michelia lactone salicylate of dimethylamine comprise that the space group is P2 1 2 1 2 1 With cell parameters of
α =90 °, β =90 °, γ =90 °, cell volume of
In an X-ray powder diffraction spectrogram of the michelia dimpled amine lactone-salicylate, characteristic peaks exist at 2 theta diffraction angles of 7.6 +/-0.2 degrees, 10.2 +/-0.2 degrees, 11.4 +/-0.2 degrees, 11.9 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.2 +/-0.2 degrees, 14.9 +/-0.2 degrees, 16.0 +/-0.2 degrees, 16.5 +/-0.2 degrees, 17.8 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.2 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.1 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.0 +/-0.2 degrees, 24.0 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.1 +/-0.2 degrees and 27.4 +/-0.2 degrees.
2. The michelia lactone-salicylate of dimethylamine of claim 1, wherein the differential scanning calorimetry analysis of the michelia lactone-salicylate of dimethylamine has a characteristic melting peak at 172 ± 2 ℃.
3. A method of producing michelia lactone-salicylate of dimethylamine according to claim 1 or 2, wherein the method comprises the steps of:
grinding and mixing michelia dimcta lactone and salicylic acid to obtain the michelia dimcta lactone-salicylate;
the molar ratio of the michelia lactone dimethylamine to the salicylic acid is 1.8-1.2;
the grinding equipment comprises a ball mill or an agate mortar;
the grinding is carried out in a solvent, and the adding volume of the solvent is 0.512-0.853 mu L, wherein the adding amount of the michelia lactone is 1 mg;
the solvent is selected from any one of methanol, acetone, acetonitrile, 1, 4-dioxane or ethyl acetate;
the grinding frequency is 15-30Hz, and the grinding time is 5-60min.
4. A method of producing michelia lactone-salicylate of dimethylamine according to claim 1 or 2, wherein the method comprises the steps of:
(1) Reacting michelia lactone dimethylamine with salicylic acid in an organic solvent to obtain a mixture;
(2) Cooling and crystallizing the mixture obtained by the reaction in the step (1) to obtain the michelia lactone-salicylate;
the molar ratio of the dimethylamine michelia lactone to the salicylic acid in the step (1) is 1;
the adding amount of the organic solvent in the step (1) is 1mL, wherein the adding amount of the michelia lactone dimethylamine is 15-60 mg;
the organic solvent in the step (1) is selected from any one of ethanol, acetone, acetonitrile, 1, 4-dioxane or ethyl acetate;
the reaction temperature in the step (1) is 40-60 ℃, and the reaction time is 30-60min;
the cooling rate of the cooling crystallization in the step (2) is 5-10 ℃/h;
and (3) the cooling end point of the cooling crystallization in the step (2) is 10-20 ℃.
5. The method according to claim 4, wherein the step (2) further comprises subjecting the crystalline material obtained after cooling crystallization to solid-liquid separation, washing and drying in this order.
6. The method according to claim 5, wherein the solid-liquid separation is performed by filtration.
7. The method according to claim 5, wherein the drying is carried out under atmospheric conditions at a temperature of 25-40 ℃ for a time of 3-6 hours.
8. Use of the minocycline-salicylate of claim 1 or 2 in the preparation of an anti-rheumatic medicament.
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| WO2004089313A2 (en) * | 2003-04-01 | 2004-10-21 | Transform Pharmaceuticals, Inc. | Novel olanzapine forms and related methods of treatment |
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| CN111303100A (en) * | 2018-12-12 | 2020-06-19 | 天津尚德药缘科技股份有限公司 | Hydrate of michelia lactone dimethylamine fumarate, preparation method and application thereof |
| WO2020201460A1 (en) * | 2019-04-02 | 2020-10-08 | University Of Limerick | Multicomponent crystal formulations |
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| WO2004089313A2 (en) * | 2003-04-01 | 2004-10-21 | Transform Pharmaceuticals, Inc. | Novel olanzapine forms and related methods of treatment |
| CN104876899A (en) * | 2014-02-28 | 2015-09-02 | 天津尚德药缘科技股份有限公司 | Dimethylamino sphaelactone fumarate and use thereof |
| CN111303100A (en) * | 2018-12-12 | 2020-06-19 | 天津尚德药缘科技股份有限公司 | Hydrate of michelia lactone dimethylamine fumarate, preparation method and application thereof |
| WO2020201460A1 (en) * | 2019-04-02 | 2020-10-08 | University Of Limerick | Multicomponent crystal formulations |
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