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Crystal form of icaritin compound, drug containing crystal form and application of crystal form

A technology for alcaradine and its compounds, which is applied in the fields of medical preparations containing active ingredients, drug combinations, organic chemistry, etc., and can solve problems such as poor stability, drug quality risks, and the coexistence of multiple crystal forms of pure alcaradine, etc. problem, to achieve the effect of long shelf life and high stability

Active Publication Date: 2014-07-23
BEIJING SHENOGEN PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the inventors of the present application have all found that there are multiple crystal forms coexisting in the obtained pure Alcoradine through the above methods.
When multiple crystalline forms coexist, the drug made of Alcoradine and excipients has poor stability during storage, which poses a certain risk to the quality of the drug

Method used

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  • Crystal form of icaritin compound, drug containing crystal form and application of crystal form
  • Crystal form of icaritin compound, drug containing crystal form and application of crystal form
  • Crystal form of icaritin compound, drug containing crystal form and application of crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Preparation of Alcoradine by Enzymatic Hydrolysis of Commercial Epimedium Extract

[0052] The epimedium extract in this example was purchased from Shaanxi Jiahe Plant Chemical Co., Ltd., with a trade name of "Epimedium extract", which contained icariin with a mass fraction of 90%.

[0053] Step 1: Preparation of Alcoradine by Enzymatic Hydrolysis

[0054] 80 g of commercially available Epimedium extract, which contains 90% icariin by mass fraction, is dispersed in 2.0 L of disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution of pH 5.2 at a concentration of 1 mol / L , add 0.6L of ethanol, 1400g of RAPIDASE pectinase, a total of 1.4L into a 5L reactor, and carry out enzymatic hydrolysis at a reaction temperature of 50°C. The specific conditions are shown in Table 1:

[0055] Table 1 Enzymolysis conditions

[0056] Epimedium extract g

Enzyme amount L

Ethanol L

Buffer L

temperature reflex

80

1.4

0.6

2.0

...

Embodiment 2

[0064] The crystals obtained in Example 1 were continuously dried at 80° C. until the weight of the crystals no longer changed. The weight of the crystals after drying at 80° C. was weighed, which was reduced relative to the weight of the crystals in Example 1.

[0065] Carry out thermal gravimetric analysis and differential scanning thermal analysis to the crystal obtained according to the above method, obtain as follows Figure 4 The graph shown.

[0066] exist Figure 4 Among them, differential scanning thermal analysis: that is, there is a melting endothermic peak at 253.0°C in the DSC curve, and the melting enthalpy is 137.29J / g. And in the thermogravimetric analysis curve, that is, when the sample is heated to 150° C. in TGA, the weight loss is 0.35%, so it can be considered from the above curve that the crystal obtained in this example is a single crystal form, that is, crystal form B.

[0067] Figure 5 Represent the nuclear magnetic resonance spectrum figure of cr...

Embodiment 3

[0070] Weigh 15 mg of the solvent-free crystalline form of Acradine obtained in Example 2 into a 1.5 mL vial, and add 1.2 mL of methanol solvent to obtain a suspension. The suspension was stirred at 20°C for 4 days, and the obtained crystals were collected by centrifugation, and subjected to thermogravimetric analysis and differential scanning thermal analysis to obtain the following: Figure 7 The graph shown. It can be seen from the spectrum that when the sample is heated to 100°C, the weight loss is 5.5%, the desolvation endothermic peaks appear at 89.0°C and 107.3°C, and there is a melting endotherm at 253.8°C, and the melting enthalpy is 117.51J / g.

[0071] pass Figure 8 It can be seen from the NMR images of the Figure 5 In contrast, a peak with an integral value of 1.04 appears at a displacement of 3.17ppm. According to the displacement, it is inferred that this peak is a characteristic peak representing methanol, because it is known that the methoxyl group in the st...

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Abstract

The invention provides a crystal form of an icaritin compound, a drug containing the crystal form and an application of the crystal form. The crystal form is a solvent-free crystal form, and the X-ray powder diffraction measured by using Cu-Ka rays has peak values at the angles 2theta which are respectively 6.0+ / -0.2 DEG, 11.4+ / -0.2 DEG, 13.0+ / -0.2 DEG and 18.9+ / -0.2 DEG. The invention also provides an application of the crystal form to preparation of a drug for treating diseases related to abnormal cell proliferation. The crystal form provided by the invention is high in stability, free of risks for converting into other crystal forms and suitable for transportation and storage in extreme weather.

Description

technical field [0001] The invention relates to a crystal form of alcradine compound, a medicine containing the crystal form and an application thereof, belonging to the field of medicine. Background technique [0002] Acradine, also known as epimeditin and epimedin, is a new effective monomer obtained by enzymatic conversion of the main active ingredient Epimedium extract isolated from the Chinese herbal medicine Epimedium. Its structural formula As shown in formula (I): [0003] [0004] In "Chinese Experimental Prescriptions" 2012, Volume 18, Issue 14, "The Effect of Icaritin on Estrogen-Dependent Breast Cancer MCF-7 Cells" was disclosed, and the research revealed that icariin and estradiol The combined effect can inhibit the proliferation of human breast cancer MCF-7 cells induced by E2. [0005] In the 2011 No. 6 issue of "Chinese Journal of Comparative Medicine", the article "In vitro anti-lymphoma cell proliferation effect of icariin" was published, and the artic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/30A61K31/352A61P35/00A61P7/06
CPCC07D311/30
Inventor 孟坤汤城张波
Owner BEIJING SHENOGEN PHARMA GRP
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