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Method for preparing amorphous-form Romidepsin

A romidepsin, amorphous technology, applied in the field of medicine, can solve the problems of unstable process, unsuitable for industrial production, difficult removal of dioxane, etc., and achieves the effects of high stability and stable freeze-drying process

Active Publication Date: 2016-07-27
SHANGHAI ARYL PHARMTECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the sample is dissolved in dioxane / water, and the amorphous form can be obtained by freeze-drying. However, in this scheme, mixed crystals appear when a 2g enlarged sample is freeze-dried, and the process is unstable. In addition, dioxane is difficult to remove; the sample is dissolved in dioxane In methyl chloride, the amorphous form can be obtained by rotary evaporation; when the sample is dissolved in solvents such as water / dichloromethane, methanol / trifluoroethanol, the amorphous form can be obtained by rapid evaporation, and the process is unstable and fast Evaporation is not suitable for industrial production

Method used

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  • Method for preparing amorphous-form Romidepsin
  • Method for preparing amorphous-form Romidepsin
  • Method for preparing amorphous-form Romidepsin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: Solubility experiment of romidepsin in ethanol aqueous solution with different concentrations

[0034] Take 6 parts of 20mg romidepsin and put them into 10ml ethanol aqueous solution with different volume percentage respectively, stir at room temperature for 60 minutes, then take samples respectively and use 0.45μm membrane (SCAA-103, Shanghai Anpu Experiment Technology Co., Ltd. ) to filter, the sample obtained uses HPLC external standard method to analyze its content and calculate its solubility. See Table 1 for the solubility of romidepsin in various concentrations of ethanol at room temperature.

[0035] Table 1: Solubility of romidepsin in aqueous ethanol solutions of different concentrations

[0036] Ethanol concentration (%) 5 10 20 30 40 50 Solubility (mg / L) 423 506 763 2310 3948 7710

Embodiment 2

[0037] Embodiment 2: The influence of the pre-cooling temperature of the freeze-drying chamber of the freeze-dryer on the form of romidepsin

[0038]Take 1g of romidepsin and dissolve in 50mL of ethanol, then take 9mL of this solution and add 21mL of water to mix well. Then place the solution in the freeze-drying chamber at room temperature, pre-cooled to -5 ° C, -20 ° C and -70 ° C in the freeze dryer for pre-freezing (-40 ° C for 4 hours), through drying (-20 ℃ for 16 hours; -10°C for 6 hours; 30°C for 8 hours; 40°C for 8 hours) to obtain romidepsin as a solid. The solid form of romidepsin was determined by X-ray powder diffractometer, and the results are shown in Table 2. See figure 1 See figure 2 .

[0039] Table 2: Effect of pre-cooling of freeze-drying chamber temperature on freeze-dried romidepsin

[0040]

Embodiment 3

[0041] Example 3: Effects of different raw material concentrations and different ethanol concentrations on freeze-dried romidepsin

[0042] Take 0.3, 0.5, 0.75, 1.0 and 1.25g romidepsin and dissolve them in 50mL ethanol respectively, then take appropriate above-mentioned solutions and add water to make sample solutions with ethanol concentration as shown in Table 3, mix well and place in Pre-cooled to -20°C in a freeze-drying bin (-40°C for 4 hours), through drying (-20°C for 16 hours; -10°C for 6 hours; 30°C for 8 hours; 40°C for 8 hours) ) to obtain romidepsin solid. The solid state of romidepsin was determined by X-ray powder diffractometer, and the results are shown in Table 3.

[0043] Table 3: Effects of different raw material concentrations and different ethanol concentrations on freeze-dried romidepsin

[0044]

[0045] Note: " / " means no experiments are scheduled

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Abstract

The invention relates to a method for preparing amorphous-form Romidepsin. The method comprises the steps that Romidepsin is dissolved in an alcoholic solution, water is added, the mixture is stirred to be uniform before being put in a pre-cooled freeze-drying bin, and lastly pre-freezing and drying are conducted to obtain amorphous-form Romidepsin. According to the method, technological operation is simple, cost is low, and prepared amorphous-form Romidepsin is good in stability and quite suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for preparing amorphous romidepsin. Background technique [0002] Malignant tumors are one of the most serious diseases threatening human health. For a long time, tumor treatment has been a major research topic in the medical field, and finding new drugs for treating malignant tumors is the primary task of drug researchers. Among the anti-tumor drugs, the research and development of non-cytotoxic drugs that selectively inhibit the growth of cancer cells is the current research focus of anti-tumor drugs. In recent years, a class of zinc ion-dependent metalloproteinases—histone deacetylases (HDACs) has become a hot spot in the research of anticancer drugs. [0003] Romidepsin, also known as FK228 and FR901228, is an HDAC inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the regulation of gene ex...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/103C07K1/02A61K38/07A61P35/00
CPCA61K38/07C07K5/101
Inventor 张辉王继栋姜南郑玲辉张灵坚金秀玲邓爱文白骅
Owner SHANGHAI ARYL PHARMTECH CO LTD
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