Method for acquiring medicinally-advantageous crystal form of tolbutamide through rapid cooling and crystallization

A technology of rapid cooling and glycolysis, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve problems such as environmental protection and complicated operation process

Inactive Publication Date: 2015-07-22
TIANJIN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the above method may have the disadvantage of complex operation pr

Method used

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  • Method for acquiring medicinally-advantageous crystal form of tolbutamide through rapid cooling and crystallization

Examples

Experimental program
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Effect test

Embodiment 1

[0014] A method for obtaining a medicinally advantageous crystal form of tolamide by rapid cooling and crystallization, comprising the steps of:

[0015] (1) Prepare a supersaturated tolamide solution: add 0.48 g of tolamide I crystal form to 15 ml of ethanol aqueous solution with a volume concentration of 66.7%, and ultrasonically dissolve at 30°C for 20 minutes; use an organic filter with a pore size of 0.22 μm Membrane filtration to remove insoluble matter;

[0016] (2) Put the filtered supersaturated tolamide solution in a crystallization bottle, seal it with a sealing film and make a small hole so that the pressure inside and outside the crystallization bottle is the same; keep the temperature at 30°C for 13 minutes, then quickly cool down to 0 °C, the cooling rate was controlled at 13 °C / min, and the medicinally advantageous crystal form IV of Jiatangning was obtained. Use XRD to investigate the crystal polymorphism obtained in the solution, such as figure 1 shown.

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Embodiment 2

[0019] (1) Prepare a supersaturated tolamide solution: add 0.53 g of tolamide I crystal form in proportion to 15 ml of ethanol aqueous solution with a volume concentration of 60%, and ultrasonically dissolve at 30°C for 30 minutes; use a 0.22 μm pore size Organic membrane filtration to remove insoluble matter;

[0020] (2) Put the filtered supersaturated tolamide solution in a crystallization bottle, seal it with a sealing film and pierce a small hole so that the pressure inside and outside the crystallization bottle is the same; keep it at a constant temperature of 30°C for 10 minutes, then quickly cool down to -5 °C, the cooling rate was controlled at 10 °C / min, and the pharmaceutically advantageous crystal form IV of Jiatangning was obtained. The crystal polymorphs obtained in the solution were investigated by XRD, and the crystal form IV of togatonin was also obtained.

Embodiment 3

[0022] (1) Prepare a supersaturated tolamide solution: add 0.50 g of tolamide I crystal form to 15 ml of ethanol aqueous solution with a volume concentration of 70% in proportion, and ultrasonically dissolve at 35°C for 20 minutes; Organic membrane filtration to remove insoluble matter;

[0023] (2) Put the filtered supersaturated tolamide solution in a crystallization bottle, seal it with a sealing film and make a small hole so that the pressure inside and outside the crystallization bottle is the same; keep the temperature at 30°C for 15 minutes, then quickly cool down to 4°C , the cooling rate was controlled at 15°C / min, and the pharmaceutically advantageous crystal form IV of Jiatangning was obtained. The crystal polymorphs obtained in the solution were investigated by XRD, and the crystal form IV of togatonin was also obtained.

[0024] The invention was funded by the National Natural Science Foundation of China (project number: 21106094)

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Abstract

The invention discloses a method for acquiring a medicinally-advantageous crystal form of tolbutamide through rapid cooling and crystallization. The method comprises the following steps: (1) preparing an oversaturated tolbutamide solution: a step of adding, in proportion, 0.48 to 0.53 g of the crystal form I of tolbutamide into 15 ml of an aqueous ethanol solution with a volume concentration of 60 to 70%, then carrying out ultrasonic dissolving and carrying out filtering to remove insoluble substances; and (2) placing the oversaturated tolbutamide solution having undergone filtering in a crystallization bottle, sealing the crystallization bottle with a sealing film, perforating small holes in the sealing film so as to allow pressure in and out of the crystallization bottle to be identical, maintaining the solution at a temperature of 30 DEG C for 10 to 15 min and then rapid cooling the solution to -5 to 4 DEG C so as to obtain the medicinally-advantageous crystal form IV of tolbutamide. The method adopts ethanol and water without toxic and side effect as solvents and successfully guides growth of medicinally-advantageous crystal form IV with high bio-utilization activity of the diabetes therapeutic tolbutamide by changing the degree of oversaturation.

Description

technical field [0001] The invention relates to a method for regulating the crystal form of a hypoglycemic drug, in particular to a method for obtaining the medicinally dominant crystal form of Jiatangning through a rapid cooling crystallization method. Background technique [0002] Polymorphism refers to the phenomenon that a substance exists in two or more crystal forms due to different molecular arrangements or conformational changes. Polymorphism is widespread in organic pharmaceuticals. Different crystal forms of the same drug have significantly different physical and chemical properties, such as solubility, dissolution rate, melting point, stability, etc., which will affect the bioavailability and safety of the drug to varying degrees. Therefore, the regulation of polymorphic forms of solid drugs is very important, which is conducive to the screening of pharmaceutically dominant crystalline forms and the improvement of drug efficacy. Generally, metastable crystalline...

Claims

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Application Information

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IPC IPC(8): C07C311/58C07C303/44
Inventor 韩优吴宇嘉刘安元李韡张金利
Owner TIANJIN UNIV
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