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Tolvaptan crystal and medicine composition thereof

A technology for tolvaptan and composition, which is applied in the field of organic drug synthesis and can solve the problems of requiring higher temperature, difficulty in large production and the like

Active Publication Date: 2012-07-11
天津泰普制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Since anhydrous tolvaptan belongs to low water solubility, the amorphous form of the compound is used to make tablets during the preparation process, but a large amount of organic solvents will be used in the preparation process of the amorphous form, and the amorphous form is dried Higher temperature is also required, which brings many difficulties to large-scale production

Method used

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  • Tolvaptan crystal and medicine composition thereof
  • Tolvaptan crystal and medicine composition thereof
  • Tolvaptan crystal and medicine composition thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0100] Heat and dissolve 1180 g of the crude product with 20 times of acetone (23.6 L), then lower it to 25° C., add dropwise 10 times of pure water (11.8 L) under stirring, and precipitate a large amount of solid after stirring for 2 hours, keep stirring at 30° C. for 6 hours, and then Cool down to 0°C and stir for 4 hours, filter, and vacuum-dry at 50°C to a constant weight of 1120g, yield 94.9%, HPLC 99.81%. 0.5 crystalline water tolvaptan crystals were obtained (see Figure 1 for the X-ray powder diffraction pattern), with a melting point of 155-156.7°C.

Embodiment 2

[0102] Heat and dissolve 20 g of the crude product with 30 times of ethanol (600ml), then lower it to 30°C, add 15 times of pure water (300ml) dropwise under stirring, and precipitate a large amount of solid after stirring for 2 hours, keep stirring at 25°C for 3 hours, and then lower the temperature for 2 hours. Stir at ℃ for 4 hours, filter, and vacuum-dry at 50℃ to a constant weight of 18g, yield 90%, HPLC 99.6%. 0.5 crystalline water tolvaptan crystals were obtained (see Figure 1 for the X-ray powder diffraction pattern), with a melting point of 155-156° C. (content 99.81%).

Embodiment 3

[0104] Heat and dissolve 20g of the crude product in 18 times ethanol (360ml), then lower it to 25°C, add 9 times the amount of pure water (180ml) dropwise under stirring, and after stirring for 3 hours, a large amount of solid precipitates, keep stirring at 28°C for 4 hours, and then lower the temperature by 1°C Stir for 4 hours, filter, and vacuum-dry at 50°C to a constant weight of 16g, yield 80%, HPLC 99.9%. 0.5 crystalline water tolvaptan crystals were obtained (see Figure 1 for the X-ray powder diffraction pattern), with a melting point of 155.2-156° C. (content 99.81%).

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Abstract

The invention discloses a tolvaptan crystal containing 0.5 crystal water. The crystal has a tolvaptan crystal powder X-ray diffraction pattern represented by a figure 1, a differential scanning calorimetry (DSC) analytical figure represented by the figure 2, and characteristics shown in an infrared spectrum represented by a figure 4. Meanwhile, the invention further discloses 1-100mg of a medicine composition composed of a tolvaptan crystal contains 0.5 crystal water, and one or more pharmaceutically acceptable medicinal carriers. The tolvaptan crystal containing 0.5 crystal water is advantaged in simple preparation technology, good reproducibility, and easy drying. The crystal is stable to light, heat, and humidity. The crystal is suitable for long-time storage, and is suitable for large-scale productions.

Description

technical field [0001] The invention belongs to the technical field of organic drug synthesis and relates to a selective vasopressin V 2 The crystal form of receptor antagonist tolvaptan (Tolvaptan) and its preparation method, and the pharmaceutical composition containing the crystal. Background technique [0002] The traditional treatment methods for isovolumic or hypervolemic hyponatremia include water restriction, application of hypertonic saline, and demeclocycline, etc., but all have obvious side effects, which limit their clinical application. Vasopressin receptor antagonists (VRAs) mainly increase the excretion of purified water (insoluble water) by blocking the excessive production of (arginine vasopressin) AVP, and achieve the effect of increasing plasma osmotic pressure. Food and Drug Administration (FDA) approved for the treatment of isovolumic hyponatremia. Further research on this class of drugs found that VRAs can also be used to treat nephrogenic diabetes (N...

Claims

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Application Information

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IPC IPC(8): C07D223/16A61K31/55A61P3/12
Inventor 陈滔张村子韩建萍陈华
Owner 天津泰普制药有限公司
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