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Novel crystal form for temozolomide, method for preparing temozolomide and medicinal composition of temozolomide

A technology of temozolomide and its composition, which is applied in the direction of drug combination, medical preparations containing active ingredients, antineoplastic drugs, etc. It can solve the problems of being unsuitable for industrial production, difficult to meet the quality requirements of injection raw materials, and cumbersome operation, etc., to improve the appearance Color, suitable for long-term storage, simple preparation process

Active Publication Date: 2012-01-25
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] (2) It is difficult for a single impurity to reach less than 0.1%;
[0013] (3) The solvent consumption is large, the crystallization time is long, and the yield is low;
[0014] (4) The operation is cumbersome and requires column purification, which is not suitable for industrialized production;
[0015] It is difficult to control the single impurity of the above temozolomide crystal forms below 0.1%, which is difficult to meet the quality requirements of injection raw materials, and also fails to meet the relevant technical requirements of ICH, the EU quality research technical guidance principle, and the refined yield is also low. ,high cost

Method used

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  • Novel crystal form for temozolomide, method for preparing temozolomide and medicinal composition of temozolomide
  • Novel crystal form for temozolomide, method for preparing temozolomide and medicinal composition of temozolomide
  • Novel crystal form for temozolomide, method for preparing temozolomide and medicinal composition of temozolomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1 Preparation of temozolomide M crystal form

[0044]Take 10g of temozolomide and place it in a reaction flask, add 50g of acetone, 50g of acetonitrile and raise the temperature to 50-55°C while stirring, and slowly add 100g of purified water dropwise under stable reflux. With the continuous addition of purified water, the solid gradually dissolves. , slowly cooled to 30-40°C for crystallization for 1 hour, then crystallized at 15-25°C for 2 hours, and finally cooled to 5-10°C to fully separate out the solid and grow the crystal for 5 hours, then filter with suction, and wash the filter cake with water Wash with acetone / water (1:1) mixed solution and suck dry. The solid was dried at 45° C. under reduced pressure (-0.09 MPa) to obtain 8.1 g of white solid with a yield of 81%. ; Related substances 0.02%. By powder X-ray diffraction detection, such as figure 1 . It is the crystal form M of temozolomide.

[0045] HPLC purity testing method: take an appropria...

Embodiment 2

[0046] Embodiment 2 Preparation of temozolomide M crystal form

[0047] Take 10g of temozolomide and place it in a reaction flask, add 60g of acetone and 60g of acetonitrile, heat up to reflux under stirring, slowly add 40g of purified water dropwise under stable reflux, with the continuous addition of purified water, the solid gradually dissolves, after the dropwise addition, slowly Cool to 30-40°C to crystallize for 1 hour, then crystallize at 15-25°C for 2 hours, finally cool down to 5-10°C to fully separate out the solid and grow the crystal for 8 hours, filter with suction, rinse the filter cake with water and then use acetone / water (1:1) mixed solution was washed and drained. The solid was dried with phosphorus pentoxide as desiccant at 45° C. under reduced pressure (-0.09 MPa) to obtain 8.4 g of white solid with a yield of 84% and a purity of 100%. It was detected by powder X-ray diffraction that it was Temozolomide M crystal form.

Embodiment 3

[0048] Example 3 Preparation of Temozolomide M Crystal Form

[0049] Take 5 g of temozolomide and place it in a reaction flask, add 40 g of acetone and 20 g of acetonitrile, heat up to reflux under stirring, slowly add 30 g of purified water dropwise under stable reflux, and gradually dissolve the solid with the continuous addition of purified water. After the dropwise addition, slowly Cool to 30-40°C to crystallize for 1 hour, then crystallize at 15-25°C for 2 hours, finally cool down to 5-10°C to fully separate out the solid and grow the crystal for 10 hours, filter with suction, rinse the filter cake with water and then use acetone / water (1:1) mixed solution was washed and drained. The solid was dried with phosphorus pentoxide as desiccant at 45° C. under reduced pressure (-0.09 MPa) to obtain 4.3 g of white solid with a yield of 86% and a purity of 100%. It was detected by powder X-ray diffraction that it was Temozolomide M crystal form.

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Abstract

The invention provides a novel crystal form for temozolomide, a method for preparing the temozolomide and a medicinal composition of the temozolomide. The novel crystal form for the temozolomide is characterized in that: Cu is used for radiation, and diffraction peaks of 2 theta represented by degrees exist at 8.2+ / -0.2 and 6.0+ / -0.2 in an X-ray diffraction pattern. The invention has the advantages that: a temozolomide crystal-shaped object which is suitable for industrialized production is provided; and the problems in the prior art are solved. The preparation process is simple and easy to operate, the industrialized production is convenient to operate, the quality is controllable, and the yield is stable. The crystal-shaped object obtained by the preparation process can remarkably improve the appearance and color and luster of products; the temozolomide M crystal-shaped object prepared by the method has high stability and can be stored for a long time; and in the method, the crystal-shaped object is prepared by using an organic solvent with lower toxicity, so the potential influence effect of the positioning of organic residue on human bodies is reduced to a certain degree. The advantages ensure that the invention is beneficial to the remarkable improvement on the quality of the products and is more suitable for industrialized production.

Description

technical field [0001] The invention relates to a new crystal form of temozolomide, a preparation method and a composition thereof, belonging to the technical field of medicine. Background technique [0002] The chemical name of Temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, and its chemical structure is: [0003] [0004] Temozolomide (trade name Temodal TM ) was developed by M..F.G Stevens, E.S Newlands, etc., and was transferred to Schering-Plough in 1992 for production. In October 1997, it was approved under the unanimous recommendation of the EU CPMP, and temozolomide capsules were launched in Europe in 1998. In January 1999, the US FDA expert advisory group unanimously recommended to speed up the approval of temozolomide, and it was approved by the FDA on August 11, 1999 to be marketed in the United States. At the same time, the company has applied for listing in 16 countries including Canada, Australia, New Zealand, Swi...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4188A61K9/19A61K9/48A61P35/00
Inventor 赵俊杜有国宗在伟
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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