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Pemetrexed disodium compound and composition thereof

A technology of pemetrexed disodium and compounds, applied in the field of pemetrexed disodium compounds and their compositions, can solve the problems of loss of crystal water, poor stability of pemetrexed disodium, toxic and side effects, etc. Low labor and labor requirements, ideal stability and efficacy, and the effect of ensuring drug safety

Active Publication Date: 2013-03-20
SHANXI PUDE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The technical problems it solves are: the stability of pemetrexed disodium is relatively poor, it is easy to degrade under high temperature, oxidation and light conditions, and produces impurities that may cause toxic and side effects, the stability of the freeze-dried preparation is poor, and the compatible solution cannot be used in clinical use. Leave it for a long time
The technical problem it solves: the stability of pemetrexed disodium is poor
However, the 2.5 hydrate is unstable. Although the stability of the 3 hydrate is better than the former, it is difficult to control the amount of crystal water when drying, and 2.5 hydrate may appear.
The quality of the 7 hydrate is stable, but it is very easy to lose part of the crystallization water when stored under high temperature, low humidity or vacuum conditions, and the drying process of the hydrate also increases the process of treating with wet nitrogen flow and corresponding equipment, increasing cost of production
Technical problem to be solved: the current purification methods of pemetrexed disodium and pemetrexed all involve the process of heating and crystallizing with a mixed solvent. characteristics, so it is bound to accelerate their oxidation during the heating process to reduce the quality and yield of products
[0015] But above-mentioned technical method all can't really meet the high requirement that pemetrexed disodium raw material proposes in freeze-dried preparation itself and clinical application process, therefore, still remains to find a kind of ideal pemetrexed disodium compound, in order to further Obtain the composition preparation that stability, curative effect etc. are significantly better than prior art

Method used

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  • Pemetrexed disodium compound and composition thereof
  • Pemetrexed disodium compound and composition thereof
  • Pemetrexed disodium compound and composition thereof

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0042] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. The preparation of embodiment 1 pemetrexed disodium compound

[0043] (1) Weigh 100g of crude pemetrexed disodium, dissolve 96g of it in water (1.2L) whose volume is equivalent to 12 times the weight of pemetrexed disodium crude (g / ml), stir well to obtain a solution a.

[0044] (2) Fully dissolve the remaining 4g of pemetrexed disodium crude product in a mixture of acetone and isopropanol at 42°C with a stirring speed of 25rmp to form solution B. The volume of acetone and isopropanol in the mixture The ratio is 1:6; the volume of the mixed solution is 1.5 times that of solution A.

[0045] (3) Within 3 hours, add solution B dropwise to solution A at a constant speed, while controlling the temperature of solution A at 22°C, stirring at a low speed of 8rmp during the dropwise addition.

[0046] (4) After the dropwise addition, the temp...

Embodiment 2

[0048] The preparation of embodiment 2 pemetrexed disodium compound

[0049] (1) Weigh 100g of crude pemetrexed disodium, dissolve 98g of it in water whose volume is equivalent to 15 times the weight of the crude pemetrexed disodium, and stir evenly to obtain solution A;

[0050] (2) Dissolve the remaining 2g of crude pemetrexed disodium in a mixture of acetone and isopropanol at 40°C with a stirring speed of 20rmp to form solution B. The volume of acetone and isopropanol in the mixture is 1:3, the volume of the mixed solution is 0.8 times that of solution A;

[0051] (3) Within 2 hours, add solution B dropwise to solution A at a constant speed, while controlling the temperature of solution A at 20°C, stirring at a low speed of 5rmp during the dropping process;

[0052] (4) After the dropwise addition, the temperature of the solution was lowered to 5°C, and the crystal was left to grow for 8 hours, filtered, the filter cake was washed with acetone, and dried at low temperatur...

Embodiment 3

[0054] The preparation of embodiment 3 pemetrexed disodium compound

[0055] (1) Weigh 100g of pemetrexed disodium crude product, dissolve 94g of it in water whose volume is equivalent to 10-15 times the weight of pemetrexed disodium crude product, stir well to obtain solution A;

[0056] (2) Fully dissolve the remaining 6g of pemetrexed disodium crude product in the mixture of acetone and isopropanol at 45°C with a stirring speed of 30rmp to form solution B. The volume of acetone and isopropanol in the mixture 1:7, the volume of the mixed solution is twice that of solution A;

[0057] (3) Within 2-4 hours, add solution B dropwise to solution A at a constant speed, while controlling the temperature of solution A at 25°C, stirring at a low speed of 10rmp during the dropping process;

[0058] (4) After the dropwise addition, the temperature of the solution was lowered to 0°C, and the crystal was left to grow for 12 hours, filtered, the filter cake was washed with acetone, and d...

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Abstract

The invention discloses a pemetrexed disodium compound expressed by the formula (I) and a composition thereof, wherein the pemetrexed disodium compound is measured by powder X-ray diffractometry so that the X-ray powder diffraction pattern expressed by the diffraction angle of 2theta+ / -0.2 of the compound shows feature diffraction peaks at 10.05 degrees, 10.90 degrees, 11.40 degrees, 12.51 degrees, 14.22 degrees, 15.94 degrees, 18.33 degrees, 19.72 degrees, 21.44 degrees, 22.92 degrees, 23.84 degrees, 28.08 degrees, 29.98 degrees, 31.95 degrees and 33.32 degrees. The pemetrexed disodium compound provided by the invention is obviously improved in stability, low in organic solvent residual volume, controllable in quality, and not easy to change even though being placed for a long time; therefore, the medication safety of the patient is greatly improved.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, in particular to a pemetrexed disodium compound and a composition thereof. Background technique [0002] Pemetrexed disodium is a new anti-metabolite preparation of folic acid, which can inhibit the activity of various folic acid-dependent enzymes and exert its anticancer effect. On February 4, 2004, the FDA approved the combination of pemetrexed disodium and cisplatin for the treatment of malignant pleural mesothelioma. On August 19, 2004, FDA approved pemetrexed disodium as a second-line drug for locally advanced or metastatic non-small cell lung cancer (NSCLC). Since the product has many targets and relatively mild side effects, clinical trials on many types of tumors have been conducted internationally, showing the broad prospect of the product for anti-tumor. [0003] The prior art discloses a variety of pemetrexed disodium and related preparations, such as the improvement plan p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00
Inventor 王勇李立忠解晓荣李润宝昝建强姚荷云闫洁胡成伟
Owner SHANXI PUDE PHARMA CO LTD