Preparation method of medicinal crystal form tofacitinib citrate

A technology of tofacitinib and citric acid, which is applied in the field of preparation of pharmaceutical crystalline tofacitinib citrate, can solve the problem of increased changes in impurities, insoluble finished products, and unrepeatable temperature and solvent volume. Example and other issues to achieve good stability

Inactive Publication Date: 2015-04-22
合肥远志医药科技开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The kilogram-scale amplification process reported in this patent has undergone repeated verification tests, and after receiving the product, it has been tested and inspected by high temperature, high humidity, light and other influencing factors, and the change of impurities has a tendency to increase
[0004] Chinese patent CN103073552A reports the preparation method of amorphous tofacitinib citrate, which mentions that the product quality is relatively stable after the investigation of the influencing factors, and the examples cannot be repeated according to the temperature and solvent amount in the examples of the patent literature, The finished product is also insoluble in methanol

Method used

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  • Preparation method of medicinal crystal form tofacitinib citrate
  • Preparation method of medicinal crystal form tofacitinib citrate
  • Preparation method of medicinal crystal form tofacitinib citrate

Examples

Experimental program
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Embodiment 1

[0031] Put 70g of tofacitinib citrate raw material into the reactor, and at the same time vacuum pump 0.7kg of ethanol aqueous solution, wherein the mass ratio of isopropanol and water is 1:1; slowly heat to about 60°C to dissolve, then keep stirring After 2 hours, a clear and transparent solution was obtained; then it took 2 hours to slowly cool down to 15°C, and heat and stir for 4 hours to crystallize; the precipitated crystals were centrifuged and dried to obtain 63g off-white wet product, which was dried under reduced pressure and vacuum at 50°C for 8 Hours, 60 g of dry white solid were obtained.

[0032] It is detected by X-ray diffraction, and its X-ray pattern is as follows figure 1 As shown, it shows that the white solid is pharmaceutical crystalline form of tofacitinib citrate; the melting point of the crystal was determined by differential scanning calorimetry (TGA-DSC), and its melting point was 214-220 °C, and its TGA-DSC spectrum Such as figure 2 shown. In ad...

Embodiment 2

[0034] Drop into 70g tofacitinib citrate crude drug in reactor, simultaneously vacuum pump into 1.05kg isopropanol aqueous solution, wherein the mass ratio of isopropanol and water is 2:1, slowly heat to about 80 ℃ and make it dissolve, then Insulated and stirred for 1 hour to obtain a clear and transparent solution; then it took 2 hours to slowly cool down to about 15°C, heat and stir for 4 hours to crystallize; centrifuge and dry it to obtain 65g off-white wet product, and vacuum dry it at 30°C for 8 hours , to obtain 61g of dry white medicinal crystal form tofacitinib citrate solid.

Embodiment 3

[0036] In the reactor, drop into 70g tofacitinib citrate crude drug, simultaneously vacuum pump into 1.4kg isopropanol aqueous solution, wherein the mass ratio of isopropanol and water is 3:1, slowly heat to about 95 ℃ and make it dissolve, then Insulated and stirred for 2 hours, a clear and transparent solution was obtained; it took 1 hour to slowly cool down to 10°C, heat-preserved and stirred for 8 hours to crystallize; it was centrifuged and dried to obtain 66g of off-white wet product, and dried under reduced pressure and vacuum at 60°C for 8 hours , to obtain 59g of dry white medicinal crystal form tofacitinib citrate solid.

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Abstract

The invention provides a preparation method of medicinal crystal form tofacitinib citrate. The preparation method comprises the following steps of 1, taking a tofacitinib citrate raw material, pumping a solvent into the raw material in vacuum, heating the mixture for dissolution, and carrying out thermal insulation stirring for 1-2h, 2, carrying out slow cooling to 0-50 DEG C, and carrying out thermal insulation stirring for 4-10h for crystallization, and 3, carrying out filtration and drying to obtain the medicinal crystal form tofacitinib citrate. Through strict control of a crystallization temperature, crystallization time and a use amount of a solvent in the process, the preparation method greatly improves a yield and purity of tofacitinib citrate, the highest yield is 90% and purity is more than 99.7% The preparation method has less total impurities and has all single impurity contents less than 0.1%. A powdery X-ray diffractometer test proves that the finished product obtained by the preparation method has a single and stable crystal form and satisfies medicinal-grade bulk drug requirements.

Description

technical field [0001] The invention belongs to the technical field of medicine production, and in particular relates to a preparation method of pharmaceutical crystal form tofacitinib citrate. Background technique [0002] Tofacitinib citrate is a new type of oral JAK inhibitor developed by Pfizer of the United States. It was approved by the FDA in November 2012. The trade name is Xeljanz. Treatment of adult patients with to severely active rheumatoid arthritis. [0003] Chinese patent ZL02823587.8 (Pfizer, USA) discloses its crystal form, and its typical feature is that its differential scanning calorimetry curve has a characteristic peak at a temperature of about 203-210°C, and has an onset melting temperature of about 199-206°C. The kilogram-level amplification process reported in this patent has undergone repeated verification tests, and after obtaining the product, it has been tested and inspected by high temperature, high humidity, light and other influencing facto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 胡孟奇刘斐江浩蒋维孙松
Owner 合肥远志医药科技开发有限公司
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