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Crystallization process of Roxadustat bulk drug with controlled particle size

A technology for roxadustat and particle size control, which is applied in solution crystallization, crystallization condition screening, organic chemistry, etc., can solve the problems of fast dissolution, large particle size, and fine particle size, and achieve safe and simple crystallization process, high yield high rate effect

Pending Publication Date: 2022-01-21
NANJING VCARE PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After research, the applicant found that at present, it is impossible to obtain roxadustat API with qualified particle size through conventional pulverization methods:
[0007] (1) The particle size of roxadustat API could not be pulverized to less than 45 μm by the tooth mill, and the particle size was too large;
[0008] (2) The particle size of roxadustat API will be crushed to less than 25 μm by jet milling, the particle size is too fine and the dissolution is too fast

Method used

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  • Crystallization process of Roxadustat bulk drug with controlled particle size
  • Crystallization process of Roxadustat bulk drug with controlled particle size
  • Crystallization process of Roxadustat bulk drug with controlled particle size

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1. Dissolution contrast experiment of prescription preparations of different particle size raw materials

[0033] The effect of particle size of roxadustat raw material on the dissolution rate of capsules and the cumulative dissolution rate at the end point of dissolution was investigated.

[0034] 1) By adjusting the crystallization process and combining pulverization means to obtain roxadustat APIs with different particle sizes, as shown in Table 1:

[0035] Table 1

[0036] .

[0037] 2) Make roxadustat raw materials with different particle sizes into capsules according to the following process:

[0038] Mix roxadustat with lactose, microcrystalline cellulose, croscarmellose sodium, and povidone through a cone granulator, stir and mix in a wet granulation pot, and then stir at 200 rpm, Under the condition of cutting at 1500 rpm, add purified water to granulate, dry in a fluidized bed, granulate with a 0.8 mm sieve, add magnesium stearate for total mix...

Embodiment 2

[0050] Embodiment 2, crystallization condition screening

[0051] (a) Temperature screening

[0052] During the crystallization process, under the same stirring speed, the effect of different dropping temperature on the particle size was investigated.

[0053] Put roxadustat (I) and water in a reaction kettle, add aqueous sodium hydroxide solution, dissolve roxadustat (I), filter, place the mother liquor in a crystallization kettle, raise the temperature to different temperatures, and drop into the first Part of the acetic acid aqueous solution, adjust the pH to 6.6; add roxadustat seed crystals, and quickly add the second part of the acetic acid aqueous solution, and keep stirring the system; centrifuge while hot, dry the filter cake to obtain the raw material drug of roxadustat, and measure the particle size after sampling , the experimental results are shown in Table 3:

[0054] table 3

[0055] .

[0056] Conclusion: During the crystallization process, under the same...

Embodiment 3

[0073]

[0074] Put 5.3 Kg of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (compound II-1), 5.83 Kg of sodium glycinate and 51 Kg of methanol in the reactor for reflux reaction for 12 hours , cooling and filtering, the filter cake was dissolved in ethyl acetate and water and then separated, the water layer was warmed up to 70°C, and acetic acid aqueous solution was added, and after cooling down, it was centrifuged to obtain the wet crude product of roxadustat. Add the wet crude product of roxadustat into water, add sodium hydroxide aqueous solution, and filter the system. After the filtrate is warmed up to 65-75 °C, add acetic acid aqueous solution, filter while hot and dry to obtain 55.6 Kg of roxadustat (I), with a purity of: 99.5%, yield: 90%.

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Abstract

The invention relates to a crystallization process of a Roxadustat bulk drug with a controlled particle size. The process comprises the steps of salifying the Roxadustat (I) with alkali, filtering, heating, adding a first part of an acetic acid aqueous solution to adjust the pH value to 6.4-6.7, adding a Roxadustat seed crystal and a second part of the acetic acid aqueous solution, crystallizing, centrifuging, and drying to obtain the Roxadustat bulk drug with a controlled particle size. The particle size D (90) of the Roxadustat bulk drug prepared by the process method is 25-45 [mu] m, and the Roxadustat bulk drug meets the requirements of preparations and is suitable for industrial production.

Description

technical field [0001] The invention relates to a crystallization process of roxadustat crude drug with particle size control, belonging to the technical field of medicinal chemistry. Background technique [0002] Roxadustat (FG-4592) is the first oral small molecule HIF-PHI developed by FibroGen for the treatment of renal anemia, which can inhibit HIF-PHI under normal oxygen partial pressure Aminoacyl hydroxylase stabilizes HIF-α, promotes endogenous EPO production and improves iron absorption and utilization, comprehensively regulates and promotes erythropoiesis. In December 2018, the State Drug Administration approved the listing of Roxadustat Capsules through the priority review and approval process, specifications: 20mg, 50mg; the indication is for the treatment of anemia in patients with chronic kidney disease on dialysis; it was approved in August 2019 For the treatment of anemia in non-dialysis dependent chronic kidney disease (NDD-CKD). [0003] . [0004] In t...

Claims

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Application Information

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IPC IPC(8): C07D217/26B01D9/02
CPCC07D217/26B01D9/0077C07B2200/13
Inventor 杜振东左楠屈芮张阳阳刘雪芳龚彦春刘永强
Owner NANJING VCARE PHARMATECH CO LTD
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