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Novel processes for making- and a new crystalline form of- leflunomide

a technology of leflunomide and crystallization process, which is applied in the field of new crystalline form of leflunomide, can solve the problems of increasing cost, time-consuming method, and cost of industrial production of pharmaceuticals, and achieves the effects of high crystallization rate, easy recovery and recycling, and high yield

Inactive Publication Date: 2005-01-06
AVRUTOV IIYA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

One objective of the present invention is to provide an economic process for preparing leflunomide Form II for use in pharmaceutical compositions. We have surprisingly found that leflunomide Form II may be obtained by precipitating leflunomide from a solution in selected polar solvents and mixtures of polar solvents and an “anti-solvent” without resorting to rapid cooling. Optional slow cooling to induce and maximize crystallization of leflunomide Form II may be conducted at temperatures generally above −10° C. Leflunomide Form II is thus obtained in good yield. Even in solvent systems wherein the yield of Form II is less than 50%, the unprecipitated leflunomide may be easily recovered and recycled.

Problems solved by technology

The Form I and II crystals are not completely dissolved during this process, even with heating, since leflunomide is poorly soluble in these solvents.
This method is time-consuming because of the low transition rate of the polymorphs.
Heating or cooling can be an important factor in the cost of industrial production of pharmaceuticals.
Shock cooling requires special equipment and an additional reactor, adding to the cost.

Method used

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  • Novel processes for making- and a new crystalline form of- leflunomide
  • Novel processes for making- and a new crystalline form of- leflunomide
  • Novel processes for making- and a new crystalline form of- leflunomide

Examples

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Effect test

example 1

Crystallization of Form II from DMSO

DMSO (8 ml) was warmed to 50° C. Leflunomide (5.6 g) was added to the DMSO with stirring. After complete dissolution of the leflunomide, the stirred solution was allowed to cool to ambient temperature. Crystal formation was noted when the solution temperature reached 40° C. The mixture was stirred for another 30 minutes and then the crystals were isolated by filtration, washed with water and then dried under vacuum at 30° C. to give leflunomide Form II (3.4 g, 61%).

example 2

Crystallization of Form II from DMSO / Water

Leflunomide (1.07 g) was dissolved in stirred DMSO (6 ml) at ambient temperature. Water (12 ml) was added dropwise to the stirred solution. The mixture was stirred for 30 minutes. The crystals which formed were isolated by filtration, washed with water and then dried under vacuum at room temperature to give leflunomide Form II (1 g, 93%).

example 3

Crystallization of Form II from DME / Hexane

Leflunomide (6.1 g) was dissolved in DME (10 ml) at ambient temperature. Hexane (16 ml) was added to the stirred solution. The mixture was then stirred for about 30 min. after which time crystallization appeared to have ceased. The crystals were isolated by filtration through a paper filter and dried under vacuum at 30° C. to give leflunomide Form II (2.4 g, 39%).

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Abstract

New leflunomide Form III is disclosed, along with processes for preparing it. The present invention also provides an economic process for preparing leflunomide Form II and a process for preparing leflunomide Form I from leflunomide Form III. Pharmaceutical compositions and dosage forms containing the new form and methods of using them for the treatment of rheumatoid arthritis are also disclosed.

Description

FIELD OF THE INVENTION The present invention relates to a novel leflunomide Form III and to processes for making leflunomide Forms I, II and III. BACKGROUND OF THE INVENTION Leflunomide (5-methylisoxazole-4-carboxylic acid), having the formula 1: is an inhibitor of pyrimidine biosynthesis with antiproliferative activity and is approved in the United States for treatment of rheumatoid arthritis. The present invention relates to polymorphic forms of leflunomide. Polymorphism is the property of some molecules to adopt more than one crystalline form in the solid state. A single molecule may give rise to a variety of solids having distinct physical properties that can be measured in a laboratory like its thermal behavior—e.g. melting point and differential scanning calorimetry (“DSC”) thermogram—dissolution rate, flowability, X-ray diffraction pattern, infrared absorption spectrum and NMR spectrum. The differences in the physical properties of polymorphs result from the orientation ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/08A61K9/10A61K9/14A61K9/20A61K9/48A61K31/42A61P19/02A61P29/00C07D261/18
CPCC07D261/18A61K31/42A61P19/02A61P29/00
Inventor AVRUTOV, IIYAGERSHON, NEOMIARONHIME, JUDITH
Owner AVRUTOV IIYA
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