Leflunomide Stability via Organic Acid Stabilization

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Pharmaceutical compositions containing leflunomide suffer from instability during storage, leading to the formation of teriflunomide as a degradation product, exceeding acceptable impurity levels and failing to meet current drug approval regulations due to high teriflunomide content.

Innovation Solution

Incorporating pharmaceutically acceptable mono- or polybasic organic acids, such as tartaric acid, malic acid, and citric acid, into the compositions to stabilize leflunomide, and using acidic buffer systems to maintain a pH below 7.0, thereby reducing teriflunomide formation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If conventional leflunomide preparations are stored, then teriflunomide degradation product forms, but stability and purity requirements are not met

Engineering Contradiction:

ImprovestabilityVSAvoidteriflunomide degradation product

Core Design Contradiction:

Stability of the object's compositionVSObject-generated harmful factors

Solution Approach 1:

An acidic substance is introduced as an intermediary component in the pharmaceutical composition to mediate between leflunomide and its degradation pathway. The acid suppresses the formation of teriflunomide by maintaining an acidic environment that stabilizes leflunomide, thereby preventing the harmful degradation reaction without directly interacting with the active ingredient itself.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The pH parameter of the pharmaceutical composition is changed and maintained in the acidic range (below 7.0) through the addition of acidic substances. This parameter change fundamentally alters the stability profile of leflunomide, preventing degradation to teriflunomide while maintaining the therapeutic efficacy of the active ingredient throughout the shelf life.

Inventive Principle:

Principle #35Parameter changes

2Duration of action of stationary object

If leflunomide compositions are stored for extended periods, then teriflunomide levels increase, but regulatory approval cannot be obtained

Engineering Contradiction:

Improvestorage periodVSAvoidpurity

Core Design Contradiction:

Duration of action of stationary objectVSReliability

Solution Approach 1:

The acidic substance is incorporated into the formulation in advance, before storage begins. This preliminary action establishes a protective acidic environment that prevents degradation throughout the entire storage period, ensuring that purity requirements are met even after extended storage and enabling regulatory approval.

Inventive Principle:

Principle #10Preliminary action

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The addition of organic acids and acidic buffers significantly improves the stability of leflunomide compositions, maintaining teriflunomide levels below 1% even after extended storage periods, meeting regulatory requirements for stability and purity.

Implementation Method 1

using acidic buffer systems to maintain a pH below 7.0, thereby reducing teriflunomide formation

Methodology Applied

Scientific EffectpH control:

Data Source

PatentEP2004149B2Pharmaceutical compositions containing leflunomid

Publication Date: 2015.03.04 ALFRED E TIEFENBACHER (GMBH & CO KG)

AI summary

The current invention relates to leflunomid-containing pharmaceutical compositions including an organic or anorganic acid characterized by improved stability.