Pemetrexed Disodium Aqueous Formulation Oxidative Stability
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Solution Overview
Problem
Existing aqueous parenteral formulations of Pemetrexed suffer from chemical instability due to oxidative degradation, leading to rapid formation of degradants and unacceptable levels of impurities, which hinders long-term stability and commercial viability.
Innovation Solution
A stable, ready-to-use aqueous parenteral composition of Pemetrexed disodium is formulated with a mixture of antioxidants, including monothioglycerol and methionine, along with pH modifiers and buffering agents, to prevent oxidative degradation and maintain chemical stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If aqueous parenteral formulations of Pemetrexed are used, then the drug can be administered parenterally, but chemical instability due to oxidative degradation occurs leading to rapid formation of degradants and impurities
Solution Approach 1:
The patent introduces antioxidants (such as methionine, monothioglycerol, L-cysteine, or thioglycolic acid) as intermediary substances that mediate between the Pemetrexed and oxidative degradation. These antioxidants act as sacrificial agents that preferentially undergo oxidation, thereby protecting the Pemetrexed from degradation and maintaining chemical stability in the aqueous parenteral formulation.
Solution Approach 2:
The patent creates an inert protective environment by incorporating antioxidants that establish a reducing atmosphere within the formulation. This inert environment prevents oxidative reactions from occurring with the Pemetrexed, effectively isolating it from harmful oxidative stressors in the aqueous solution.
2Stability of the object's composition
If antioxidants are added to prevent oxidative degradation, then long-term stability is achieved, but the formulation complexity increases
Solution Approach 1:
The patent employs antioxidants that are relatively simple, cost-effective compounds (such as methionine, monothioglycerol, L-cysteine, or thioglycolic acid) rather than complex stabilization systems. These antioxidants are single-function molecules that provide adequate protection for the intended shelf life, avoiding the need for complex multi-component stabilization systems.
Solution Approach 2:
The patent optimizes the concentration parameters of the antioxidants within specific ranges (e.g., 2.4 mg/ml for monothioglycerol, L-cysteine, or thioglycolic acid; or 0.1-1 mg/ml for methionine) to achieve effective stabilization with minimal added complexity. By carefully controlling these parameter values, the formulation achieves long-term stability without requiring excessive amounts of stabilizing agents.
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 formulation achieves long-term stability, with minimal formation of degradants and impurities, maintaining the active ingredient's potency and safety for extended storage periods without the need for freeze-drying.
Implementation Method 1
Existing aqueous parenteral formulations of Pemetrexed suffer from chemical instability due to oxidative degradation
Data Source
AI summary
The present invention provides a stable, ready to use aqueous parenteral composition comprising Pemetrexed, wherein the composition comprises Pemetrexed disodium, mixture of antioxidants and pharmaceutically acceptable excipients. Further the present invention provides process for preparation of said composition.