Pemetrexed Sodium Salt Formulation Stability
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Solution Overview
Problem
Current lyophilized injectable formulations of pemetrexed are unstable in aqueous solutions, leading to rapid oxidation and microbial contamination risks, with complex and costly manufacturing processes, and existing methods to enhance stability are difficult to scale up for commercial production.
Innovation Solution
A method involving freezing a solution containing pemetrexed and an antioxidant, followed by degassing under reduced pressure in a sealed chamber to remove dissolved oxygen, resulting in a stable, ready-to-use liquid formulation suitable for commercial production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If pemetrexed is formulated as a lyophilized powder for injection, then stability is improved, but the manufacturing process becomes complex and costly with long drying cycles
Solution Approach 1:
The patent removes the need for complex lyophilization equipment and processes by extracting the stability-enhancing function to a simple formulation approach using pemetrexed sodium salt in aqueous solution with controlled pH and antioxidants, eliminating the long drying cycle and equipment complexity while maintaining stability
Solution Approach 2:
The patent changes the formulation parameters by using pemetrexed sodium salt instead of free base, controlling pH within specific ranges (5.5-7.5), and adding antioxidants to achieve stability without requiring lyophilization, thereby simplifying the manufacturing process while maintaining or improving stability
2Stability of the object's composition
If pemetrexed is formulated as a lyophilized powder, then stability is improved, but the reconstitution process becomes cumbersome and time-consuming
Solution Approach 1:
The patent performs preliminary stabilization by formulating pemetrexed sodium salt with antioxidants and appropriate pH control in the aqueous solution before administration, eliminating the need for time-consuming reconstitution and drying cycles while maintaining stability throughout storage and use
3Stability of the object's composition
If antioxidants are added to prevent oxidation, then stability is improved, but the formulation complexity increases
Solution Approach 1:
The patent simplifies the overall formulation approach by changing to pemetrexed sodium salt form and controlling pH within 5.5-7.5, which inherently reduces oxidation susceptibility, requiring only minimal antioxidant additions rather than complex formulation systems
4Ease of operation
If a ready-to-use liquid formulation is developed, then user convenience is improved, but oxidation stability deteriorates
Solution Approach 1:
The patent changes multiple parameters simultaneously - using pemetrexed sodium salt, controlling pH to 5.5-7.5, adding antioxidants, and preparing in aqueous solution - to achieve both ready-to-use liquid convenience and oxidation stability without requiring reconstitution or special storage conditions
Solution Approach 2:
The patent introduces antioxidants as intermediary substances that mediate between the aqueous liquid formulation and oxidation, protecting pemetrexed while maintaining the convenient ready-to-use liquid state without requiring complex preservation systems
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 method provides a stable, room-temperature-storable pharmaceutical composition with improved stability and reduced risk of oxidation, suitable for large-scale commercial production without the need for complex degassing processes, maintaining the formulation's integrity and extending shelf life.
Implementation Method 1
pemetrexed is rapidly oxidized in an aqueous solution and as a result, produces various related compounds
Implementation Method 2
freezing a solution including pemetrexed or a pharmaceutically acceptable salt thereof, an antioxidant and an aqueous solvent
Implementation Method 3
degassing the frozen product under reduced pressure to obtain a degassed and frozen product
Data Source
AI summary
Provided are a composition containing an unstable drug against oxidation like pemetrexed with improved stability and a preparation method thereof, by removing oxygen during the preparation. The method is readily applicable for manufacturing by freezing and degassing in a sealed chamber, and can provide formulations with significantly increased stability for the unstable drug against oxidation.