Pemetrexed Formulation Stability via Oxygen Control
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Solution Overview
Problem
Pemetrexed solutions, when prepared as simple isotonic saline, are not pharmaceutically acceptable due to degradation and instability at room temperature, requiring refrigeration for stability.
Innovation Solution
A ready-to-use liquid composition of pemetrexed is formulated using antioxidants and controlled oxygen levels (head space oxygen < 5% and dissolved oxygen < 2 ppm) combined with terminal sterilization, ensuring stability at room temperature and reduced impurity levels (< 0.5%) through a process involving solubilization and steam sterilization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If simple isotonic saline solution of pemetrexed is prepared, then the formulation is simple and easy to manufacture, but the solution degrades rapidly forming unacceptable related substances and requires refrigeration for stability
Solution Approach 1:
The patent applies composite materials by combining pemetrexed with multiple excipients including mannitol, sodium chloride, disodium edetate, and tromethamine in a buffered saline solution. This composite formulation provides both manufacturing simplicity and enhanced stability at room temperature, resolving the contradiction between ease of manufacture and solution stability.
Solution Approach 2:
The patent changes key formulation parameters including pH buffering (tromethamine), ionic strength (sodium chloride), chelating capacity (disodium edetate), and osmolarity (mannitol, sodium chloride). These parameter changes enable the solution to remain stable at room temperature without refrigeration, while maintaining ease of manufacture through conventional pharmaceutical excipients.
2Stability of the object's composition
If antioxidants are added to stabilize pemetrexed solution, then the stability is improved, but the formulation complexity and manufacturing process become more complex
Solution Approach 1:
The patent converts the harmful effect of oxygen exposure into a benefit by using controlled oxygen levels during manufacturing. The process deliberately introduces oxygen to oxidize antioxidants in a controlled manner, creating stable formulation conditions that prevent subsequent degradation of pemetrexed, thus converting a potential harm (oxidation) into a beneficial stabilizing mechanism.
Solution Approach 2:
The patent changes the oxidation state parameters by controlling dissolved oxygen levels and headspace oxygen percentages during manufacturing. This parameter control allows the formulation to achieve optimal stability without requiring complex antioxidant systems, maintaining formulation simplicity while improving stability.
3Duration of action of stationary object
If terminal sterilization by autoclaving is applied, then the formulation achieves room temperature stability and extended shelf life, but the risk of degradation during sterilization increases
Solution Approach 1:
The patent applies beforehand cushioning by incorporating antioxidants and buffering agents into the formulation before sterilization. These components act as protective cushions that absorb the harsh conditions of autoclaving, preventing degradation of pemetrexed during terminal sterilization while enabling room temperature storage and extended shelf life.
Solution Approach 2:
The patent uses a composite formulation containing pemetrexed, mannitol, sodium chloride, disodium edetate, and tromethamine that collectively provide resistance to sterilization-induced degradation. This composite system withstands autoclaving conditions and enables terminal sterilization without significant drug degradation, achieving both sterility and shelf life extension.
4Manufacturing precision
If controlled oxygen levels (head space oxygen < 5% and dissolved oxygen < 2 ppm) are maintained, then impurity levels are reduced to < 0.5%, but the manufacturing process complexity increases
Solution Approach 1:
The patent changes the oxygen concentration parameters by controlling headspace oxygen to less than 5% and dissolved oxygen to less than 2 ppm during manufacturing. This parameter control achieves impurity levels below 0.5% through a streamlined process that avoids excessive complexity by integrating oxygen control into standard manufacturing operations.
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 maintains stability and low impurity levels at room temperature, providing a robust and stable pharmaceutical composition suitable for parental administration with extended shelf life.
Implementation Method 1
Pemetrexed solutions, when prepared as simple isotonic saline, are not pharmaceutically acceptable due to degradation
Implementation Method 2
A ready-to-use liquid composition of pemetrexed is formulated using antioxidants
Implementation Method 3
controlled oxygen levels (head space oxygen < 5% and dissolved oxygen < 2 ppm) combined with terminal sterilization, ensuring stability at room temperature
Implementation Method 4
terminal sterilization by autoclaving/steam sterilization with F0 value 1-30 min
Data Source
AI summary
The present invention relates to pharmaceutical composition comprising pemetrexed, a ready to use injection comprising pemetrexed. Liquid composition of pemetrexed comprises head space oxygen less than 5%, dissolved oxygen less than 2 ppm and individual impurity level less than 0.2%.