Pemetrexed Liquid Composition Stability via Buffering and Antioxidants
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Solution Overview
Problem
Current pharmaceutical compositions of pemetrexed for parenteral administration suffer from chemical instability due to oxidative and acidic degradation, leading to insufficient long-term stability and potential toxicity concerns, making it challenging to create a stable, ready-to-use reconstituted solution without freeze drying.
Innovation Solution
A liquid pharmaceutical composition comprising pemetrexed diacid, arginine, a monothiolic antioxidant, propylene glycol, and optional chelating agents, prepared in an inert gas atmosphere to achieve a pH range of 8.3 to 9.1, which enhances stability and safety by preventing acidic degradation and oxidation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If a simple isotonic saline solution is used to dissolve pemetrexed, then the preparation process is simple, but the solution degrades rapidly due to oxidative and acidic degradation
Solution Approach 1:
The patent introduces several intermediary substances that mediate between the pemetrexed and the saline solution environment. Sodium citrate acts as a buffer to control pH and prevent acidic degradation. Sodium thiosulfate serves as an antioxidant to prevent oxidative degradation. These intermediaries protect pemetrexed from the harmful effects of the saline solution without requiring complex preparation procedures.
Solution Approach 2:
The patent modifies the chemical parameters of the saline solution by adding specific concentrations of buffer (sodium citrate) and antioxidant (sodium thiosulfate). By controlling the pH through buffering and adjusting the redox potential through the antioxidant, the solution maintains chemical stability while remaining isotonic and easy to prepare.
2Stability of the object's composition
If antioxidants are added to prevent degradation, then chemical stability is improved, but the composition becomes more complex and may introduce toxicological concerns
Solution Approach 1:
The patent optimizes the concentration parameters of the antioxidants and buffering agents to achieve stability with minimal complexity. Sodium thiosulfate is used at 0.1-10 mg/ml and sodium citrate at 1-50 mg/ml, concentrations that are sufficient to prevent degradation while maintaining pharmacological safety. This parameter optimization balances stability requirements with composition simplicity and toxicological safety.
3Stability of the object's composition
If oxygen content is controlled to prevent degradation, then stability is improved, but the handling and preparation become more difficult
Solution Approach 1:
Instead of controlling oxygen content directly, the patent introduces sodium thiosulfate as an intermediary antioxidant that scavenges oxygen and free radicals. This approach is much easier to implement than oxygen control, as it simply requires adding the antioxidant to the solution during preparation, while effectively preventing oxidative degradation of pemetrexed.
4Stability of the object's composition
If freeze drying techniques are used to create stable formulations, then long-term stability is improved, but the manufacturing process becomes more complex and time-consuming
Solution Approach 1:
The patent extracts the stability-enhancing components (antioxidant and buffer) from the complex freeze-drying process and incorporates them directly into the liquid formulation. This allows the solution to be stable in liquid form without requiring freeze drying, eliminating the need for complex lyophilization equipment and processes while maintaining long-term stability.
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 composition exhibits excellent long-term stability, with impurity levels below 2% after 6 months at 25°C and 18 months at 2-8°C, ensuring a safe and effective treatment for malignant pleural mesothelioma and non-small cell lung cancer.
Implementation Method 1
The chemical instability of pemetrexed is mainly attributed to oxidative and acidic degradation. In the presence of oxygen, two oxidative degradants result.
Implementation Method 2
Under acidic conditions, decarboxylation of glutamic acid is observed.
Implementation Method 3
In the presence of oxygen, two oxidative degradants result.
Data Source
AI summary
The present invention relates to a liquid pharmaceutical composition suitable for parenteral administration comprising: a) pemetrexed diacid; b) at least one organic amine; c) at least one antioxidant; d) 10-200 mg/ml of propylene glycol; and e) one or more parenteral solvents, wherein the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1 The invention further relates to the use of said liquid pharmaceutical composition as medicament in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.