Fentanyl Formulation Terminal Sterilization Stability
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Solution Overview
Problem
Commercially available fentanyl citrate solutions have limited stability upon dilution and cannot be terminally sterilized in IV bags due to assay loss, requiring immediate administration and introducing risks of contamination and impurity introduction.
Innovation Solution
Development of stable parenteral liquid formulations with fentanyl or its salts, using a non-sugar diluent and a buffer at an acidic pH range of 3 to 4.5, allowing for terminal sterilization in infusion containers and maintaining 95% or more of the initial fentanyl concentration for extended storage periods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If commercially available fentanyl citrate solutions are diluted for administration, then they can be administered to patients, but the stability is limited and unacceptable loss of fentanyl concentration occurs during storage
Solution Approach 1:
The invention performs the dilution action in advance during manufacturing, creating a pre-diluted formulation that is ready for immediate administration. This eliminates the need for bedside dilution and ensures the formulation is optimized for stability from the start, maintaining fentanyl concentration integrity during storage while being administration-ready.
Solution Approach 2:
The invention changes the pH parameter to an acidic range (3.0-4.5) and modifies the diluent composition to exclude sugars and saccharides. These parameter changes stabilize the fentanyl concentration in the diluted formulation, preventing degradation and maintaining potency during storage while keeping the solution ready for administration.
2Ease of operation
If vial solutions are diluted externally, then administration is possible, but time-consuming dilution steps introduce potential impurities and increase contamination risk
Solution Approach 1:
The invention merges the dilution step with the manufacturing process, combining the fentanyl citrate with the diluent and buffering system in a controlled manufacturing environment. This eliminates the separate bedside dilution step that introduces contamination risks, while still providing administration flexibility through ready-to-use formulations in various volumes.
Solution Approach 2:
The formulation is designed to be self-sufficient, containing all necessary components (fentanyl citrate, diluent, buffer) in the correct proportions during manufacturing. This self-service approach eliminates the need for external dilution operations that could introduce impurities or contamination, while maintaining administrative readiness.
3Reliability
If fentanyl citrate solution is terminally sterilized in IV bags, then sterility is ensured, but significant loss of fentanyl concentration occurs due to absorption onto plastic components
Solution Approach 1:
The invention changes the pH parameter to an acidic range (3.0-4.5) and modifies the chemical composition by excluding sugars and saccharides. These parameter changes reduce fentanyl's tendency to absorb onto plastic components, enabling terminal sterilization in IV bags while maintaining acceptable fentanyl concentration levels.
Solution Approach 2:
The invention modifies the local chemical environment by introducing a specific buffering system and acidic pH condition. This creates a localized chemical atmosphere that prevents fentanyl from interacting with and absorbing onto the plastic bag material, thereby maintaining concentration integrity during terminal sterilization and storage.
4Reliability
If conventional fentanyl formulations are used with terminal sterilization, then sterility is achieved, but the assay loss makes the formulation unacceptable
Solution Approach 1:
The invention changes multiple parameters simultaneously: pH to acidic range (3.0-4.5), diluent composition to exclude sugars and saccharides, and buffering system selection. These parameter changes work together to prevent fentanyl degradation and absorption during terminal sterilization, achieving both sterility and acceptable concentration accuracy.
Solution Approach 2:
The invention creates a composite formulation system combining fentanyl citrate with a specific diluent mixture (excluding sugars) and a buffering system. This composite approach provides synergistic protection against fentanyl loss during terminal sterilization, maintaining manufacturing precision while ensuring sterility.
Data Source
AI summary
The stable liquid formulations for parenteral administration include fentanyl or a pharmaceutically acceptable salt thereof. The formulations include a diluent and buffer, either containing sodium, in an aqueous solution that has a pH of about 3 to about 4.5. The parenteral liquid formulations are stable formulations that are supplied as a ready-to-administer product in an infusion container or bag. The stable formulations are terminally sterilized in the infusion container. The stable formulations are suitable for administration to a patient in need of therapy with fentanyl or a pharmaceutically acceptable salt thereof.