Phenobarbital Sodium Stabilization via Ethanol Lyophilization
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Solution Overview
Problem
Phenobarbital sodium formulations are unstable due to hydrolysis, leading to high impurity levels and toxicity risks, especially in neonates, where existing solvents like benzyl alcohol and propylene glycol pose safety concerns and hyperosmolality issues.
Innovation Solution
A lyophilized pharmaceutical composition of phenobarbital sodium with an ethanol content ranging from 5000 ppm to 70000 ppm, which inhibits degradation and maintains low impurity levels during extended storage, avoiding the use of benzyl alcohol and propylene glycol.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If phenobarbital sodium is formulated with traditional solvents like benzyl alcohol and propylene glycol to improve stability, then stability is improved, but toxicity risk and hyperosmolality increase
Solution Approach 1:
The patent changes the chemical composition parameters by replacing traditional solvents (benzyl alcohol, propylene glycol) with ethanol at optimized concentrations (5-70,000 ppm), and adjusts pH to 9-11, thereby maintaining stability while reducing toxicity risk in neonates
Solution Approach 2:
The patent uses ethanol, a safer and more readily metabolizable substance compared to propylene glycol, as the stabilizing agent. Ethanol can be effectively eliminated by neonates through metabolic pathways, reducing the accumulation of toxic substances
2Stability of the object's composition
If phenobarbital sodium is formulated with higher concentrations of cosolvents to improve stability, then stability is improved, but osmolality increases above 500 mOsm
Solution Approach 1:
The patent optimizes the concentration parameters of ethanol (5-70,000 ppm) and adjusts pH to 9-11, achieving stable formulation while maintaining osmolality below 500 mOsm, thus avoiding hyperosmolality-related adverse effects in preterm infants
Solution Approach 2:
The patent creates a composite formulation combining phenobarbital sodium with ethanol and pH adjusters, achieving both stability and acceptable osmolality through the synergistic effect of multiple components at optimized concentrations
3Quantity of substance
If phenobarbital sodium is stored as aqueous solution to maintain solubility, then solubility is maintained, but hydrolysis increases leading to higher impurity levels
Solution Approach 1:
The patent changes the pH parameter to 9-11 and adds ethanol at 5-70,000 ppm to the aqueous solution, which suppresses hydrolysis of phenobarbital sodium while maintaining its solubility, thereby reducing impurity formation during storage
Solution Approach 2:
The patent uses ethanol as an intermediary substance that interferes with the hydrolysis pathway of phenobarbital sodium. Ethanol molecules interact with the phenobarbital sodium structure, preventing water molecules from attacking the barbituric acid ring and causing hydrolysis
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 provides stability and reduces impurities to less than 0.2% over two years, ensuring safety and efficacy for neonatal seizures treatment without the toxicity risks associated with traditional solvents.
Implementation Method 1
One of the problems associated with a phenobarbital composition, however, is its instability due to hydrolysis... The presence of hydroxyl ions from the water in the composition results in a hydrolysis pathway that can destroy the phenobarbital ring complex
Implementation Method 2
U.S. Patent Application Publication No. 20210085608 relates to phenobarbital sodium formulations and lyophilization
Data Source
AI summary
A lyophilized pharmaceutical composition of hydrolytically unstable pharmaceutical compounds, such as phenobarbital or salts thereof, is provided. An aqueous solution for injection of phenobarbital or salts thereof that is reconstituted from the lyophilized pharmaceutical composition is provided. The pharmaceutical compositions of the present disclosure have an ethanol content in the range from about 5000 ppm to about 70000 ppm. The composition of the present disclosure, in certain embodiments, is stable following two years of storage, wherein the total impurities do not exceed 0.5%. The pharmaceutical compositions of the present disclosure may be used for the treatment of neonatal seizures.