Trazodone Hydrochloride Liquid Formulation pH and Cosolvent Optimization
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Solution Overview
Problem
Current liquid pharmaceutical compositions of trazodone hydrochloride have low concentrations, are incompatible with ethanol consumption, and undergo physical changes due to degradation, making them unstable and inconvenient for oral administration.
Innovation Solution
A stable liquid pharmaceutical composition with a pH range of 5.0 to 6.0, using at least two cosolvents from the group of glycols and polyglycols, such as propylene glycol and polyethylene glycol, to achieve solubility levels above 3% (w/v) and incorporating antioxidants to prevent oxidative degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the concentration of trazodone hydrochloride in liquid formulation is increased, then therapeutic dosage efficiency is improved, but stability and physical appearance deteriorate due to oxidative degradation
Solution Approach 1:
The patent changes the pH parameter from conventional acidic range (4.3-4.7) to a slightly alkaline range (5.0-6.0), which fundamentally alters the oxidation behavior of trazodone hydrochloride. This parameter change prevents oxidative degradation while allowing high concentration formulations (up to 15% w/v) to remain stable and colorless during storage.
Solution Approach 2:
The patent introduces cosolvents (propylene glycol, polyethylene glycol, or their mixtures) as intermediary substances that mediate between the trazodone hydrochloride and the aqueous environment. These cosolvents enable high concentration formulations while maintaining stability through their protective effect against oxidative degradation.
2Quantity of substance
If ethanol is used as cosolvent to improve solubility, then concentration capability is improved, but compatibility with ethanol consumption is worsened
Solution Approach 1:
The patent extracts ethanol from the cosolvent system and replaces it with alternative cosolvents (propylene glycol, polyethylene glycol) that do not interact adversely with ethanol consumption. This substitution maintains the solubility enhancement function while eliminating the harmful interaction with ethanol.
Solution Approach 2:
The patent changes the chemical composition parameters of the cosolvent system, selecting propylene glycol and polyethylene glycol which have different chemical properties compared to ethanol. These alternative cosolvents provide comparable solubility enhancement without the harmful interaction with ethanol consumption.
3Ease of operation
If conventional liquid formulation is used, then ease of administration is improved, but modularity and personalization of therapeutic dose are worsened
Solution Approach 1:
The patent changes the concentration parameter of the liquid formulation from conventional low concentrations (2.5% maximum) to high concentrations (up to 15% w/v). This parameter change enables precise dose modulation through small volume adjustments, thereby improving modularity and personalization while maintaining ease of oral administration.
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 achieves a 140% increase in trazodone hydrochloride concentration, maintaining stability and preventing yellowing, allowing for higher therapeutic dosages without ethanol and prolonged stability without precipitate formation.
Implementation Method 1
a liquid pharmaceutical composition comprising an aqueous solution of a pharmaceutically acceptable salt of acid addition of trazodone in which the pH value is between 5.0 and 6.0 and which contains at least two cosolvents selected from the group comprising glycols and polyglycols
Implementation Method 2
incorporating antioxidants to prevent oxidative degradation
Data Source
AI summary
A stable liquid pharmaceutical composition comprising an aqueous solution of a pharmaceutically acceptable salt of acid addition of trazodone, characterized in that said pharmaceutical composition has a pH value between 5.0 and 6.0, and comprises at least two cosolvents selected from the group comprising glycols and polyglycols.