Voriconazole Inclusion Complexes with Cyclodextrin
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Solution Overview
Problem
Voriconazole is not stable in water, degrades under oxidative conditions, and has low solubility, making it challenging to formulate effective pharmaceutical formulations for intravenous administration.
Innovation Solution
Formulating voriconazole with 2-hydroxypropyl-β-cyclodextrin, which forms stable inclusion complexes, enhancing solubility and stability by adjusting the molar substitution of hydroxypropyl groups and maintaining a pH range of 4-7, along with optional pH adjusting agents and organic carboxylic acids.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If voriconazole is formulated in water for intravenous administration, then solubility is improved, but stability deteriorates due to degradation in water and under oxidative conditions
Solution Approach 1:
The patent uses 2-hydroxypropyl-β-cyclodextrin as an intermediary substance that forms inclusion complexes with voriconazole. The cyclodextrin acts as a mediator between the hydrophobic voriconazole molecule and the aqueous environment, providing both solubility enhancement and stability protection by shielding the drug from water and oxidative degradation
Solution Approach 2:
The invention creates a composite formulation system consisting of voriconazole incorporated within the cyclodextrin host structure. This composite inclusion complex combines the properties of both components, achieving water solubility through the hydrophilic cyclodextrin exterior while maintaining drug stability through the protective inclusion complex structure
2Quantity of substance
If conventional solubilization methods are used (oils, surfactants, water miscible co-solvents), then solubility is improved, but the formulation becomes less suitable for intravenous administration due to semi-polar nature of voriconazole
Solution Approach 1:
The patent changes the physical-chemical parameters of the formulation system by using cyclodextrin inclusion complexes. This approach fundamentally alters how voriconazole interacts with the aqueous environment, transitioning from direct contact with conventional solubilizing agents to indirect interaction through the cyclodextrin medium, thereby achieving both solubility and intravenous compatibility
3Productivity
If voriconazole is stored at elevated temperatures, then processing efficiency is improved, but degradation increases greatly
Solution Approach 1:
The cyclodextrin inclusion complex provides beforehand protection against thermal degradation. By pre-encapsulating the voriconazole molecule within the cyclodextrin cavity before thermal stress occurs, the formulation is cushioned against temperature-induced degradation, allowing more flexible processing conditions while maintaining 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 formulation significantly reduces degradation and impurities, providing a stable and soluble form of voriconazole suitable for intravenous infusion, with improved stability at elevated temperatures and pH control.
Implementation Method 1
The mechanism for this solubilization is rooted in the ability of 2-hydroxypropyl-β-cyclodextrin to form non-covalent dynamic inclusion complexes in a solution, in which the guest and host molecules are in dynamic equilibrium with the complex
Implementation Method 2
Voriconazole is not stable in water, degrades under oxidative conditions
Implementation Method 3
Voriconazole degrades in water, it is susceptible to oxidative degradation and decomposes in acidic and basic media
Data Source
AI summary
Described are voriconazole formulations including 2-hydroxypropyl-β-cyclodextrins and the preparation thereof.