Tiotropium Bromide Solvate Stabilization via Saturated Vapor
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Solution Overview
Problem
Tiotropium bromide solvates face instability issues during micronization and shelf life, particularly in pharmaceutical formulations, leading to polymorphic changes when used in inhalable powders or aerosols, with limited data on the stability of solvate formulations.
Innovation Solution
Micronized or milled solvates of tiotropium bromide are stabilized by depositing them in a saturated atmosphere of the adequate solvent for a sufficient period, allowing solvent recovery, which enhances their stability and maintains a uniform crystalline modification, especially when combined with lactose.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If solvates of tiotropium bromide are used in inhalable powders or aerosols, then the active ingredient can be delivered by inhalation, but the solvates undergo polymorphic changes during storage and micronization
Solution Approach 1:
The solvate is stabilized by exposure to saturated solvent vapor before formulation and storage. This preliminary action of solvent re-equilibration prevents subsequent polymorphic changes during micronization and shelf life, allowing the solvate to maintain its crystalline structure while being processed into inhalable formulations
Solution Approach 2:
The invention controls the solvent activity and humidity parameters during storage and processing by using saturated solvent vapor environments. This parameter control prevents the solvate from losing its solvent of crystallization and undergoing polymorphic transformation, thereby maintaining stability during micronization and storage in inhalable formulations
2Length of moving object
If solvates are micronized for pharmaceutical formulations, then the active ingredient achieves suitable particle size, but the crystalline modification changes during processing
Solution Approach 1:
Before micronization processing, the solvate is pre-stabilized by exposure to saturated solvent vapor to ensure it is in equilibrium with its solvent of crystallization. This preliminary stabilization prevents polymorphic changes during the mechanical stress of micronization, maintaining crystalline modification consistency while achieving the required particle size reduction
Solution Approach 2:
The solvate is pre-treated with saturated solvent vapor to create a protective effect against polymorphic transformation during subsequent processing. This beforehand cushioning ensures that even under the mechanical stress of micronization, the crystalline structure remains stable and does not undergo unwanted modifications
3Duration of action of stationary object
If solvates are stored during shelf life, then the formulation can be used over time, but the solvate converts to other forms with limited stability data
Solution Approach 1:
The solvate is pre-stabilized by exposure to saturated solvent vapor before storage, ensuring it is in thermodynamic equilibrium with its solvent of crystallization. This preliminary action creates a stable state that resists conversion to other forms during shelf life, enabling long-term storage with predictable stability for inhalable formulations
Solution Approach 2:
The solvate is stored in an atmosphere saturated with its own solvent vapor, creating a controlled environment that prevents solvent loss and polymorphic transformation. This inert-like environment maintains the solvate in its stable crystalline form throughout shelf life, enabling reliable long-term storage of inhalable formulations
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 stabilization method significantly improves the polymorphic stability of tiotropium bromide solvates, ensuring they remain unchanged under long-term and accelerated storage conditions, even in the presence of lactose, making them suitable for inhalable pharmaceutical formulations.
Implementation Method 1
deposited in a saturated atmosphere of the adequate solvent for the time period sufficient for recovery of the solvent
Data Source
AI summary
A method for stabilization of micronized or milled solvates of tiotropium bromide, in which the solvates are deposited in a saturated atmosphere of the adequate solvent for the time period sufficient for recovery of the original amount of solvent in the solvate. A stable tiotropium bromide solvate with 1,3-propanediol.