Inhalable Particles via Supercritical Anti-Solvent Precipitation
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Solution Overview
Problem
Current methods for preparing inhalable or insufflable powder formulations of antimuscarinic agents like tolterodine face challenges due to unhelpful crystalline habits and issues with particle size distribution and cohesion, leading to poor aerosolization and handling problems.
Innovation Solution
The use of supercritical anti-solvent (SAS) precipitation to produce particles with a D50 of 4 μm or less and a D90 of 10 μm or less, resulting in more readily inhalable or insufflable particles with improved shape and size distribution, avoiding the issues associated with milling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional crystallisation is used to prepare inhalable powder formulations, then the process is simple, but it produces needle-shaped crystals with unhelpful crystalline habits that cannot be directly prepared in required particle sizes
Solution Approach 1:
The patent changes the physical parameters of the system by using supercritical fluids (supercritical anti-solvent) instead of conventional liquid solvents. This parameter change enables control over particle size distribution while maintaining crystalline structure, resolving the contradiction between process simplicity and particle size control.
Solution Approach 2:
The patent utilizes phase transition of the anti-solvent from supercritical state to gaseous state during the precipitation process. This phase transition enables precise control over particle formation and size distribution, allowing production of particles with D50 ≤ 4 μm and D90 ≤ 10 μm while avoiding needle-shaped crystal formation.
2Manufacturing precision
If milling/micronisation is used to reduce particle size, then respirable particle ranges are achieved, but the material becomes highly charged and cohesive causing severe downstream handling and processing issues
Solution Approach 1:
The patent replaces mechanical milling/micronisation with a chemical-physical process (supercritical anti-solvent precipitation). This substitution eliminates mechanical stress that causes particle charging and cohesion, producing respirable particles (D50 ≤ 4 μm, D90 ≤ 10 μm) that are free-flowing and easy to handle.
Solution Approach 2:
The supercritical anti-solvent acts as an intermediary medium that enables controlled particle formation. It allows precipitation of particles in the required size range without the mechanical violence of milling, thus avoiding particle charging and cohesion issues while maintaining respirable particle dimensions.
3Manufacturing precision
If milling is used to produce fine particles, then particle size is reduced, but irregular shaped and sized particles are produced with bimodal distribution and poor aerosolization
Solution Approach 1:
The patent changes the formation mechanism from mechanical fracture (milling) to controlled precipitation (supercritical anti-solvent). This parameter change results in uniform, regular-shaped particles with monomodal size distribution (D50 ≤ 4 μm, D90 ≤ 10 μm) rather than irregular particles with bimodal distribution, significantly improving aerosolization performance.
4Manufacturing precision
If amorphous hygroscopic domains are formed during milling, then particle size is reduced, but particle recrystallisation and growth occur upon uptake of water
Solution Approach 1:
The patent uses supercritical anti-solvent precipitation to form stable crystalline particles directly in the required size range, avoiding formation of amorphous hygroscopic domains. The crystalline structure produced is stable and does not undergo recrystallisation or growth upon water uptake, resolving the stability issue associated with milled particles.
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
This approach enables the production of fine, free-flowing powders with a narrow particle size distribution, facilitating rapid aerosolization and improved clinical outcomes by reducing the required dose and enabling rapid onset of action.
Implementation Method 1
contacting a stream of anti-solvent with a stream of solution of antimuscarinic agent to form particles of antimuscarinic agent
Implementation Method 2
to precipitate particles of antimuscarinic agent
Data Source
AI summary
A powder formulation, or pharmaceutical composition comprising or consisting of particles of an antimuscarinic agent, said particles being obtainable by supercritical anti-solvent (SAS) precipitation and having a D50 of 4 μm or less and a D90 of 10 μm or less. Methods of forming the formulation and composition are also disclosed, as are uses of the composition.