Micronised Formoterol Particle Size Control for Inhalation Agglomeration
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Solution Overview
Problem
The formation of agglomerates during the preparation of micronised active ingredients for inhalation leads to non-uniform distribution and dosage accuracy issues in dry powder inhaler formulations, particularly for low-dosage strength active agents, resulting in stability problems and reproducibility challenges.
Innovation Solution
A powder formulation comprising micronised formoterol fumarate dihydrate with specific particle size characteristics, blended with larger carrier particles, to prevent agglomeration and ensure homogeneous dispersion, achieving a relative standard deviation of the active ingredient content of 2.5% or less, and a respirable fraction with a mass median aerodynamic diameter of 1.7 micron or higher.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Length of moving object
If the active ingredient is micronised to achieve respirable particle sizes (0.5-10 μm), then the particles can penetrate into the lower airways, but the cohesion forces increase and favour agglomerate formation
Solution Approach 1:
The patent applies parameter changes by precisely controlling the particle size distribution parameters (d10, d50, d90) and their relationships (ratios and differences) to achieve optimal respirability while minimizing agglomeration. The specific constraints on d(v,0.1), d(v,0.5), d(v,0.9) and their ratios create a parameter window that balances penetration and stability
Solution Approach 2:
The patent implements preliminary action by pre-establishing the correct particle size distribution before blending with the carrier. The active ingredient is micronised to meet specific size criteria before mixing, preventing agglomerate formation during the blending process and ensuring uniform distribution from the outset
2Quantity of substance
If the active ingredient concentration is reduced to achieve low-dosage strength, then the therapeutic potency is optimized, but the uniformity of distribution deteriorates due to agglomerates
Solution Approach 1:
The patent uses parameter changes by defining specific particle size distribution parameters that prevent agglomeration even at low active ingredient concentrations (≤4 mg nominal dose). The controlled d(v,0.1), d(v,0.5), d(v,0.9) values and their relationships ensure that fine particles remain dispersed uniformly in the powder formulation
Solution Approach 2:
The patent replaces mechanical mixing processes with a physically-based solution where particle size distribution physics naturally prevents agglomeration. Instead of relying on mixing intensity or duration, the invention uses the inherent properties of particles within the specified size range to ensure uniform distribution through their interaction with the carrier particles
3Reliability
If finer particles are used to improve deposition in lower airways, then the respirability increases, but the cohesion forces become stronger and favour agglomerate formation
Solution Approach 1:
The patent applies parameter changes by optimizing the particle size distribution parameters to find the optimal balance point. The constraints on d(v,0.1) ≥ 0.8 μm, d(v,0.5) ≥ 1.7 μm, and d(v,0.9) ≤ 10 μm, along with their ratios and differences, create a parameter window where respirability is maximized while cohesion forces are kept manageable
Solution Approach 2:
The patent implements preliminary action by pre-controlling the particle size distribution parameters before the blending process. The active ingredient is processed to meet specific size criteria in advance, ensuring that when mixed with the carrier, the particles have the right characteristics to resist agglomeration while maintaining respirability
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 solution ensures a uniform distribution of the active ingredient, enhances dosage accuracy, and maintains stability and performance of the delivered dose, particularly in medium- or high-resistance multidose dry powder inhaler devices.
Implementation Method 1
the particles of said active ingredient fulfilling the following conditions: i) no more than 10% of the particles have a volume diameter [d(v,0.1)] lower than 0.8 micron; ii) no more than 50% of the particles have a volume diameter [d(v,0.5)] lower than 1.7 micron; and iii) at least 90% of the particles have a volume diameter [d(v,0.9)] lower than 10 micron
Implementation Method 2
said volume diameter being measured by laser diffraction
Data Source
AI summary
The invention relates to micronised particles of a low-dosage strength active ingredient to be used in dry powder formulations for inhalation and methods for preparing them. In particular the invention provides micronised particles of low-dosage strength active ingredients which can easily and homogenously disperse in a dry powder formulation to be administered by means of a dry powder inhaler device. The invention is also directed to the formulations thereof in the form of powders for inhalation.