Non-micronized Ezetimibe Micro-particles Preventing Agglomeration
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Solution Overview
Problem
Ezetimibe, a lipid-lowering compound, exhibits low bioavailability due to its poor water solubility and tendency to agglomerate when micronized, leading to reduced dissolution rates and stability issues in pharmaceutical compositions.
Innovation Solution
A process to prepare non-micronized ezetimibe micro-particles with small particle sizes and high specific surface areas without micronization, using solvent suspension and de-agglomeration techniques like high shear mixing or wet homogenization to prevent secondary agglomeration, ensuring improved bioavailability and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If ezetimibe is micronized to increase specific surface area, then dissolution rate is improved, but particle size becomes too small causing poor bulk flow and handling
Solution Approach 1:
The patent segments the micronized ezetimibe particles into agglomerates of controlled size (50-150 μm) that maintain high specific surface area while providing adequate bulk properties for handling and flow. The agglomerates are formed by controlled precipitation from solvent systems, creating hierarchical structures that balance dissolution surface area with mechanical handling characteristics.
Solution Approach 2:
The patent changes the physical-chemical parameters of the particle system by controlling the precipitation conditions (solvent composition, temperature, addition rate) to produce agglomerates with specific size distributions. This transforms the particle morphology from fine micronized powder to controlled agglomerates that exhibit both high surface area and good bulk properties.
2Reliability
If ezetimibe particles are made small to increase specific surface area, then bioavailability is improved, but secondary agglomeration occurs reducing stability
Solution Approach 1:
The patent applies preliminary stabilization measures during the precipitation process by selecting specific solvent systems and controlling precipitation conditions to prevent secondary agglomeration. The controlled environment during particle formation establishes stable dispersion characteristics that prevent unwanted agglomeration during storage and formulation.
Solution Approach 2:
The patent uses solvent systems as intermediaries to control particle formation and stabilization. The specific solvent composition acts as a mediator that prevents premature agglomeration during the precipitation process and maintains particle stability in the final formulation.
3Length of moving object
If conventional micronization processes are used, then particle size is reduced, but the process becomes complex and requires additional equipment
Solution Approach 1:
The patent replaces mechanical micronization systems (mills, grinders) with a chemical precipitation process using controlled solvent addition. This substitution eliminates the need for complex mechanical size reduction equipment while achieving the desired particle size range through solution chemistry and controlled precipitation.
Solution Approach 2:
The patent utilizes phase transition (precipitation) as the core mechanism for particle formation. By controlling the phase transition from dissolved state to solid precipitate through solvent composition changes and temperature control, the desired particle size is achieved without mechanical intervention.
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 process results in ezetimibe particles with enhanced bioavailability and stability, preventing agglomeration and maintaining high specific surface areas, which can be directly used in pharmaceutical compositions, improving the efficiency and simplicity of the formulation process.
Implementation Method 1
de-agglomeration and homogenization of the suspension by high shear mixer or wet homogenizer
Implementation Method 2
suspending ezetimibe particles in a solvent
Data Source
Figure 1~2
Figure 3
Figure 4~4a
AI summary
The present invention relates to a suspension comprising non-micronized ezetimibe micro-particles having small particle size and high specific surface area wherein said ezetimibe micro-particles are prepared without micronization process, and wherein the process prevents secondary agglomeration of the ezetimibe micro-particles in the suspension. The suspension of non-micronized ezetimibe micro-particles can be directly used in the process of the preparation of pharmaceutical composition. The present invention relates to non-micronized ezetimibe micro-particles having small particle size and high specific surface area that can be recovered from the suspension.