Sequential Flash Nanoprecipitation for High-Loading Nanoparticles
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Solution Overview
Problem
Existing methods for encapsulating hydrophobic agents or hydrophobic ion-pair agents in nanoparticles struggle to achieve loadings greater than 10%, and recent technologies using metal-organic frameworks (MOFs) only reach up to 35% core loading, necessitating improved methods for higher encapsulation efficiency.
Innovation Solution
A two-step process involving sequential mixing in confined chambers, where the nanoparticle core material nucleates in the first chamber and the stabilizing amphiphilic stabilizer is applied in the second chamber, with a delay time between 10 ms to 10,000 ms, to form smaller nanoparticles with higher loadings.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If a single confined, continuous mixing chamber is used for nanoparticle formation, then the process is simple and continuous, but the core loading is limited to less than 10% (or up to 35% with MOFs)
Solution Approach 1:
The single mixing chamber is segmented into two sequential mixing chambers. The first chamber performs initial mixing and nanoparticle nucleation, while the second chamber performs stabilization. This segmentation allows each chamber to be optimized for its specific function, enabling high core loading (up to 95% w/w) while maintaining continuous operation.
Solution Approach 2:
The first mixing chamber performs preliminary mixing and nanoparticle formation before the second chamber applies stabilization. By separating the nucleation and stabilization steps in sequence, the system achieves high core loading because the stabilizer is applied after the core is already formed, rather than being present from the beginning which would limit loading capacity.
2Quantity of substance
If stabilizer is present from the beginning of mixing, then nanoparticle stability is maintained, but core loading is limited to less than 10%
Solution Approach 1:
The stabilizer is applied in the second mixing chamber after the nanoparticle core has already nucleated and formed in the first chamber. This preliminary formation of the core without stabilizer interference allows maximum core loading (up to 95% w/w), while the subsequent stabilizer application ensures nanoparticle stability is maintained.
Solution Approach 2:
The two mixing chambers are connected in series with continuous flow, ensuring that the nanoparticle core formed in the first chamber continuously receives stabilizer in the second chamber. This continuous sequential action maintains both high core loading and nanoparticle stability without interruption.
3Productivity
If nanoparticle size is reduced for better delivery, then delivery efficiency improves, but achieving small particles at high loading requires complex processes
Solution Approach 1:
The process segments nanoparticle formation into two distinct stages: nucleation in the first chamber and stabilization in the second chamber. This segmentation enables production of small nanoparticles (improving delivery efficiency) at high core loading (up to 95% w/w) through a systematic two-step process that is simpler than alternative approaches.
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 method achieves nanoparticle core loadings of up to 95% w/w, maintaining particle size stability over 48 hours in aqueous solution and up to 9 months, enhancing drug delivery efficiency and imaging sensitivity.
Implementation Method 1
In the first mixing chamber, the nanoparticle core material nucleates and forms the nanoparticle core
Implementation Method 2
continuously mixing the first process solution with a more polar antisolvent stream to form a mixed solution
Implementation Method 3
In the second mixing chamber, the stabilizing amphiphilic stabilizer is applied
Data Source
AI summary
From diagnostic imaging to drug delivery, nanoparticles have found a tremendous variety of uses across fields. Often, when designing these nanoscale constructs, the two most important criteria are particle size and core loading. For example, small particles below 100 nm can have many advantages for drug delivery—including improved specificity to tumors through the enhanced permeability and retention (EPR) effect. Likewise, higher loading nanoparticles translate very well to more effective drug delivery and cancer imaging—allowing for lower dosage and reduced costs. Traditional formulations of nanoparticles using drug absorption or precipitation methods generally struggle to obtain >50% loading. Disclosed herein is a precipitation process allowing for production of stable particles at very high core loading by taking advantage of different time scales while maintaining biologically relevant sizes. New mixing designs allow for the separation of the precipitation and stabilization steps to generate these high loading nanoparticles.