Gelatin Nanoparticle Size Control via Continuous Flow Mixing
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Solution Overview
Problem
Existing methods for preparing gelatin nanoparticles are difficult to control, leading to broad size distribution and inconsistent release and transport behavior, which is disadvantageous for uniform drug delivery.
Innovation Solution
A continuous process in a reactor with a mixing element, where an aqueous gelatin solution and a water-miscible organic solvent are fed at controlled rates to form a suspension of non-crosslinked gelatin nanoparticles, which are then crosslinked, allowing for controlled nanoparticle size and polydispersity index, and enabling efficient and reproducible production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If batch process with drop by drop addition of organic solvent is used, then nanoparticles can be formed, but the process is difficult to control and leads to broad size distribution
Solution Approach 1:
The patent transitions from batch process to continuous flow process, where reactants are continuously fed through mixing elements and reactors. This continuous action eliminates the difficulty of controlling drop-by-drop addition while maintaining narrow size distribution, as the steady-state flow conditions provide consistent mixing and reaction parameters throughout the process.
Solution Approach 2:
The continuous process divides the nanoparticle formation into distinct stages using separate mixing elements and reactors. The first mixing element creates the initial suspension, followed by a reactor for controlled crosslinking. This segmentation allows each step to be optimized independently, improving size control without increasing overall process complexity.
2Productivity
If continuous flow process is used, then manufacturing efficiency is improved, but control over nanoparticle formation becomes challenging
Solution Approach 1:
The patent uses a first mixing element to pre-mix the gelatin solution and organic solvent before they enter the main reactor. This preliminary mixing ensures that the reactants are properly combined before the crosslinking reaction begins, maintaining size control in the continuous flow process. The pre-formed suspension enters the reactor with consistent properties, enabling efficient production with narrow size distribution.
3Speed
If high concentration of organic solvent is added quickly, then nanoparticle formation is accelerated, but large aggregates are formed instead of nanoparticles
Solution Approach 1:
The continuous flow process dynamically controls the concentration of organic solvent over time through steady flow rates. Instead of sudden addition that causes aggregation, the system maintains a constant, optimized flow rate ratio that allows rapid nanoparticle formation while preventing aggregate formation. The continuous replenishment of reactants ensures consistent nanoparticle size throughout the process.
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 continuous process achieves nanoparticles with a narrow polydispersity index and controlled sizes, providing a reliable and efficient method for producing gelatin-based nanoparticles with high reproducibility and flexibility in process parameters.
Implementation Method 1
A) feeding separately an aqueous gelatin solution at a first rate and a water-miscible organic solvent at a second rate to the process channel of the reactor to be mixed therein, to form a suspension of non-crosslinked gelatin based nanoparticles
Implementation Method 2
the reactor has a mixing efficiency as determined by the Villermaux/Dushman method of between 0.1 and 1.5
Implementation Method 3
B) crosslinking the non-crosslinked gelatin based nanoparticles
Data Source
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AI summary
The present invention relates to a continuous process for the preparation of gelatin based nanoparticles in a reactor comprising a process channel comprising a mixing element therein, the process comprising the following steps: A) feeding separately an aqueous gelatin solution at a first rate and a water-miscible organic solvent at a second rate to the process channel of the reactor to be mixed therein, to form a suspension of non-crosslinked gelatin based nanoparticles and B) crosslinking the non-crosslinked gelatin based nanoparticles, wherein the sum of the first rate and the second rate is chosen such that the reactor has a mixing efficiency as determined by the Villermaux/Dushman method of between 0.1 and 1.5 and the period from the time point at which the aqueous gelatin solution is fed to the reactor to the time point at which the mixture of the aqueous gelatin solution and the organic solvent contacts the mixing element is at most 15 seconds.