Oil-in-Water Emulsion Droplet Size Control

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Solution Overview

Problem

Existing methods for producing oil-in-water emulsions, such as MF59, face challenges in achieving uniform droplet size and stability, leading to emulsion degradation due to larger oil droplets acting as nucleation sites during storage.

Innovation Solution

A method involving multiple passes through a homogenizer and microfluidization devices, followed by filtration through a hydrophilic polyethersulfone membrane, to reduce the average oil droplet size and significantly decrease the number of droplets larger than 1.2 μm, enhancing emulsion stability and filtration performance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If high-speed mixing is used to form a coarse emulsion, then the emulsion can be produced quickly, but the oil droplet size distribution becomes wide with larger droplets present

Engineering Contradiction:

Improveemulsion production speedVSAvoidoil droplet size uniformity

Core Design Contradiction:

ProductivityVSManufacturing precision

Solution Approach 1:

The emulsification process is segmented into multiple stages: initial high-speed mixing to form coarse emulsion, followed by sequential microfluidization passes to progressively reduce droplet size. This segmentation allows each stage to optimize for its specific function, achieving both productivity and precision.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The preliminary high-speed mixing creates a coarse emulsion that serves as the starting material for subsequent microfluidization. This preliminary action prepares the emulsion for more refined processing, enabling the final uniform droplet size distribution.

Inventive Principle:

Principle #10Preliminary action

2Stability of the object's composition

If the emulsion is filtered through a 0.22 μm membrane to remove large droplets, then emulsion stability improves, but the manufacturing process becomes more complex

Engineering Contradiction:

Improveemulsion stabilityVSAvoidfiltration process complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

Microfluidization is performed as a preliminary action before filtration to pre-remove large droplets and reduce the burden on the filtration step. This preliminary microfluidization reduces the number of large droplets that would otherwise require filtration, simplifying the overall process while maintaining stability.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The mechanical filtration process is partially replaced by the microfluidization process, which uses controlled shear forces to break down large droplets. This substitution reduces reliance on complex filtration systems while achieving similar stability outcomes.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Manufacturing precision

If multiple microfluidization passes are used to reduce large droplets, then droplet size uniformity improves, but the processing time increases

Engineering Contradiction:

Improvedroplet size uniformityVSAvoidprocessing time

Core Design Contradiction:

Manufacturing precisionVSLoss of time

Solution Approach 1:

The microfluidization process is segmented into multiple passes, with each pass targeting specific droplet size ranges. This segmentation allows efficient progression from coarse to fine emulsion without excessive time investment in any single pass.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The microfluidization passes are performed in continuous sequence without interruption, maintaining the useful action of droplet size reduction throughout. This continuous processing minimizes idle time while achieving the desired droplet size uniformity.

Inventive Principle:

Principle #20Continuity of useful action

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 method results in a stable oil-in-water emulsion with a reduced number of large droplets, improving filtration efficiency and maintaining emulsion stability over time, suitable for use as a vaccine adjuvant.

Implementation Method 1

formation of a first emulsion having a first average oil droplet size using a homogenizer, wherein the first emulsion is formed by circulating the first emulsion components through a homogenizer a plurality of times

Methodology Applied

Scientific EffectMechanical shearing: Shear Stress

Implementation Method 2

microfluidization of a first emulsion having a first average oil droplet size to form a second emulsion having a second average oil droplet size which is less than the first average oil droplet size

Methodology Applied

Scientific EffectHydrodynamic cavitation: Hydrodynamic Cavitation

Implementation Method 3

microfluidization of a first emulsion having a first average oil droplet size to form a second emulsion having a second average oil droplet size which is less than the first average oil droplet size

Methodology Applied

Scientific EffectShear stress: Shear Stress

Implementation Method 4

filtration through a hydrophilic polyethersulfone membrane, to reduce the average oil droplet size and significantly decrease the number of droplets larger than 1.2 μm

Methodology Applied

Scientific EffectSize exclusion filtration: Filter (physical)

Data Source

PatentUSRE46906E1Methods for producing vaccine adjuvants

Publication Date: 2018.06.26 NOVARTIS AG

AI summary

An improved method for the manufacture of an oil-in-water emulsion involves three procedures: (i) preparation of a preliminary emulsion; (ii) microfluidization of the preliminary emulsion to reduce its droplet size; and (iii) filtration of the microfluidized emulsion through a hydrophilic membrane.