Sodium Hyaluronate Fermentation and Ultrafiltration for Controlled Molecular Weight
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Solution Overview
Problem
Current methods for producing sodium hyaluronate, such as extraction from animal tissues and fermentation, face challenges like contamination, high costs, and inability to control molecular weight, with existing fermentation processes using organic solvents and quaternary ammonium salts leading to inefficiencies and impurities.
Innovation Solution
A process involving large-scale fermentation of Streptococcus equi subsp. zooepidemicus under aerobic conditions using a specific nutrient medium, followed by ultrafiltration, heat treatment, and precipitation with organic solvents to produce high-purity sodium hyaluronate with controlled molecular weight, avoiding animal-derived ingredients and reducing manufacturing time and costs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If extraction from animal tissues is used, then sodium hyaluronate can be obtained, but contamination by degrading enzymes and inflammatory reactions occur
Solution Approach 1:
The invention extracts hyaluronate production from animal tissues and relocates it to a controlled fermentation system using Streptococcus zooepidemicus bacteria. This transfers the production process to a synthetic medium containing no animal-derived ingredients, eliminating contamination by animal enzymes and viruses while maintaining high yields through optimized fermentation conditions
Solution Approach 2:
The fermentation process uses a chemically defined synthetic medium with no animal-derived ingredients, creating an inert environment that prevents contamination by animal enzymes (HAase) and viruses. The controlled aerobic fermentation conditions ensure sterile production free from inflammatory contaminants
2Manufacturing precision
If quaternary ammonium salts are used for purification, then impurities are removed, but lengthy precipitate re-dissolution times and residual salts in the end product occur
Solution Approach 1:
The invention removes quaternary ammonium salts from the purification process entirely. Instead, it uses a multi-step filtration and precipitation system employing inert filtration aids and controlled pH adjustment that achieves high purity without introducing problematic residual chemicals or requiring lengthy re-dissolution steps
Solution Approach 2:
The process uses disposable inert filtration aids and single-use precipitation reagents that are removed completely in subsequent filtration steps, avoiding the need for extensive re-dissolution and purification cycles required by quaternary ammonium salt methods
3Manufacturing precision
If organic solvents and multiple precipitation steps are used, then purification is achieved, but costs associated with purification and waste disposal increase
Solution Approach 1:
The invention optimizes purification by changing physical parameters rather than using extensive chemical treatments. Tangential flow filtration uses controlled pressure and flow rates to separate hyaluronate based on size, while precipitation uses controlled pH and temperature changes rather than multiple organic solvent washes, reducing both cost and waste
Solution Approach 2:
The process replaces chemical purification methods (organic solvent precipitation) with mechanical/physical methods including tangential flow filtration and controlled precipitation. This substitution reduces chemical waste disposal costs while maintaining high purity through physical separation mechanisms
4Productivity
If conventional fermentation processes are used, then sodium hyaluronate is produced, but molecular weight control is limited and polydispersity is high
Solution Approach 1:
The invention performs preliminary molecular weight control during the fermentation process itself by optimizing bacterial growth conditions, nutrient composition, and fermentation parameters. This preliminary control produces hyaluronate with narrower molecular weight distribution directly, reducing the need for post-production fractionation and improving overall manufacturing precision
Solution Approach 2:
The process controls molecular weight by changing fermentation parameters including pH, temperature, aeration rate, and nutrient composition during the fermentation process. These parameter changes direct the bacterial synthesis to produce hyaluronate with specific molecular weights and reduced polydispersity, achieving precision manufacturing through process optimization
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 achieves high yields of highly purified sodium hyaluronate with rapid dissolution, low thermolability, and reproducible molecular weight, ensuring safety, purity, and reduced manufacturing time and costs, while avoiding contamination and inflammatory reactions.
Implementation Method 1
large-scale fermentation of Streptococcus equi subsp. zooepidemicus under aerobic conditions
Implementation Method 2
subsequent separation of the bacteria from the resulting culture broth, and isolation of sodium hyaluronate from the culture broth
Implementation Method 3
followed by ultrafiltration, heat treatment, and precipitation with organic solvents to produce high-purity sodium hyaluronate with controlled molecular weight
Implementation Method 4
followed by ultrafiltration, heat treatment, and precipitation with organic solvents to produce high-purity sodium hyaluronate
Data Source
AI summary
Disclosed is a process for the production of sodium hyaluronate with a molecular weight of between 60 and 2400 kDa and low polydispersity (1.4 Mw/Mn), which comprises: a) a step of fermentation of Streptococcus equi subsp. Zooepidemicus CNCM 1-4645 in a suitable culture medium; b) a step of ultrafiltration of the cell-free filtered solution; by concentrating and diafiltering the solution under differential pressure conditions (ΔP) of 1.0-5.0 bar(g) and transmembrane pressure (TMP) of 0.5-4 bar(g).