I am preparing chitosan–TPP nanoparticles for drug delivery with ionic gelatination. My current formulation uses 0.05% chitosan in 1% acetic acid (2.5 mg chitosan in 5 mL; 0.5 mg/mL). The TPP stock is 2 mg/mL, and I work at a chitosan:TPP weight ratio of 2.5:1.
When I adjust the pH of chitosan to ≥ 4.2 and then load the drug, the pH shifts again and precipitation often occurs. The same problem appears when I transfer the nanoparticles into an alginate solution—aggregation or precipitation is observed.
I have also noticed:
Using PBS with TPP sometimes leads to aggregation. When I remove PBS from the TPP preparation, no visible nanoparticle formation occurs (clear solution) and zeta potential measurements are low. I want more than 30 at least for chitosan:tpp.
Has anyone encountered similar stability issues with chitosan–TPP nanoparticles during drug loading or alginate encapsulation?
How can I maintain particle stability at lower pH without compromising drug loading?
Should TPP always be prepared in PBS, or would deionized water be better? And why with out PBS I can't see any nanoparticles formation.
How can I increase zeta potential to improve stability?
Any advice or protocols to prevent precipitation in this context would be greatly appreciated.
Thanks.
Prevent chitosan–TPP nanoparticle aggregation by optimizing chitosan:TPP ratio, using deionized water (not PBS) for TPP, and maintaining pH around 4.0–4.2. Increase zeta potential and stability by balancing ionic crosslinking and avoiding excess TPP or salts.
The formation of stable chitosan-tripolyphosphate (CS-TPP) nanoparticles for drug delivery applications requires careful optimization of preparation conditions to prevent aggregation and precipitation, particularly during drug loading and subsequent alginate encapsulation. The stability challenges primarily arise from electrostatic interactions, pH sensitivity, and crosslinking density variations. To address these issues, a multi-faceted approach focusing on nanoparticle formation, drug incorporation, and encapsulation techniques is essential.
For optimal CS-TPP nanoparticle formation, key parameters must be controlled. Using chitosan with a medium molecular weight (50-300 kDa) and high deacetylation degree (>75%) improves solubility and cationic charge density. The ionic gelation process should employ a carefully optimized CS:TPP mass ratio (typically 3:1 to 5:1), with TPP added dropwise under constant stirring to prevent localized over-crosslinking. Maintaining the pH between 4.5-6.0 using dilute acetic acid (0.1-1% v/v) ensures proper chitosan solubility while allowing effective TPP crosslinking. Incorporating stabilizers like poloxamers (Pluronic F68), Tween 80, or PEG during nanoparticle formation can significantly reduce surface tension and prevent particle aggregation.
Drug loading presents additional stability challenges that can be addressed through strategic approaches. For hydrophobic drugs, pre-loading during nanoparticle formation is preferable, using minimal organic solvents (ethanol/water mixtures
Other buffer or salinity conditions might be considered to keep a certain pH or ionic screening.
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