Zeta potential is affected by ionic strength of the media. Also, more often than not, surface charge of a nanoparticle is manifestation of ionizable functional groups present on the nanoparticle surface. Therefore, pH will also have an effect on the zeta potential of nanoparticles.

As for the selection of dispersing media, one should try to measure zeta potential in low ionic strength medium preferably of monovalent salts such as NaCl. High ionic strength can cause agglomeration of nanoparticles as it effectively shields the surface charge. To start with, you can measure zeta potential in 5-10 mM NaCl solution. Also, make sure that you measure the pH of the suspension before you measure the zeta potential.

Dear Vishesh 

Thanks for your reply. I prepare the nanoparticle for oral formulation as a tablet dosage form. I have some more doubts in it. 

If the nanoparticles which I prepared tends to aggregate in acidic pH will it affect the drug release in acidic pH (stomach environment)? 

Suppose if the nanoparticles have produced stable zeta potential in an acidic pH then is that a proof that we can say it will not affect the drug release in the acidic environment (stomach)?

Is it possible for us to develop a nanoparticle that will not have any problem with zeta potential in both acidic and alkaline pH? 

Hope you understand my query 

Note: I also attached an SOP for Zeta Potential measurement by Zetasizer just for information 

Thanks once again

Low pH might affect release of drug from nanoparticles. Aggregation can be one of the reasons for altered release profile of drug from nanopartices. Another reason can be lower stability of polymer or swelling of polymer at lower pH. To check this you can study the release of drug in simulated gastric fluid. You can check our paper for details on this.

In my opinion, particle stability at lower pH will not mean that drug won't be released from nanoparticles. It only means that nanoparticles will stay as individual particles at lower pH conditions as in case of stomach.

To circumvent effect of pH altogether you can modify the surface of nanoparticles with neutral polymers. Polymers increase the stability of nanoparticles due to stearic hindrance. Polymer stabilized nanoparticles are stable even at high ionic strength.

Always measured it in NaCl 10mM 

Zeta potential depends of the media.. At isoelectric pH it will be 0, at higher pHs negative and lower pHs positive. When charge is 0 tends to the aggregation and when is more charged to repulsion... The Ionic force will screen charges and make electrostatic effects weaker.

We use three different diluents for zeta potential analysis and have found that most samples can be analyzed using them. They are: 1 mM KCl (in case the sample should remain at its native pH), 50 mM Acetate buffer at pH=4 (for samples that require acidic conditions) and 50 mM Ammonia buffer at pH=9. These diluents are filtered over an 0.45 µm filter (to remove dust particles) and stored in a bottle with pumping dispenser on top in order to keep them dust-free.. 

I usually use 3 diluents for zeta potential measurement: KCl buffer, Desionised water and NaOH buffer, to see the variability of zeta potential in those media. If your nanoparticles are used in a biological environment, NaCl was the best diluent for your zeta-potential analysis

Thanks for all your reply

I have a concern 

If we consume the Nanoparticles by oral route these nanoparticles will first reach the stomach where the pH is 1.2 followed by Small Intestine and Large Intestine where the pH slowly increases to 4.5 to 7.8. 

Is it possible for us to develop nanoparticles that have high Zeta Potential in both low acidic pH (1.2 Stomach) and high alkaline pH (7.8 intestine)?

If we want to check the Zeta Potential to correlate with Internal Biological Medium should we want to check it with both acidic (1.2) and alkaline pH (7.8)?

Thanks in advance 

Yes, i always check the zeta potential at a range of pH, with a measurement always around pH 7.4. If your pH meter can go down to pH 1,2 then you can check the zeta potential in acidic conditions. 

I guess it could be possible to develop such NPs if their IEP is around pH 5-6 and they are very stable at acidic and basic pH. I suppose it will depend on the surface groups you have, but this is just a supposition on my part, perhaps others can provide additional information.

You want to have positive charge at a large range of pH. I think that your particle has to have positive charges at the surface that don't loose the charge below 7,4. Maybe aliphatic amines. Just a supposition..

As most important biomolecules are anionic I would not recommend making cationic nanoparticles; they will show strong interaction with all these molecules. For maintaining charge strong acidic surface groups are needed like e.g. sulphate or sulphonate groups, these will remain charged even at low pH values.

Although it can be used to glean insights regarding the surface structure and surface chemistry of particles, zeta potential is not an intrinsic property of a material or particle and is the product of the combined particle-fluid system. For this reason the suspension medium should in general be selected to most closely represent the target application of the particles. This means pH, ionic strength and aqueous/organic nature of the media depend on the application. To inhibit agglomeration also consider adding adsorbates such as citrate or other carboxylates, which seem to be quite effective in facilitating strongly negative zeta potentials across multiple pH ranges.