[jeffmoonchop]

Hi all, my work has moved from crystal growth to lipid nanoparticles. In the case of crystals I know Ostwald's ripening is heavily controlled by supersaturation. This is easily explained for compounds with a clear metastable band width.

My question is would similar principles apply for lipids? Lipids self assemble in a similar way to crystalizable compounds, except they are amorphous so is often more of a rapid process.

For example, a phospholipid dissolved in ethanol self assembles into micelles rapidly when mixed with water. Would the final particle size of the micelles depend on the supersaturation of the lipid, and could control be obtained by reducing the supersaturation in order to slow down self assembly, and cause Ostwalds ripening to increase the final particle size?

Lipids are often highly insoluble in water, are there ways to further reduce particle size? Rapid mixing may cause smaller particles reducing the solubility gradient causing immediate labililty and self assembly. Any other methods?

I often make suggestions to my boss comparing crystallization to self assembly but he seems to think they are different.

[wildfyr]

The thing with lipids micelles is that their size and concentration is controlled by concentration directly. I've never really thought of the time component. For instance, you get NO particles below the critical micele concentration.

In my mind, ostwald ripening is driven by the desire of particles to reduce the energy of the system by lowering the total surface area. So the ripening is really when things run into each other and clump.

Do your lipid nanoparticles behave this way? I've always thought that lipids would would be in an equilibrium with the solution phase handing individual molecules back and forth with the solvent and this is what would drive their size and concentration Behavior.

Really interesting question though! And without any actual research I could be wrong.

[jeffmoonchop]

Thanks for the reply. The lipid nanoparticles contain a PEG-lipid component which prevents agglomeration AFTER the particles have been formed, or after mixing with the aqueous phase.

But DURING the particle formation stage, which is extremely rapid (<0.1sec), we are finding that the final particle size varies depending on certain characteristics of the buffers used. So in my crystal growth trained mind changing the buffer to increase particle size must be causing lipid solubility to increase, and as such reduce supersaturation which allows more time for ripening hence larger particles. The opposite must also be true.

For example, we find that adding salt during formation increases particle size, but maybe then some type of ionic interactions are causing a slow down of formation, or an increase in solubility of the lipids.

[wildfyr]

See, I think the buffer is just increasing or decreasing solubility of free lipid. The less soluble the free lipid is, the bigger the particles.

Doesn't Ostwald ripening usually significant periods of time? Minutes, hours, days, years? Key wordL "ripen." That really implies time elapsing. You say things are basically set within 0.1 seconds. That is much too fast in my mind for Ostwald ripening. At that time scale, its just the particle size that forms under that condition.

[jeffmoonchop]

The rate of formation would depend on the solubility of the solute. So in the case of lipids the solubility is so low in water that formation rate is much faster than say citric acid. I agree normally we would consider ripening to be long term, but when the kinetics are so rapid, who's to say the ripening doesn't happen to some extent in small time periods.

In my mind, I want to know why the less soluble the free lipid is, the bigger the particles. So as long as the particle hasn't stabilised (preventing growth), or when free lipid is available, free lipid will try to find a larger particle to latch onto. So solubility changes only change the rate of formation, allowing for more (or less) time for this brief ripening to occur, resulting in larger or smaller particles.