ABSTRACT
In general one can distinguish hydrophobic and hydrophilic active ingredients to be released from nanoparticles. In the case of hydrophobic active ingredients solid nanoparticles can be used (as opposed to nanocapsules). If one applies such a loaded system in aqueous media the driving force for the active ingredient to diffuse out of the particle is limited, especially if the polymer is rigid or even crosslinked. In the case of hydrophilic active ingredients at first instance using a nanocapsule or nanogel seems logical. However, if the concentration of the hydrophilic active ingredient is high inside the nanocapsule there is a strong tendency for water to go in (osmotic pressure). So for the nanocapsule not to be blown up and burst, osmotic pressure matching in the final formulation is needed. In general the diffusion of water through a wall of a nanocapsule is fast and even leakage of bigger active ingredients over a period of months or years from (responsive) nanocapsules is difficult
to prevent. One of the reasons is that responsive polymer walls of nanocapsules are usually not highly crosslinked because else they would lose their responsiveness. First diffusion through polymeric walls will be discussed and then it will become clear that nanobottles as a new concept might be useful. 6.1 Diffusion of Water and Active Ingredients
through a Polymeric WallTo protect water-sensitive compounds often one likes to resort to the nanoencapsulation of these compounds. There are two factors to be taken into account. First of all there is the thermodynamic driving force toward an equilibrium water concentration in the close vicinity of the water-sensitive (hydrophilic) compound. Second there is the rate of water diffusion through the nanomembrane. The two factors combined result in a certain efficacy to protect the water-sensitive compound. For a polymer nanolayer to completely keep water molecules out kinetically is very difficult. Encapsulation of a hydrophilic water-sensitive compound to protect is from a reaction with water, for example, with a 10 nm thick polystyrene layer, theoretically cannot work. With a diffusion coefficient (D) of 10-15 m2/s (value for a water molecule) the rate of diffusion through a normal polymer layer of 10 nm (x1) is about 0.1 sec. The Fourier number for a flat disk:
Fo D t
x
t t= ¥ Æ = ¥
¥ Æ =
10 10
0 1
( )
. sec (6.1)
With Fo = 1 there is almost complete concentration levelling on both sides of the 10 nm layer within this 0.1 sec. Even for bigger molecules such a polymer layer cannot keep that inside a nanocapsule for a long time. For a molar mass of 1000 Da the diffusion coefficient is about a factor of 10 lower than for water. So in this case the other side of the wall is reached within 1 sec. More impermeable polymer layers are the ones with high degrees of crosslinking or crystallinity or containing certain inorganic compounds like clay materials. The diffusion coefficients
can drop by a factor of 100. But for the same layer thickness of 10 nm this still means that water gets through in 10 sec! However, such layers, at thicknesses of several micrometers can slow down water diffusion to days or months and a highly crosslinked polymer layer can be effective in keeping bigger active ingredients retained in nanocapsules for a considerable amount of time. In summary, keeping water away kinetically from a hydrophilic active ingredient inside a nanocapsule is almost impossible. But what about the thermodynamics? The rate of reaction of the sensitive molecule with a water molecule depends on the concentration. Strongly lowering the equilibrium concentration of water close to the sensitive compound is a much better approach. In case of a water-sensitive hydrophilic compound, making the molecule itself more hydrophobic or embedding it in a hydrophobic polymer will lead to much better results. 6.2 The Concept of the NanobottleSo in Section 6.1 it has been made clear that leakage of the smaller active ingredient from nanocapsules is difficult to prevent over long periods of time. The slowest leakage would occur for highly crosslinked, crystalline, or hybrid polymer layers (e.g., polymer with oriented clay inside). It is difficult to combine low leakage of a nanocapsule and fast responsive release (through at most a slightly crosslinked responsive polymeric wall). In general nanocapsule walls are uniformous but it would be interesting to make part of the wall highly impermeable (most likely highly crosslinked) and another small part of the wall responsive (most likely hardly crosslinked). To achieve this, the design of a nanobottle would be interesting (Fig. 6.1). So the wall of the nanobottle (the container) is highly impermeable but the lid is responsive. In this way leakage of the active ingredient is minimized. Another advantage is that the size of the total structure is changing much less than in the case of a nanocapsule completely constructed out of responsive polymer. The size of the nanoparticles is also important for targeting certain tissue in the human body (Chapter 7 and Part II of this book).
