Processing and Scale-up of Polymeric Nanoparticles - Intracellular Delivery: Fundamentals and Applications - page 444

3.1 Pilot-Scale Production of Nanoparticles

by Emulsification-Solvent Diffusion Method

Large scale production of nanocapsules by emulsification-solvent diffusion method
was developed up to a production of batches of 15 L each (Colombo et al. 2001 ;
Galindo-Rodriguez et al. 2005 ). The pilot set up comprises several vessels for the
preparation of the different solutions which are connected through a system of flex-
ible tubing to a main reactor. Transfer of solutions from the vessels to the reactor
occurred by simple gravity. The rational behind this design was to reproduce as
much as possible fluid motions produced in the laboratory scale set up (60 mL)
(Galindo-Rodriguez et al. 2005 ). By introducing a few modifications, this pilot set
up can be used for the production of nanoparticles by the emulsification-reverse
salting out method (Galindo-Rodriguez et al. 2005 ).
In both cases, agitation is an important process parameter to consider during the
preparation of the emulsion (Colombo et al. 2001 ). It greatly influences the size of
the nanoparticles produced at the end of the procedure. Optimal conditions of agita-
tion were found by using stirring rates above 1,000 rpm for the emulsification-
solvent diffusion method and 790 rpm for the emulsification-reverse salting-out
method. By applying the optimal conditions, the methods are reproducible and
provide with nanoparticle dispersions with a narrow size distribution (Galindo-
Rodriguez et al. 2005 ).

3.2 Pilot-Scale Production of Nanoparticles by a One Step

Procedure Based on the Nanoprecipitation of a Polymer

Success of the nanoprecipitation method resides on the way the organic and the
aqueous phases mix together resulting in the precipitation of the polymer as nano-
particles. Progresses in the comprehension of nanoprecipitation phenomena high-
lighted that it is controlled by a few key parameters. It was established that the time
of mixing must be faster than the time required to induce nanoparticle formation
(Johnson and Prud'homme 2003 ). Ideal conditions are obtained at the beginning of
the mixing of the two phases. In conditions found in the lab scale production, the
amounts of organic solution of polymer and that of the non-solvent are small. Ideal
conditions of nanoprecipitation are fulfilled at the beginning of the mixing and are
almost maintained during mixing of the total amounts of solutions used to produce
small batch of nanoparticles in small reactors (lab scale production of a few mL).
However, production of large batches of nanoparticles by nanoprecipitation in a
reactor is not suitable as the conditions for nanoprecipitation change from the
beginning to the end of the two phases mixing. To maintain a homogenous condi-
tion for nanoprecipitation along mixing time, the two phases need to be brought
together in the same conditions all along the process. Briançon et al. ( 1999 ) have
suggested to inject the two phases in a mixing device which is continuously feed at