•Chitosan nanoparticles were prepared using TPP as a cross-linking agent.•A membrane was used for micromixing the TTP and chitosan solutions.•The anti-Alzheimer's drug tacrine was loaded in the chitosan nanoparticles.•Nanoparticles had a mean size of 90–100nm and a polydispersity index of 0.22.•Tacrine encapsulation efficiency was found to equal 66.1%. Chitosan nanoparticles were prepared by a novel technique based on ionic gelation using sodium tripolyphosphate (TPP) as cross-linking agent. In this method, the TPP solution flows through the pores of a microengineered membrane into the chitosan solution put in a stirred cell. It is shown that favorable micromixing conditions are created on top of the membrane surface to form chitosan–TPP nanoparticles. The influence of several formulation parameters (chitosan and TPP concentrations, ratio between volumes of the two solutions, pH of the two solutions, chitosan molecular weight) and process parameters (membrane characteristics, injection speed, stirring rate) were investigated. Under optimum conditions, chitosan–TPP nanoparticles had a mean size around 90–100nm, polydispersity index around 0.22, and zeta potential close to +31mV. The encapsulation of the anti-Alzheimer's drug tacrine did not change the mean size and polydispersity index of unloaded nanoparticles, whereas the zeta potential was increased to +38mV due to the positively charge of tacrine. Under optimum conditions, tacrine encapsulation efficiency into nanoparticles was found equal to 66.1%. In addition, chitosan–TPP nanoparticles were shown to be stable at least during 25 days in an acidic medium at 4 or 25°C. This study demonstrates that ionic gelation using a stirred cell with microengineered membrane is a suitable technique for preparation of chitosan–TPP nanoparticles.