DIOP_GONZALEZ_Marco_thesis.pdf

Abstract

Flash NanoPrecipitation (FNP) is a useful technique for enhancing the bioavailability and dissolution of poorly soluble antimalarial drugs. Combined with spray drying processes, FNP has great promise as a cost-effective, scalable method of producing affordable drugs for global health applications. However, since it involves drying large volumes of dilute nanoparticle suspensions, this nanofabrication and spray drying process takes a long time. This limitation could hinder the implementation of FNP on an industrial level. Therefore, finding ways of concentrating nanoparticles and reducing the volume of liquid in the nanoparticle suspensions will significantly reduce the time required to dry the liquid suspension of nanoparticles.

This work investigated acid flocculation as a potential method of concentrating nanoparticles prior to the drying process. Through FNP and dialysis, dialyzed and non-dialyzed suspensions of hydroxypropyl methylcellulose acetate succinate (HPMCAS) stabilized lumefantrine nanoparticles were formed with particle sizes ranging from 95nm - 160nm. After reducing the pH of the suspensions using acidic solutions, the nanoparticles aggregated into larger clusters. Nanoparticles in dialyzed suspensions had superior stability to nanoparticles in non-dialyzed suspensions. The presence of organic solvents in the liquid suspensions also inhibited particle flocculation.

In this study, we demonstrated that the flocculation process was reversible by adding basic solutions to the flocculated nanoparticles. This made it possible to compare the dissolution kinetics of spray dried and oven dried samples of the larger nanoparticle aggregates. The spray dried powders reached 90% release after three hours and maintained a release over 90% for six hours under simulated gastrointestinal conditions. The oven dried nanoparticles only reached 31% release after three hours and achieved a maximum release of 56% under the same conditions. Thus, spray drying the flocculated nanoparticles provided better drug release than oven drying the nanoparticles. Additionally, we established that the flocculation of nanoparticles exhibits diffusion-limited aggregation. Most significantly, the findings of this work reveal a potential method of continuously producing, concentrating, and drying nanoparticle formulations of lumefantrine that could enhance the effectiveness of antimalarial treatments.