(665f) Evaluation of Recovery Pathways for Improved Bioavailability of Clofazimine Nanoparticles

Clofazimine is an anti-mycobacterial agent used as part of a multidrug treatment for leprosy for over four decades. Recently clofazimine has shown promising activity against multidrug resistant tuberculosis. Due to its extremely poor aqueous solubility and high lipophilicity, the formulation development has focused on the solubility enhancement. Nanoparticles enhance bioavailability by two mechanisms. First, relative to larger drug crystals, nanoparticles have higher surface-to-volume ratios, which enhances dissolution rates. Second, rapid nanoparticle precipitation can trap drug molecules in higher energy, amorphous states, which have higher solubility. Here we use Flash Nanoprecipication (FNP) to form clofazimine-loaded nanoparticles with hypromellose acetate succinate (HPMC-AS) as polymer stabilizers, and investigate how to recover the clofazimine-loaded nanoparticles from the aqueous dispersions. Dry nanoparticle powders that can be readily reconstituted would enable delivery of drug dispersions to children and infants. Three approaches were used to produce dry powders: direct salt precipitation, spray drying and lyophilization. The yield efficiency, particle morphology, drug loading, dissolution rate and the amorphous/crystalline state of clofazimine in the dry powders are determined and compared among the processes. Based on these results, we evaluate the advantages and disadvantages of each process regarding the maintenance of the bioavailability after drying.