Abstract In recent years, polyester polymers such as poly(lactic acid) (PLA) have been extensively studied for drug delivery systems due to their biocompatible, biodegradable, and nontoxic pharmacological properties. Moreover, dithiocarbazate Schiff bases containing sulfur‐nitrogen donor atoms are interesting in the context of coordination chemistry and pharmacological applications. The aim of the present study was to optimize the encapsulation of 1‐(S‐benzyldithiocarbazate)‐3‐methyl‐5‐phenyl‐pyrazole (DTC) into PLA nanoparticles (NPs) by using a simplex‐centroid design to investigate the effect of mixture component ratios on the response. The effect of NP composition (PLA, DTC, and PVA surfactant) on two dependent responses (polydispersity index PDI and size distribution) was studied. The mathematical models established were well‐fitted to the experimental data, and their response surfaces allowed the PDI (0.09 ± 0.01) and size distribution (119 ± 3 nm) to be predicted. Afterwards, the optimized DTC‐loaded PLA NPs were prepared and lyophilized. Univariate analysis was used to study the effects of a cryoprotectant, sample dilution, and pH on the colloidal stability of the NPs. The developed NPs exhibited good colloidal stability with adequate mean size (123 ± 9 nm), monomodal size distribution (PDI = 0.10 ± 0.01), and high‐anionic zeta potential (−39.5 ± 3.3 mV). The encapsulation efficiency and drug loading were 29 and 2, respectively. The use of sucrose as a cryoprotectant is necessary to stabilize the NPs during the lyophilization process and maintain their spherical shape. The pH medium of NPs (5.0, 7.0, or 9.0) did not exhibit significant changes in the analytical response, while highly diluted NP samples (100‐fold) might affect their colloidal stability. Finally, this multivariate optimization allowed for the preparation of colloidally stable NPs with narrow size distribution.
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