The
physical properties of nanoparticles may affect the uptake
mechanism, biodistribution, stability, and other physicochemical properties
of drug delivery systems. This study aimed to first develop a model
exploring the factors controlling the nanogel physical properties
using a single drug (propranolol), followed by an evaluation of whether
these models can be applied more generally to a range of drugs. Size,
polydispersity, ζ potential, and encapsulation efficiency were
investigated using a design of experiment (DOE) approach to optimize
formulations by systematically identifying the effects of, and interactions
between, parameters associated with nanogel formulation and drug loading.
Three formulation factors were selected, namely, chitosan concentration,
the ratio between the chitosan and cross-linker—sodium triphosphate—and
the ratio between the chitosan and drug. The results indicate that
the DOE approach can be used not only to model but also to predict
the size and polydispersity index (PDI). To explore the application
of these prediction models with other drugs and to identify the relationship
between the drug structure and nanogel properties, nanogels loaded
with 12 structurally distinct drugs and 6 structurally similar drugs
were fabricated at the optimal condition for propranolol in the model.
The measured size, PDI, and ζ potential of the nanogels could
not be modeled using distinct DOE parameters for dissimilar drugs,
indicating that each drug requires a separate analysis. Nevertheless,
for drugs with structural similarities, various linear and nonlinear
trends were observed in the size, PDI, and ζ potential of nanogels
against selected molecular descriptors, indicating that there are
indeed relationships between the drug molecular structure and the
performance outcomes, which may be modeled and predicted using the
DOE approach. In conclusion, the study demonstrates that DOE models
can be applied to model and predict the influence of formulation and
drug loading on key performance parameters. While distinct models
are required for structurally unrelated drugs, it was possible to
establish correlations for the drug series investigated, which were
based on polarity, hydrophobicity, and polarizability, thereby elucidating
the importance of the interactions between the drug and the nanogels
based on the nanogel properties and thus deepening the understanding
of the drug-loading mechanisms in nanogels.
