Selecting Counterions to Improve Ionized Hydrophilic Drug Encapsulation in Polymeric Nanoparticles

Abstract

Hydrophobic ion pairing (HIP) can successfully increase the drug loading and control the release kinetics of ionizable hydrophilic drugs, addressing challenges that prevent these molecules from reaching the clinic. Nevertheless, polymeric nanoparticle (PNP) formulation development requires trial-and-error experimentation to meet the target product profile, which is laborious and costly. Herein, we design a preformulation framework (solid-state screening, computational approach, and solubility in PNP-forming emulsion) to understand counterion–drug–polymer interactions and accelerate the PNP formulation development for HIP systems. The HIP interactions between a small hydrophilic molecule, AZD2811, and counterions with different molecular structures were investigated. Cyclic counterions formed amorphous ion pairs with AZD2811; the 0.7 pamoic acid/1.0 AZD2811 complex had the highest glass transition temperature (T g; 162 °C) and the greatest drug loading (22%) and remained as phase-separated amorphous nanosized domains inside the polymer matrix. Palmitic acid (linear counterion) showed negligible interactions with AZD2811 (crystalline-free drug/counterion forms), leading to a significantly lower drug loading despite having similar log P and pK a with pamoic acid. Computational calculations illustrated that cyclic counterions interact more strongly with AZD2811 than linear counterions through dispersive interactions (offset π–π interactions). Solubility data indicated that the pamoic acid/AZD2811 complex has a lower organic phase solubility than AZD2811-free base; hence, it may be expected to precipitate more rapidly in the nanodroplets, thus increasing drug loading. Our work provides a generalizable preformulation framework, complementing traditional performance-indicating parameters, to identify optimal counterions rapidly and accelerate the development of hydrophilic drug PNP formulations while achieving high drug loading without laborious trial-and-error experimentation.

In Vitro Release from Polymeric Core/Shell Nanoparticles through the Lens of Multiscale Modeling

“…This arises from the fact that electrostatic interactions were not explicitly biased, in order to limit the number of collective variables for the sake of computational efficiency; in this scenario, we focused on the enhanced sampling of ring stacking because of its important role in the choice of the hydrophobic counterion as highlighted in a previous work. 16 Transitions between stacked conformations characterized by different electrostatic interactions (determined by the different relative positions of the charged moieties) could be observed in unbiased simulations, suggesting that the energy barrier is low enough so that enhanced sampling is not needed. In this regard, the role of electrostatic interactions can be assessed by reweighting the free energy surface, which allowed obtaining a new FES as a function of ring coordination and the Debye−Huckel (DH) interaction energy (eq 3) as qualitative estimation of electrostatic interactions (Figure 6c).…”

“…In this scenario, the hydrophobic ion pairing strategy was adopted to tune the solubility of the active compound in order to improve encapsulation efficiency and tailor the release rate. 18 The actual attainment of a HIP has been both computationally and experimentally assessed in the solid state 16 and experimentally observed in solution; 18 in more detail, solid-state simulations highlighted the importance of stacking interactions 16 to promote the assembly.…”

“…It is assumed that there is an initial barrier to achieving equilibrium due to the mobility of polymer chains. The shell initially exhibits a rigid glass-like behavior until it reaches the temperature employed for release experiments (37 °C), close to the glass transition temperature of the polymer (45 °C); at this point, polymer chains are assumed to be mobile enough to allow solute partition and its diffusion through the shell. Such a lag time for partition and release is not considered since it can be reasonably assumed that thermal equilibration occurs almost instantaneously given the large specific surface of the nanoparticles.…”

“…Although the core can be in equilibrium with the shell before release onset, the initial amount of the HIP in the polymer can be considered negligible by virtue of its low solubility. 16 Focusing on boundary conditions, at the core/shell interface HIP partitioning between the core and polymer phase occurs (eq 11) and HIP concentration is equal to its solubility in the polymer c sol,pol , while at the shell/medium interface interphase mass transport is accounted for (eq 12):…”

“…15 The amorphous solid core is obtained through hydrophobic ion pairing and contains AZD2811 and pamoic acid, chosen as suitable hydrophobic counterion. 16 In general, hydrophobic ion pairing 17 exploits the interactions between charged hydrophilic molecules and oppositely charged ions with hydrophobic moieties, which result in a less soluble, uncharged complex usually referred to as hydrophobic ion pair (HIP). This strategy was employed since it leads to both a high drug loading and a high encapsulation efficiency when including hydrophilic molecules in nanocarriers.…”