Selecting Counterions to Improve Ionized Hydrophilic Drug Encapsulation in Polymeric Nanoparticles

Area of Science:

• Materials Science
• Pharmaceutical Sciences
• Chemical Engineering

Background:

• Hydrophobic ion pairing (HIP) enhances drug loading and controls release kinetics for hydrophilic drugs, but polymeric nanoparticle (PNP) formulation is challenging.
• Current PNP development relies on laborious and costly trial-and-error experimentation to achieve target product profiles.
• Understanding counterion-drug-polymer interactions is crucial for efficient PNP formulation of HIP systems.

Purpose of the Study:

• To design and validate a preformulation framework to accelerate PNP formulation development for HIP systems.
• To investigate counterion-drug interactions and their impact on drug loading and nanoparticle properties.
• To establish a generalizable method for identifying optimal counterions for hydrophilic drug PNP formulations.

Main Methods:

• Solid-state screening, computational modeling, and solubility studies in PNP-forming emulsions were employed.
• Hydrophobic ion pairing interactions between AZD2811 (hydrophilic drug) and various counterions (cyclic and linear) were investigated.
• Characterization of ion pair properties, including glass transition temperature (Tg), drug loading, and phase behavior within a polymer matrix.

Main Results:

• Cyclic counterions, specifically pamoic acid, formed amorphous ion pairs with AZD2811, exhibiting high Tg (162 °C) and drug loading (22%).
• These amorphous ion pairs formed stable, phase-separated nanosized domains within the polymer matrix.
• Linear counterions like palmitic acid showed minimal interaction, resulting in significantly lower drug loading despite similar physicochemical properties.

Conclusions:

• The developed preformulation framework effectively predicts and accelerates the selection of optimal counterions for HIP-based PNP formulations.
• Cyclic counterions facilitate stronger interactions with hydrophilic drugs, leading to enhanced drug loading and stable nanoparticle formation.
• This approach reduces the need for extensive experimentation, streamlining the development of advanced drug delivery systems.