Rapid micromixing technologies have emerged as versatile platforms for the controlled production of nanocarriers through nanoprecipitation, enabling improved control over nucleation and particle growth compared with conventional bulk mixing approaches [1,2]. During nanoprecipitation, rapid mixing between solvent and non-solvent induces solute supersaturation, leading to nucleation followed by particle growth or aggregation, which determine the final nanoparticle characteristics [1]. Among these strategies, impinging jet mixing (IJM) is based on the high-velocity collision of liquid streams within a confined chamber, generating rapid solvent exchange and supersaturation that promote near-instantaneous nanoparticle nucleation and the formation of homogeneous nanostructures [2]. Due to its very short mixing time, IJM has been increasingly explored as a scalable strategy for producing nanoparticles with controlled size distribution in drug delivery systems [3]. Although IJM differs from conventional microfluidic systems, both approaches rely on precise control of mixing dynamics to regulate supersaturation and nanoparticle nucleation during nanoprecipitation [2]. In oral drug delivery, enteric methacrylate copolymers are important pH-responsive materials widely used in formulations designed to remain stable under gastric conditions and dissolve at intestinal pH, enabling site-specific release in the gastrointestinal tract [4]. Commercial enteric copolymers such as Eudragit® (Evonik) and Kollicoat® (BASF) are widely used in oral delivery systems due to their pH-dependent solubility and suitability for delayed intestinal release formulations [5]. In this study, the objective was to evaluate the formation of polymeric nanoparticles based on enteric methacrylate copolymers using a rapid micromixing nanoprecipitation approach based on impinging jet mixing, employing a systematic formulation design to identify optimal conditions for the future nanoencapsulation of bioactive compounds intended for oral intestinal delivery. Nanoparticles were produced using Impinging Jet Micromixing system (Helix Biotech) operating at a flow rate ratio (FRR) of 1:3 (v/v) and total flow rate (TFR) of 3 mL/min. The organic phase consisted of Eudragit® S100 or Kollicoat® MAE 100P (10 mg/mL) dissolved in different solvents, including ethanol, acetone, and an ethanol:acetone mixture (1:1 v/v). The aqueous phase was composed of water or acetate buffer, combined with non-ionic amphiphilic stabilizers, specifically Kolliphor® EL (BASF) or Pluronic® F68 (BASF) at a concentration of 0.5% (w/v). The resulting nanosystems were characterized by dynamic light scattering (DLS) to determine size (nm), polydispersity index (PDI) and zeta potential (mV). The results demonstrated that nanoparticle formation strongly depended on the composition of both organic and aqueous phases. Formulations prepared in the presence of non-ionic surfactant stabilizers showed significantly improved colloidal properties, yielding nanoparticles in the nanometric size range with homogeneous size distribution (PDI ≤ 0.3) and negative zeta potential values around −30 mV prior to active compound incorporation. Overall, the rapid micromixing nanoprecipitation strategy enabled the controlled formation of stable enteric polymer nanoparticles using relevant formulation excipients and solvents. These findings support the continuity of studies focused on the incorporation of active compounds requiring controlled intestinal release after oral administration and highlight the potential of impinging jet micromixing as a scalable and reproducible platform for the development of polymer-based nanocarriers for oral delivery applications.

References

1- L. Xu, Z. Lan, M.B. Zewail, Y. Fan, C.-X. Zhao Curr. Opin. Colloid Interface Sci. 2026, 102014.

2- T. Chen, Y. Peng, M. Qiu, C. Yi, Z. Xu Nanoscale 2023, 15, 3594.

3- Y. Liu, G. Yang, Y. Hui, S. Ranaweera, C.-X. Zhao Nano-Micro-Small 2022, 18, 2106580.

4- A. Nikam, P. Nikam, P.S. Giram, S. Rathi, R.K. Bhinge, V. Salunkhe, S.R. Chaudhari, S. Mohite, V. Malyala Pharmaceutics 2023, 15, 587.

5- M. Gunawan, D. Ramadon, K.S. Setio Putri, R. Iswandana J. Appl. Pharm. Sci. 2025, 15, 63.

Acknowledgments

The authors acknowledge the financial support in part by the Fundação Araucária (Fundação Araucária de Apoio ao Desenvolvimento Científico e Tecnológico do Estado do Paraná) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil) - Finance Code 001.