Linear Scalability In Turbulent-Jet Mixing For Nanoparticle Processing: Scientific Foundations And Advantages

The translation of nanoparticle formulations from benchtop to commercial scale remains a critical challenge in nanomedicine and material science. Key parameters such as particle size, polydispersity, encapsulation efficiency, and internal structure often shift unpredictably as scale grows. Linear scalability—the property that process dynamics and outcomes are preserved across scale-up—is essential to reduce development time, ensure reproducibility, and satisfy regulatory demands.

Turbulent-jet mixing (including confined impinging jet (CIJ) and coaxial turbulent jet in coflow mixers) has emerged as a leading technology enabling such linear scalability. In particular, the work by Costa, DIANT Pharma, and collaborators elucidates how turbulent-jet mixers maintain performance from small volumes to large, continuous and GMP-compatible production settings.

Scientific basis of turbulent jet mixing and micromixing dynamics

Turbulent-jet mixers accelerate mixing by generating controlled high-Reynolds-number fluid flows where inertial forces dominate viscous resistance. In such flows, convective transport quickly dominates over diffusion. According to the micromixing theory of “engulfment-deformation-diffusion” (EDD), mixing time (τ_mix) is governed by the generation of vortical structures, their folding/deformation of fluid elements, and finally diffusion across thin lamellae. This theory holds in the turbulent-jet regime and provides scaling laws for τ_mix vs Reynolds number and flow geometry.

For example, Xu, Costa et al. showed in “Liposome Formation Using a Coaxial Turbulent Jet in Co-Flow” that liposome production under coaxial turbulent-jet mixing yields monodisperse unilamellar liposomes; the authors observed that once the Reynolds number and flow geometry produce turbulence, the liposome size becomes relatively insensitive to small perturbations, implying robustness.

Similarly, high throughput nanoparticle synthesis via a coaxial turbulent jet mixer has been shown to maintain homogeneous size distributions even at throughputs up to ~3 kg/day, a scale relevant for in vivo or early clinical supply.

DIANT and linear scalability

DIANT Pharma has developed systems that implement coaxial turbulent jet in coflow mixers that are designed to be linearly scalable. In a recent press release, DIANT introduced the LARU Discovery system, a low-volume research unit that maintains the same turbulent mixing technology as used in their larger commercial systems (e.g. LiFT). According to DIANT’s statement, the LARU Discovery preserves the key hydrodynamic features (jet geometry, flow velocities, mixing energy) even at much smaller hold-up volumes.

Costa et al., in “Process Robustness in Lipid Nanoparticle Production: A Comparison of Microfluidic and Turbulent Jet Mixing” (Laramy et al., with Costa) conducted a design-of-experiments comparing LNPs made via a coaxial turbulent jet mixer versus microfluidic mixers, under matched formulation and process parameters. The results showed that the jet mixer produced smaller particles, narrower size distributions, higher encapsulation efficiency, and more consistent results across formulation and process parameter variations. These data support the claim that turbulent jet mixing produces reproducible nanoparticle attributes even when scaling flows and volumes.

Benefits of linear scalability enabled by turbulent jet mixing

  • Predictable Size and Uniformity: Because turbulent jet mixing allows control over Reynolds number, velocity ratios, and mixing geometry, particle formation occurs under similar turbulence intensity across scales. This leads to repeatable particle sizes and low polydispersity. Evidence from Laramy et al. shows that size and PDI remain consistent when scaling from research to higher throughput.
  • Encapsulation Efficiency and Internal Structure: The rapid mixing ensures lipids and nucleic acids interact under steep concentration gradients and minimal side reactions or aggregation. In comparisons, ASO-LNPs (antisense oligonucleotide) formed with coaxial turbulent jets show higher encapsulation than those from microfluidic mixers.
  • Robustness to Parameter Variation: Linear scalability implies that when flow rates, temperatures, or concentrations shift, the resulting nanoparticles still retain desired attributes. The DIANT coaxial jet systems and the DOE studies show relatively modest sensitivity, which reduces the need for re-optimization when moving from, say, mL to liter scales.
  • Regulatory and Manufacturing Advantages: Maintaining the same mixing physics reduces risk during scale-up; regulators expect control strategies and demonstrations that critical quality attributes (CQA) are preserved from lab to production. DIANT’s continuous manufacturing systems with turbulent jet mixing, offered in scalable modules (e.g. LARU → LiFT), support GMP compliance and facilitate filing.
  • Efficiency and Throughput: Turbulent mixing supports high flow-rate operation. The coaxial turbulent jet mixers have been demonstrated to produce NP batches at kg/day scale without sacrificing homogeneity. This means that relatively early in the development pipeline, one can produce materially sufficient for preclinical or even clinical studies in a process architecture mirroring commercial scale.

Technical constraints and considerations

  • Reynolds Number & Velocity Ratio: Achieving turbulent regimes requires sufficient Reynolds numbers; flow rates and mixer geometry must be scaled appropriately. Designs must maintain similar dimensionless numbers (e.g., Re, jet-to-coflow velocity ratio) to ensure dynamic similarity.
  • Mixing Time (τ_mix): τ_mix must remain small relative to the kinetics of nanoparticle nucleation/assembly. In coaxial jets, τ_mix in the turbulent regime can be in the order of milliseconds (or less) and is predictable via models like EDD.
  • Materials Compatibility, Cleanability: For commercial scale, mixers must handle solvents, biopharmaceutical raw materials, and be cleanable / sterilizable.

Conclusion

Linear scalability of nanoparticle processing—from benchtop research to commercial output—is not merely an operational convenience; it is scientifically essential and strategically transformative. Turbulent jet mixing (confined impinging jets, coaxial turbulent jets in coflow) provide a mix of fast, high-energy mixing, predictable micromixing dynamics, and dimensionless control (Reynolds number, velocity ratios) that preserve critical process parameters across scale. The work by Costa, DIANT Pharma, and their collaborators provides compelling experimental evidence that small-volume research systems (like DIANT’s LARU Discovery) can utilize the same mixing physics as large GMP-capable systems, maintaining particle size, distribution, encapsulation, and overall robustness.

For researchers and developers of nanoparticle systems, adopting turbulent jet mixing early (including during benchtop optimization) yields advantages in reproducibility, regulatory readiness, and time-to-clinic. Given the accelerating pace of nucleic acid therapeutics, lipid nanoparticle platforms, and theranostics, technologies that support linear scalability are likely to be central to future successes.

References

Costa, A.P., Xu, X., Khan, M.A. et al., “Liposome Formation Using a Coaxial Turbulent Jet in Co-Flow,” Pharm Res. 2016.

High-throughput NP synthesis via coaxial turbulent jet mixer, ACS Nano, 2014.

Laramy, M.N.O., Costa, A.P., et al., “Process Robustness in Lipid Nanoparticle Production: A Comparison of Microfluidic and Turbulent Jet Mixing,” Molecular Pharmaceutics 2023.

DIANT Pharma, “DIANT launches LARU Discovery,” PR Newswire 2024.