Merits and advances of microfluidics in the pharmaceutical field: design technologies and future prospects

Abstract

Microfluidics is used to manipulate fluid flow in micro-channels to fabricate drug delivery vesicles in a uniform tunable size. Thanks to their designs, microfluidic technology provides an alternative and versatile platform over traditional formulation methods of nanoparticles. Understanding the factors that affect the formulation of nanoparticles can guide the proper selection of microfluidic design and the operating parameters aiming at producing nanoparticles with reproducible properties. This review introduces the microfluidic systems' continuous flow (single-phase) and segmented flow (multiphase) and their different mixing parameters and mechanisms. Furthermore, microfluidic approaches for efficient production of nanoparticles as surface modification, anti-fouling, and post-microfluidic treatment are summarized. The review sheds light on the used microfluidic systems and operation parameters applied to prepare and fine-tune nanoparticles like lipid, poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles as well as cross-linked nanoparticles. The approaches for scale-up production using microfluidics for clinical or industrial use are also highlighted. Furthermore, the use of microfluidics in preparing novel micro/nanofluidic drug delivery systems is presented. In conclusion, the characteristic vital features of microfluidics offer the ability to develop precise and efficient drug delivery nanoparticles.

Keywords: Microfluidics; drug delivery; micromixers; nanoparticles; scale-up.

Figure 1.

Y- and T-shaped micromixers: A) Y-shaped and B) T-shaped.

Figure 2.

Chaotic advection passive micromixers; A) Zigzag channel, B) 3D serpentine channel, C) Herringbone grooves channel, D) Spiral channel micromixers, and E) Sequential lamination channel (Split and Recombine channels) (Redrawn under permission of Elsevier from reference (Hamdallah et al., 2020)). W is the channel width, S, and L are the linear length of the periodic step and the zigzag microchannel, respectively.

Figure 3.

A collective diagram representing different passive micromixers; A) Flow focusing channel (Redrawn under permission of Elsevier from reference (Lu et al., 2016)), B) Coaxial channel micromixers (Redrawn under permission of Elsevier from reference (Vladisavljević et al., 2013)), and C) Parallel lamination channel (Redrawn under permission of Elsevier from reference (Sabry et al., 2018)).

Figure 4.

Active micromixers; A) Pressure field disturbance and B) Acoustic micromixers.

Figure 5.

Mixing within slugs (Redrawn under permission of Elsevier from reference (Sivasamy et al., 2010); A) Straight and B) Serpentine-shaped channels.

Figure 6.

Segmented micromixers: A) T-configuration, B) Flow focusing, and C) Gas-liquid multiphase.

Figure 7.

Influence of microfluidic structure and operation conditions on particle size (z-average diameter) and polydispersity index (PDI) of the nanoparticles (Redrawn under permission of Elsevier from reference (Riewe et al., 2020)). (A) Segmented-flow micromixer with large (A1; 58 μm) or small (A2; 29 μm) diameter ethanol channel; (B) High-pressure micromixer and (C) Staggered herringbone micromixer with different TFRs (C1 = 2 or C2 = 10 mL/min) in the mixing channel. The apparatus were used to mix (1) 5 mg/mL castor oil and 2.5 mg/mL polysorbate 80 in ethanol with water or (2) 10 mg/mL glycerol monooleate in ethanol with 0.222 mg/mL poloxamer 407 in water. TFR is total flow rate, D is channel diameter, and P is pressure.

Figure 8.

Comparison between A) post microfluidics and B) in-situ microfluidic techniques for the preparation of charged cell-penetrating peptides (CPP)-coated PLGA nanoparticles showing the different distribution of CPP through the formed nanoparticles (Redrawn under permission of Elsevier from reference (Streck et al., 2019a)) CPP is charged cell-penetrating peptides.

Figure 9.

Preparation of chitosan/ATP nanoparticles by ionic gelation via regular and central aqueous stream microfluidic methods. The figure shows the effect of the conducted methods on the particle size (PS) and polydispersity index (PDI) (Data in this figure was obtained from Pessoa et al. (2017)).