Microfluidic Platforms for the Production of Nanoparticles at Flow Rates Larger Than One Liter Per Hour

Abstract

processes, which are essential for the preparation of nanoparticles (NPs) with specific properties. A proof of acceptance of these modern drug formulation processes has been the recent FDA and EMA approval of nucleic acid nanomedicines, first Onpattro [10] and nowadays COVID-19 vaccines, [11] where microfluidics plays an essential R&D role. [12] Regarding massproduction, a limitation of the present microfluidic technology is the relatively low throughput, [13] which is insufficient to meet the good manufacturing practice (GMP) standards of the pharmaceutical industry in terms of final product volumes. Therefore, continuous efforts are being made to upscale the NPs preparation processes, and this is precisely the subject to be analyzed in the present work.Before entering the specific scaling-up problem, it is worth discussing the topic in a wider context. Up to date, nanomedicine has not reached the expected success, which can be explained by the challenges that still remain in formulation, the lack of robust and reproducible manufacturing, the highly demanded characterization methods, and stringent regulatory requirements. [14] Microfluidics has the potential to solve some of these issues and influence the way pharmaceutical R&D is conducted; [15] thus governmental agencies are now backing such initiatives, as mentioned above. It is worth mentioning that microfluidics is not a product but an enabling technology, a versatile tool that has been constantly evolving during the last two decades. [16] For example, early microfluidic components were expensive and time consuming, not only for chips fabrication but also for handling and operation. However, today there is a broad availability of microfabrication, integration, and liquid-handling methods, [17][18][19] which is quickly enlarging the number of users in both industry and academy. There are three expanding sectors producing the major demands on microfluidic technology: i) lab-on-a-chip devices for point-of-care testing, [20] ii) microfluidics-based 3D cell culture systems, such as organ-on-a-chip for precision medicine, [21] and iii) microfluidic platforms for the preparation of smart drug delivery nanosystems. [1][2][3][4] Furthermore, the combination of these applications is generating a number of novel opportunities for the biomedical market, and it is also accelerating the clinical translation of NPs, as envisioned some years ago. [22] Nevertheless, the conversion of these nanomedicine prototypes into marketed products is still limited.The pharmaceutical industry is regarded as rather conservative, a conduct that is well-understood considering the strict The convergence of microfluidics and nanotechnology has demonstrated a synergetic potential for the preparation of advanced pharmaceutics. Nowadays, there is a renewed interest in the subject, boosted by the approval of nucleic acid-loaded lipid-based nanoparticles. Microfluidics enables the physical scenario to achieve well-controlled formulations and plays an essential role in nanocarriers development; ne...

Facile production of quercetin nanoparticles using 3D printed centrifugal flow reactors

“…Despite the challenges involved, recent studies have highlighted the research progress made to develop microfluidic devices that can sustain greater flow rates (including patented designs). 39 …”

“…Finally, if scale-up remains a challenge (particularly for pre-clinical research purposes), microfluidic chips can be operated in parallel and under continuous-flow regime, allowing for increased production rates. 32,35,37–40…”

“…Numerous systems exploiting this technology have been developed in recent years. 31,[35][36][37][38][39] Considering differences between these systems, microuidic devices for nanoprecipitation share common advantages over batch methods. The conned space of microchannels allows the manipulation of small liquid volumes, which reduces the mixing path of solvent and antisolvent.…”

“…Finally, if scale-up remains a challenge (particularly for pre-clinical research purposes), microuidic chips can be operated in parallel and under continuous-ow regime, allowing for increased production rates. 32,35,[37][38][39][40] Despite more than two decades of continued research, the utility of microuidic devices is not without limitations. Productivity at industrial scales is possible via device parallelization 39,41 or the design of chips capable of withstanding greater ow rates, 30,39 but it requires signicant development and optimization time.…”

“…32,35,[37][38][39][40] Despite more than two decades of continued research, the utility of microuidic devices is not without limitations. Productivity at industrial scales is possible via device parallelization 39,41 or the design of chips capable of withstanding greater ow rates, 30,39 but it requires signicant development and optimization time. Additionally, most microuidic devices require expensive syringe or pressure-controlled pumps for their operation, which hinders translation and widespread adoption of these techniques.…”