(4dm) A Continuous Flow Process for the Controlled Formation Nanoparticles: An Approach for Tuning Nanoparticle Properties and for Elucidating Nanoparticle Formation Mechanisms

Nanoparticle engineering has attracted significant research interest in the last few decades driven by the versatile applications of nanoparticles across a spectrum of disciplines, including drug delivery and optoelectronics. While several methods have been developed for the synthesis of nanoparticles, the industrial translation is still limited as these techniques suffer from a lack of precise control over critical synthesis parameters, face substantial challenges with reproducibility, and scaling up the production from the lab scale to the industrial scale is challenging¹. Moreover, understanding the formation mechanism of these non-equilibrium structures is often lacking. Hence, there is a growing need for processes that provide improved control, ensure reproducibility, and ensure the possibility of scaling up production while maintaining precise control over the synthesis outcome.

In my future research, I’m interested in developing and studying the synthesis of nanoparticles using scalable synthesis processes, that offer robust control over the process parameters and improve reproducibility. My goal is also to explore new synthesis pathways that are unachievable with current synthesis methods and to gain a better understanding of the nanoparticle formation mechanism.

During my PhD at the Institute National Polytechnique of Toulouse, France, I worked in the group of Dr. Kevin Roger. My thesis project focused on designing a continuous flow process for the synthesis of anisotropic silver nanoparticles and identifying the key process variables. These nanoparticles presented several interesting properties that highly depend on their intrinsic characteristics. During this project, I successfully developed a new continuous flow approach for the controlled synthesis of anisotropic silver nanoparticles via sequential reagent addition. I demonstrated that nanoparticle properties could be precisely tuned by changing the reagent addition order and time in the sub-second time scales. This presented a novel strategy to achieve tunability without any composition variation. This was achieved using a continuous flow set-up that consisted of rapid millifluidic mixers connected in a series arrangement. This setup allowed us to control synthesis parameters and to precisely vary the reagent addition order and addition time in the subsecond time scales. This presented an ex-situ approach for understanding the formation mechanism and revealing the origin of the emergence of nanoparticle anisotropy. This strategy offered a method for understanding the mechanism and identifying the origin of anisotropy emergence in our system. I demonstrated that anisotropy emerges from the onset of the nucleation by tuning the chemical environment and the simple delaying of this tuning by 3 ms resulted in the removal of anisotropy.

Currently, I am an NYU Provost Postdoctoral Fellow conducting research in Professor Nathalie M. Pinkerton's research group at NYU Tandon. Here I have expanded my continuous flow manufacturing skill set to include Flash NanoPrecipitation (FNP), a controlled nanoprecipitation often used for the formation of drug-loaded polymeric nanoparticles². FNP is a well-established one-step synthesis method, that relies on rapid mixing and diffusion-limited self-assembly^3-5. My current project has focused on developing the next generation of controlled precipitation processes, called Sequential NanoPrecipitation (SNaP) which is based on the same rapid mixing and controlled self-assembly principles as FNP. However, unlike FNP, SNaP is a two-step process, which decouples the nanoparticle core formation and stabilization. After spearheading the development of a new sequential mixer design, I was able to attain delay times between the mixing steps of similar order to the nano-assembly time scale (5-50 ms). I demonstrated that the nanoparticle size can be varied without changing formulation composition, but instead by simply varying the delay time between the two steps. Such variation is in the order of a few milliseconds. I observed that by changing the delay time from 5.8 ms to 10.5 ms, the size of the formed nanoparticle increased from 198 nm to 233 nm. Additionally, this new approach enables me to access a new particle size regime, the micrometer, that was unachievable with current nanoprecipitation methods. With SNaP, microparticles with a size of up to 1.2µm can be formed. In comparison, the size limit of particles formed through FNP is 400 nm. The SNaP process will be further applied to understand the formation mechanism of drug-loaded polymeric nanoparticles. Moreover, SNaP has the potential to tackle certain challenges with current methods used to produce drug-loaded nanoparticles, such as enhancing encapsulation efficiency and providing better stability to the formed nanoparticles, as well as providing solutions to encapsulate difficult-to-encapsulated drugs.

For my future research, I’m interested in the use of continuous flow processes for the controlled and reproducible formation of nanostructures. These processes offer scalable approaches that could enable the translation of nanoparticles in industry and expand the range of nanoparticle applications. Additionally, they offer fine control over the synthesis parameters, providing a valuable tool for unveiling their formation mechanism^{6, 7}. Indeed, understanding the formation mechanism of these non-equilibrium structures can be challenging, as multiple mechanisms may be at play simultaneously. Continuous flow processes, unlike batch processes, offer the possibility to access the intermediate formation step, which provides insight into the parameters impacting the synthesis outcome, such as reagents' addition time and sequence. Additionally, as nanoparticle formation follows kinetic pathways, this process can provide the time control necessary for fine-tuning nanoparticle properties and provide a tool for identifying new synthetic routes to unlock new synthesis pathways^{6, 8}. I also aim to develop new continuous flow set-ups that provide control, scalability, and simplicity of use.

Teaching Interest:

I am also interested in teaching, as I believe that teaching is a great opportunity for researchers to grow and evolve by interacting with students. To provide the best guidance and help to students, it is imperative to stay up to date on current developments and to develop innovative and boundary-pushing ideas and projects. I was able to develop my interest in teaching through various teaching experiences throughout my academic journey.

During the 2023 fall semester, I co-taught an undergrad polymeric materials class, a core Chemical and Biomolecular Engineering course with 53 students. In addition to lecturing, I also held weekly office hours to answer students' questions. Additionally, I held review sessions before exams to help students prepare for the exam.

During my PhD, I had the opportunity to teach a physical chemistry lab class for two years. My responsibilities included supervising students, explaining the necessary information, helping the students to understand each problem, and correcting and grading reports at the end of each session.

I greatly enjoyed teaching and mentoring the students, which has strongly influenced my desire to continue my career path in academia rather than industry.

Specifically, I’m interested in transmitting my passion for nano-chemistry, covering the fundamental principles of nanoparticle synthesis, the various characterization techniques used for unveiling nanoparticle properties, their behavior in suspension, and their application in various fields.

Nano-chemistry is an interdisciplinary field that applies knowledge in biology, utilizing nanoparticles for drug delivery and bio-imaging, in energy, such as solar cells and batteries, and in electronics, including computer chips and sensors.

1. N. Desai, The AAPS journal, 2012, 14, 282-295.
2. W. S. Saad and R. K. Prud’homme, Nano Today, 2016, 11, 212-227.
3. N. M. Pinkerton, M. E. Gindy, C. V. Calero-Ddel, T. Wolfson, R. F. Pagels, D. Adler, D. Gao, S. Li, R. Wang, M. Zevon, N. Yao, C. Pacheco, M. J. Therien, C. Rinaldi, P. J. Sinko and R. K. Prud'homme, Adv Healthc Mater, 2015, 4, 1376-1385.
4. N. M. Pinkerton, A. Grandeury, A. Fisch, J. Brozio, B. U. Riebesehl and R. K. Prud’homme, Molecular Pharmaceutics, 2013, 10, 319-328.
5. B. K. Johnson and R. K. Prud’homme, Physical Review Letters, 2003, 91, 118302.
6. K. Roger and N. El Amri, Journal of Colloid and Interface Science, 2021, 608.
7. N. E. Amri and K. Roger, Journal of Colloid and Interface Science, 2020, 576, 435-443.
8. S. Teychené, I. Rodríguez-Ruiz and R. K. Ramamoorthy, Current Opinion in Colloid & Interface Science, 2020, 46, 1-19.