Brust-Schiffrin synthesis (BSS) of metal nanoparticles has emerged as a major breakthrough in the field for its ability to produce highly stable thiol functionalized nanoparticles. In this work, we use a detailed population balance model to conclude that particle formation in BSS is controlled by a new synthesis route: continuous nucleation, growth, and capping of particles throughout the synthesis process. The new mechanism, quite different from the others known in the literature (classical LaMer mechanism, sequential nucleation-growth-capping, and thermodynamic mechanism), successfully explains key features of BSS, including size tuning by varying the amount of capping agent instead of the widely used approach of varying the amount of reducing agent. The new mechanism captures a large body of experimental observations quantitatively, including size tuning and only a marginal effect of the parameters otherwise known to affect particle synthesis sensitively. The new mechanism predicts that, in a constant synthesis environment, continuous nucleation-growth-capping mechanism leads to complete capping of particles (no more growth) at the same size, while the new ones are born continuously, in principle leading to synthesis of more monodisperse particles. This prediction is validated through new experimental measurements.

The two-step particle synthesis mechanism, also known as the Finke-Watzky (1997) mechanism, has emerged as a significant development in the field of nanoparticle synthesis. It explains a characteristic feature of the synthesis of transition metal nanoparticles, an induction period in precursor concentration followed by its rapid sigmoidal decrease. The classical LaMer theory (1950) of particle formation fails to capture this behavior. The two-step mechanism considers slow continuous nucleation and autocatalytic growth of particles directly from precursor as its two kinetic steps. In the present work, we test the two-step mechanism rigorously using population balance models. We find that it explains precursor consumption very well, but fails to explain particle synthesis. The effect of continued nucleation on particle synthesis is not suppressed sufficiently by the rapid autocatalytic growth of particles. The nucleation continues to increase breadth of size distributions to unexpectedly large values as compared to those observed experimentally. A number of variations of the original mechanism with additional reaction steps are investigated next. The simulations show that continued nucleation from the beginning of the synthesis leads to formation of highly polydisperse particles in all of the tested cases. A short nucleation window, realized with delayed onset of nucleation and its suppression soon after in one of the variations, appears as one way to explain all of the known experimental observations. The present investigations clearly establish the need to revisit the two-step particle synthesis mechanism.

A novel continuous heterogeneous crystallization process is developed in which the active pharmaceutical ingredient (API) is crystallized directly on the surface of an excipient within the crystallizer. The product is subsequently dried and formed into tablets without the need for complex downstream processing steps, such as milling, sieving, granulation, and blending. The aim is to eliminate many steps of the particle processing in drug product manufacturing. The APIs and excipients systems were selected by investigating heteroepitaxial mechanisms. The effects of various process parameters, such as temperature, residence time, and mode of operation, on drug loading were studied. Three different process designsmixed suspension mixed product removal with a traditional impeller, Viscojet mixing, and a fluidized bed crystallizerwere utilized for direct crystallization of the API on the surface of the crystalline excipient. The excipient selection and process design parameters have a significant impact on drug loading, avoidance of bulk nucleation and crystallization, control of API crystal shape and size, and process control. The maximum drug loading of the excipient with API in this study was 47%. Also, it was demonstrated that increasing the supersaturation ratio and residence time increased the drug loading. The products were collected from the crystallizer and directly compressed into tablet form. The tablet hardness and dissolution profile were also studied. The fully continuous process eliminates the downstream steps, resulting in the production of crystalline compounds and the final form (tablets) in a significantly faster, more efficient, and more economical manner with a smaller footprint. mentioned steps. 6−10 The precise final dosage, content uniformity, composition, mechanical properties, and critical quality attribute of every single tablet, which are highly regulated, 2,11−13 highly depend on the performance of the involved stages, for instance, component segregation, which can be caused by differences in particle size, density, or shape, and segregation in blending, hoppers, transfer lines, or feeders, and results in heterogeneity in tablet compositions. 14−17 Significant academic research and industrial development have been invested to overcome drug product line challenges and enable consistent manufacturing of high-quality tablets. 18−22 These challenges, and subsequent effects, are more problematic in the continuous manufacturing arena, 23,24 where the continuous flow of material, continuous workload of the drug product line, residence time distribution, and validation of "batches" of the final product enter into the design of already complicated processes. 17,20,21,23,24 Recent endeavors in shifting from the traditional batch pharmaceutical processes to the modern and emerging

The two-phase Brust-Schiffrin method (BSM) is used to synthesize highly stable nanoparticles of noble metals. A phase transfer catalyst (PTC) is used to bring in aqueous phase soluble precursors into the organic phase to enable particle synthesis there. Two different mechanisms for phase transfer are advanced in the literature. The first mechanism considers PTC to bring in an aqueous phase soluble precursor by complexing with it. The second mechanism considers the ionic species to be contained in inverse micelles of PTC, with a water core inside. A comprehensive experimental study involving measurement of interfacial tension, viscosity, water content by Karl-Fischer titration, static light scattering, (1)H NMR, and small-angle X-ray scattering is reported in this work to establish that the phase transfer catalyst tetraoctylammonium bromide transfers ions by complexing with them, instead of encapsulating them in inverse micelles. The findings have implications for particle synthesis in two-phase methods such as BSM and their modification to produce more monodispersed particles.