Old Polymorph, New Technique: Assessing Ritonavir Crystallinity Using Low-Frequency Raman Spectroscopy.

Two decades ago, postmarket discovery of a second crystal form of ritonavir with lower solubility had major implications for drug manufacturers and patients. Since then, ritonavir has been reformulated via the hot-melt-extrusion process in an amorphous form. Here, quantitative low- and mid-frequency Raman spectroscopy methods were developed to characterize polymorphs, form I and form II, in commercial ritonavir 100 mg oral tablets as an alternate analysis approach compared to X-ray powder diffraction (XRPD). Crystallization in three lots of ritonavir products obtained from four separate manufacturers was assessed after storage under accelerated conditions at 40 °C and 75% relative humidity (RH). Results were compared with quantitative XRPD methods developed and validated according to ICH Q2 (R1) guidelines. In a four-week open-dish study, form I crystallization occurred in two of the four products and form II crystallization was detected in another ritonavir product. The limits of detection for XRPD, low-frequency Raman (LFR), and mid-frequency Raman (MFR) were determined to be 0.7, 0.8, and 0.5% for form I and 0.6, 0.6, and 1% for form II, respectively. Root-mean-squared-error of predictions were 0.6-1.0 and 0.6-2.5% for LFR- and MFR-based partial least-squares models. Further, ritonavir polymorphs could also be identified and detected directly from ritonavir tablets using transmission LFR. In summary, LFR was applied for the assessment of polymorphism in real-world samples. While providing analytical performance similar to conventional techniques, LFR reduced the single measurement time from 66 min (XRPD) to 10 s (LFR) without the need for tedious sample preparation procedures.

Stability of Oxygen Nanobubbles under Freshwater Conditions.

The use of nanobubbles (NBs) has gained significant attention in various applications (e.g., aeration in biological water treatment, water disinfection, membrane defouling, and ground water and sediment remediation) in recent decades because of their superior characteristics such as the improved mass transfer at the gas-liquid interfaces, their lifetime up to a couple of weeks, the formation of reactive oxygen species (ROS) with high oxidative potential. However, there is a lack of information about the effect of various factors on the stability of NBs for a long storage period under freshwater conditions. In this study, a comprehensive investigation was conducted to systematically examine the stability of oxygen NBs in water under various conditions which are closely related to a typical freshwater or the drinking water treatment. The oxygen NB stability in water was evaluated by monitoring the change in the bubble concentrations, size distribution, average diameter, and zeta potential for 60 days of storage time under different pH, hardness, ionic strength, natural organic matter (NOM), chlorine, and temperature conditions. In addition, the formation of hydroxyl radical (•OH) was investigated using disodium terephthalate which form fluorescent adducts with •OH in the presence of oxygen NBs. Among the parameters investigated, the impacts of cations, low pH, and high SUVA254 NOM on the stability of oxygen NBs were more significant than other conditions. The half-lives of oxygen NBs under various conditions follow the order Ca2+ < Na+ < pH 3 < high SUVA254 NOM < pH 5 < 30 °C. Oxygen NBs were more stable in softwater than hardwater. Oxygen NBs were relatively stable for 3 days regardless of pH. For a longer storage period, oxygen NBs disappeared faster at pH 3 than at high pH. High SUVA254 NOM destabilized NBs more than low SUVA254 NOM, indicating the impact of hydrophobicity on the NB stability. The temperature effect on the NB stability was negligible for a short storage time, while higher temperature destabilized oxygen NBs for a longer storage time. One of the main disappearance pathway of oxygen NBs in water was found to be coalescing, rising, and leaving the container, which would be promoted greatly by cations, low pH and NOM with high aromaticity. The formation of hydroxyl radical in NB solutions was detected at pH 3 by a florescent probe molecule. When oxygen NBs are released in water bodies, high calcium, high SUVA254 NOM, and low pH would significantly reduce the availability of NBs and their residence time in freshwater.

Microwave regeneration of granular activated carbon saturated with PFAS.

This study investigated the regeneration of PFAS-saturated granular activated carbons (GACs) by microwave (MW) irradiation. Two commercially available GACs (bituminous coal based GAC [BCGAC] and lignite coal based GAC [LCGAC]) were saturated with perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) and then irradiated at different MW conditions (applied power = 125 - 500 W, irradiation time = 3 - 12 min). The performance of MW regeneration for PFOS- or PFOA-saturated GACs was assessed by evaluating the variation of GAC adsorption capacity (regeneration efficiency, RE) and weight loss percentage (WL). Moreover, the effect of MW irradiation on GAC textural properties (e.g., surface area and pore volume) was examined through N2 adsorption isotherms. Additionally, five successive adsorption/regeneration cycles were carried out at the MW operational condition that allowed to reach the target temperature (T>600°C) while minimizing the WL. Both GACs exhibited a strong ability to convert MW irradiation into a rapid temperature increase (~150°C min-1 at 500 W). The highest values of RE (>90%) for both PFOA- and PFOS-saturated GACs were obtained at MW irradiation conditions that employed short regeneration time (3 min) and optimal temperature. Indeed, the highest RE did not occur at the highest temperatures (>750°C) due to the damage of GAC porous structure, particularly for LCGAC. After five cycles, the observed values of RE (~65%) and a moderate weight loss (<7%) demonstrated the good performance of MW irradiation for regenerating PFOA- and PFOS-saturated BCGAC. The obtained findings pointed out that MW irradiation is a promising alternative regeneration technique for PFAS-saturated GAC.

The Role of Oxidation during the Synthesis of Silver-Glutathione Monolayer-Protected Clusters.

The synthesis of metal monolayer-protected clusters (MPCs) is still not well understood. It was recently shown that the mechanism of MPC formation involves sequential growth, wherein small MPCs form first and then grow into progressively larger sizes. The sequential growth model does not entirely explain all experimental observations, however. For example, the evolution of MPC product sizes is found to be a non-monotonic function of reaction kinetics, whereas the sequential growth model predicts monotonic behavior. Size evolution of MPCs is studied during synthetic reactions for a wide range of kinetics and it is found that all syntheses began with the sequential growth of MPCs but also found that growth transitioned to degradation if reduction kinetics are fast enough to give way to ambient oxidation. It is identified that MPCs can degrade via oxidation during syntheses and in a manner that is opposite to sequential growth, namely by forming smaller known MPC species from larger MPC species. This sequential degradation process therefore played an important role in determining final MPC products for reactions with fast reduction kinetics. Together, complementary oxidative and reductive processes provide a more complete description of MPC synthesis as well as new tools for controlling metal MPC synthesis.

Sequential Growth as a Mechanism of Silver-Glutathione Monolayer-Protected Cluster Formation.

Silver monolayer-protected clusters (MPCs) are an important new class of small metal nanoparticles with discrete sizes and unique properties that are eminently tunable; however, a fundamental understanding of the mechanisms of MPC formation is still lacking. Here, the basic mechanism by which silver-glutathione MPCs form is established by using real-time in situ optical measurements and ex situ solution-phase analyses to track MPC populations in the reaction mixture. These measurements identify that MPCs grow systematically, increasing in size sequentially as they transform from one known species to another, in contrast to existing models. In the new sequential growth model of MPC formation, the relative stability of each species in the series results in thermodynamic preferences for certain species as well as kinetic barriers to transformations between stable sizes. This model is shown to correctly predict the outcome of silver MPC synthetic reactions. Simple analytic expressions and simulations of rate equations are used to further validate the model and study its nature. The sequential growth model provides insights into how reactions may be directed, based on the interplay between relative MPC stabilities and reaction kinetics, providing tools for the synthesis of particular MPCs in high yield.

Chemistry and Structure of Silver Molecular Nanoparticles.

Silver and gold molecular nanoparticles (mNPs) are a relatively new class of molecular materials of fundamental interest. They are high-nuclearity metal-organic compounds, with ligated metal cores, where the different character of bonding in the ligand shell and metal core gives rise to many of the unique properties of these materials. Research has primarily focused on gold mNPs, due to their good stability and the ease with which they may be synthesized and processed. To understand these materials as a general class, however, it will be necessary to broaden research efforts to other metals. Gold and silver are isoelectronic and have the same atomic radius, making the comparison of gold and silver mNPs attractive. The optical and chemical differences of the two metals provide useful contrasts, however, as well as a means to access a wider range of properties. In this Account, we focus on the synthesis, structure, and reactivity of silver mNPs. First, we review the origins and history of the field, from the ill-defined gas-phase metal clusters of the 1980s to the precisely defined mNPs of 1996 and onward. Next, we discuss the role of silver as a complement to gold mNPs in the effort to generalize lessons learned from either material and extend them into new metals. The synthesis of silver mNPs is covered in some detail, noting the choices made as the chemistry and the materials were developed. The importance of coordinating solvents and thermodynamic stability are also noted. The need to reduce solvent use is discussed and a new approach to achieving this goal is presented. Next, the structures of silver mNPs are discussed, including the Ag44 and Ag17 archetypes, and focusing on the successful de novo structure prediction of the latter. Structure and prediction of ligand shell motifs are also discussed. Finally, the postsynthetic chemistry and reactivity of silver mNPs are presented, including some of the first efforts to elucidate reaction mechanisms, beginning in 2012. Silver nanoparticles are gaining in popularity, particularly compared with gold, as the potential for silver to make a technological and economic impact is recognized. The superior optical properties of silver already make it a valuable material for plasmonics, but this may also translate to molecular species for nonlinear optics, sensors, and optoelectronics. The higher reactivity may also lead to a greater diversity of chemistry for silver compared to gold, including as an important broad-spectrum antimicrobial. Conversely, the "ultrastability" of the Ag44 archetype has already enabled unprecedented scale up with molecular precision, and may lead to the first industrial-scale production of metal mNPs. Clearly, silver mNPs are one of the most promising and significant new materials being studied today.