UHPLC-Q-TOF-MS/MS-based metabolite profiling of duvelisib and establishment of its metabolism mechanisms.

Duvelisib is a dual inhibitor of phosphoinositide 3 kinase that received global approval by the US Food and Drug Administration in 2018 to treat follicular lymphoma after at least two prior systemic therapies. An extensive literature search revealed that, to date, metabolites of duvelisib have not been characterized and information on them is not available in any of the literature. Moreover, the metabolism pathway is yet to be established. This study aimed to investigate and characterize the metabolites of duvelisib generated in microsomes and S9 fractions. In this study, five duvelisib metabolites were identified using UHPLC-Q-TOF-MS/MS analysis technique. The structural characterization of the metabolites was performed by comparing the fragmentation pattern of duvelisib and its metabolites through an accurate mass measurement technique. Three metabolites were generated through phase I hydroxylation and dechlorination reactions. The other two metabolites were generated through a phase II glucuronidation reaction. The metabolism mechanism established through this study can be useful to improve the safety profile of drugs of similar categories in the future after establishment of the toxicity profile of the identified metabolites.

Stability of Cu-islands formed on Si substrate via 'dewetting' under subsequent thermal cycling.

Very thin metallic films deposited on a substrate often dewet upon thermal exposure, forming discrete islands of micrometer and nanometer-sized metal particles. Herein, Cu islands on Si substrate, which were formed due to agglomeration (or 'dewetting') of Cu thin film at 600 °C, were exposed to thermal cycling, and the ensuing evolution in their morphology was monitored. Thermal cycling was performed between either -25 °C and 150 °C or 25 °C and 400 °C, using different heating and cooling rates. With faster heating-cooling rates, a change in the shape and size of the Cu islands was observed, whereas a slow heating-cooling rate did not induce noticeable effect on their morphology. Furthermore, the formation of new nano- and micro-sized particles, probably through the dewetting of the ultra-thin layer of Cu that was left intact during the initial agglomeration treatment, was observed during the thermal cycling performed at fast rates up to 400 °C. Finite element analysis, incorporating Anand's viscoplasticity model, revealed the existence of high strain energy density in the vicinity of the particle-Si interface when the thermal cycling is carried at a faster ramp rate, suggesting the pivotal role of thermal stresses, in addition to the maximum temperature, in controlling the morphology of the Cu particles and the dewetting of the residual ultra-thin layer of Cu on Si.

New Insights into Dewetting of Cu Thin Films Deposited on Si.

Very thin metallic films are susceptible to dewetting upon thermal excursions, resulting in fragmentation and hence loss of structural integrity. Herein, 15 to 55 nm thick Cu films deposited on a Si substrate were isothermally annealed at 400 to 700 °C inside a scanning electron microscope operating in high-vacuum mode and the ensuing dewetting behavior was studied. The in situ observations revealed that the induction time before the void nucleation varied with film thickness as per a power-law with an exponent of 4, and the activation energy for both the void nucleation and the growth was close to the activation energy for surface diffusion. Hillock formation was observed to be a prerequisite for void nucleation in relatively thicker films. To complement the experimental observations, phase-field simulations incorporating a grain boundary grooving model were performed, which showed excellent agreement with the experimental observations. This validates the surface diffusion-controlled, grain boundary grooving-driven mechanism for void nucleation and dewetting of Cu films deposited on Si.

Innovation in Strategies for Sensitivity Improvement of Chromatography and Mass Spectrometry Based Analytical Techniques.

Chromatography and mass spectrometry based techniques are the most commonly employed procedures to quantitate the analytes in pharmaceutical research. However, sensitivity of analytical methods significantly varies due to the difference in physicochemical characteristics of analytes. Sensitivity of methods greatly affects the quality of analytical results. Establishment of a sufficiently sensitive method ensures the suitability of a technique for its intended purpose. Although various types of advancement in chromatographic science are witnessed, issues related to sensitivity remain a major challenge for the analyte with low detection limit. Highly sensitive analytical methods are specifically essential to quantitate the analytes in the samples from dissolution study of sustained release formulations, cross-contamination study, impurity analysis, metabolite profiling, bioanalysis of highly potent and low bioavailable drugs. In recent years, huge involvement of researchers toward sensitivity enhancement of quantitative methods is evidenced. Wide verities of approaches are being reported in the field. Derivatization technique, introduction of ion-pairing reagents, sample pretreatment, and utilization of innovative methods such as 2-dimensional liquid chromatography, nano liquid chromatography, 2-dimensional gas chromatography, supercritical fluid chromatography, use of microcolumn are some approaches that are being employed. Online sample preparation techniques can significantly improve the sensitivity of a method by reducing sample loss and degradation. This review summarizes and critically discussed the approaches to improve the sensitivity of chromatographic and mass spectrometry based analytical methods. This article can guide the researchers to select suitable approaches for achieving the desired detection limit of analytical and bioanalytical methods based on their specific requirements.

Advancements in practical and scientific bioanalytical approaches to metabolism studies in drug development.

Advancement in metabolism profiling approaches and bioanalytical techniques has been revolutionized over the last two decades. Different in vitro and in vivo approaches along with advanced bioanalytical techniques are enabling the accurate qualitative and quantitative analysis of metabolites. This review summarizes various modern in vitro and in vivo approaches for executing metabolism studies with special emphasis on the recent advancement in the field. Advanced bioanalytical techniques, which can be employed in metabolism studies, have been discussed suggesting their particular application based on specific study objectives. This article can efficiently guide the researchers to scientifically plan metabolism studies and their bioanalysis during drug development programs taking advantage of a detailed understanding of instances of failure in the past.