Rational Preferences under Ambiguity

This paper analyzes preferences in the presence of ambiguity that are rational in the sense of satisfying the classical ordering condition as well as monotonicity. Under technical conditions that are natural in an Anscombe-Aumann environment, we show that even for such general preference model it is possible to identify a set of priors, as first envisioned by Ellsberg (1961). We then discuss ambiguity attitudes, as well as unambiguous acts and events, for the class of rational preferences we consider.Rational Preferences; Ambiguity; Unambiguous Acts and Events

Engineering Codrug Solid Forms: Mechanochemical Synthesis of an Indomethacin-Caffeine System

This article reports on the preparation and solid-state characterization of an indomethacin 12caffeine drug 12drug cocrystal (or codrug) in a 1:1 stoichiometry. These two active ingredients are frequently coadministered as part of a therapy against strong migraines, in a commercially available fixed dose combination formulation. The X-ray crystal structure of the codrug is characterized by a hydrogen bond interaction between the carboxylic moiety of indomethacin and the purinic nitrogen atom of caffeine. The combination of multinuclear and multidimensional solid-state NMR measurements (1H MAS, 13C and 15N CPMAS, 1H DQ MAS, 13C 121H HETCOR, 14N 121H J- and D-HMQC), as well as IR data, provided spectroscopic evidence about the hydrogen atom position along the hydrogen bond axis, thereby confirming the neutral nature of the cocrystal. Furthermore, dissolution kinetic tests revealed superior bioavailability of indomethacin in the codrug compared to indomethacin alone and to an indomethacin 12caffeine physical mixture. On the other hand, the melting point of indomethacin was slightly lower in the cocrystal rather than in the pure drug

A strategy for probing the evolution of crystallization processes by low-temperature solid-state NMR and dynamic nuclear polarization

Crystallization plays an important role in many areas, and to derive a fundamental understanding of crystallization processes, it is essential to understand the sequence of solid phases produced as a function of time. Here, we introduce a new NMR strategy for studying the time evolution of crystallization processes, in which the crystallizing system is quenched rapidly to low temperature at specific time points during crystallization. The crystallized phase present within the resultant “frozen solution” may be investigated in detail using a range of sophisticated NMR techniques. The low temperatures involved allow dynamic nuclear polarization (DNP) to be exploited to enhance the signal intensity in the solid-state NMR measurements, which is advantageous for detection and structural characterization of transient forms that are present only in small quantities. This work opens up the prospect of studying the very early stages of crystallization, at which the amount of solid phase present is intrinsically low

Insights into the crystallization and structural evolution of glycine dihydrate by in situ solid-state NMR spectroscopy

In situ solid‐state NMR spectroscopy is exploited to monitor the structural evolution of a glycine/water glass phase formed on flash cooling an aqueous solution of glycine, with a range of modern solid‐state NMR methods applied to elucidate structural properties of the solid phases present. The glycine/water glass is shown to crystallize into an intermediate phase, which then transforms to the β polymorph of glycine. Our in situ NMR results fully corroborate the identity of the intermediate crystalline phase as glycine dihydrate, which was first proposed only very recently

Monitoring crystallization processes in confined porous materials by dynamic nuclear polarization solid-state nuclear magnetic resonance

Establishing mechanistic understanding of crystallization processes at the molecular level is challenging, as it requires both the detection of transient solid phases and monitoring the evolution of both liquid and solid phases as a function of time. Here, we demonstrate the application of dynamic nuclear polarization (DNP) enhanced NMR spectroscopy to study crystallization under nanoscopic confinement, revealing a viable approach to interrogate different stages of crystallization processes. We focus on crystallization of glycine within the nanometric pores (7–8 nm) of a tailored mesoporous SBA-15 silica material with wall-embedded TEMPO radicals. The results show that the early stages of crystallization, characterized by the transition from the solution phase to the first crystalline phase, are straightforwardly observed using this experimental strategy. Importantly, the NMR sensitivity enhancement provided by DNP allows the detection of intermediate phases that would not be observable using standard solid-state NMR experiments. Our results also show that the metastable β polymorph of glycine, which has only transient existence under bulk crystallization conditions, remains trapped within the pores of the mesoporous SBA-15 silica material for more than 200 days