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The design of new pharmaceutical solids with improved physical and chemical properties can be reached through in-detail knowledge of the noncovalent intermolecular interactions between the molecules in the context of crystal packing. Although crystallization from solutions is well-known for obtaining new solids, the effect of some variables on crystallization is not yet thoroughly understood. Among these variables, solvents are noteworthy. In this context, the present study aimed to investigate the effect of ethanol (EtOH), acetonitrile (MeCN), and acetone (ACTN) on obtaining irbesartan (IBS) crystal forms with 2,3-dibromosuccinic acid. Crystal structures were solved by single-crystal diffraction, and the intermolecular interactions were analyzed using the Hirshfeld surfaces analysis. The characterization of physicochemical properties was carried out by powder X-ray diffraction, Fourier transform infrared spectroscopy (FT-IR), thermal analysis, and solution-state NMR techniques. Two different IBS salts were obtained, one from MeCN and ACTN (compound 1) and a different one from EtOH (compound 2). The experimental results were in agreement with the findings obtained through quantum mechanics continuum solvation models. Compound 1 crystallized as a monoclinic system P21/c, whereas compound 2 in a triclinic system P1̅. In both structures, a net of strong hydrogen bonds is present, and their existence was confirmed by the FT-IR results. In addition, the IBS cation acts as a H-bond donor through the N1 and N6 nitrogen atoms which interact with the bromide anion and the water molecule O1W in compound 1. Meanwhile, N1 and N6 nitrogen atoms interact with the oxygen atoms provided by two symmetry-related 2,3-dibromo succinate anions in compound 2. Solution-state NMR data agreed with the protonation of the imidazolone ring in the crystal structure of compound 1. Both salts presented a different thermal behavior not only in melting temperature but also in thermal stability.

10 páginas, 3 tablas, 4 figuras, Background: The real burden of human cystic echinococcosis (CE) remains elusive, due to the peculiar characteristics of the disease and the heterogeneous and incomplete data recording of clinical cases. Furthermore, official notification systems do not collect pivotal clinical information, which would allow the comparison of different treatment outcomes, and thus circumvent the difficulty of implementing clinical trials for CE. The Italian Register of CE (RIEC) was launched in 2012 and expanded in 2014 into the European Register of CE (ERCE). The primary aim of the ERCE was to highlight the magnitude of CE underreporting, through the recording of cases that were not captured by official records. We present an overview of data collated in the ERCE and discuss its future, five years after its inception. Methods: The ERCE database was explored on March 31st 2019; data concerning participating centres and registered cases were descriptively analysed. Results: Forty-four centres from 15 countries (7 non-European) were affiliated to the ERCE. Thirty-four centres (77%) registered at least one patient; of these, 18 (53%) recorded at least one visit within the past 18 months. A total of 2097 patients were registered, 19.9% of whom were immigrants. Cyst characteristics were reported for at least one cyst at least in one visit in 1643 (78.3%) patients, and cyst staging was used by 27 centres. In total, 3386 cysts were recorded at first registration; mostly located in the liver (75.5%). Data concerning clinical management could be analysed for 920 “cyst stage-location-management” observations, showing great heterogeneity in the implementation of the stage-specific management approach recommended by the WHO. Conclusions: The ERCE achieved its goal in showing that CE is a relevant but neglected public health problem in Europe and beyond, since a proportion of patients reaching medical attention are not captured by official notification systems. The ERCE may provide a valuable starting platform to complement hospital-derived data, to obtain a better picture of the epidemiology of clinical CE, and to collect clinical data for the issue of evidence-based recommendations. The ERCE will be expanded into the International Register of CE (IRCE) and restructured aiming to overcome its current criticalities and fulfil these aims, RIEC development received funding through the Research Project IZSSA07/10RC to Dr. Giovanna Masala (Sardinian Experimental Zooprophylactic Institute, Sassari, Italy), subcontracted to Enrico Brunetti, University of Pavia, Italy. The amendment of RIEC and development of the ERCE was funded through the European Commission, under the Seventh Framework Programme (FP7, Theme Health.2013.2.3.4-1, grant agreement. no. 602051, Project HERACLES: Human Cystic Echinococcosis ReseArch in Central and Eastern Societies; http://www.herac les-fp7.eu/) to Adriano Casulli, Istituto Superiore di Sanità, Rome, Italy. ERCE activities are currently supported by EULAC Health (http://eulac healt h.eu/) and the Italian Ministry of Health - PERITAS project (molecular ePidemiological studiEs on pathways of tRansmIssion and long lasTing cApacity building to prevent cyStic echinococcosis infection) to Adriano Casulli, Istituto Superiore di Sanità, Rome, Italy.

We report the synthesis and biological evaluation of a new series of 3- or 4-(substituted)phenylisoxazolones as HNE inhibitors. Due to tautomerism of the isoxazolone nucleus, two isomers were obtained as final compounds (2-NCO and 5-OCO) and the 2-NCO derivatives were the most potent with IC50 values in the nanomolar range (20–70 nM). Kinetic experiments indicated that 2-NCO 7d and 5-OCO 8d are both competitive HNE inhibitors. Molecular modelling on 7d and 8d suggests for the latter a more crowded region about the site of the nucleophilic attack, which could explain its lowered activity. In addition molecular dynamics (MD) simulations showed that the isomer 8d appears more prone to form H-bond interactions which, however, keep the reactive sites quite distant for the attack by Ser195. By contrast the amide 7d appears more mobile within the active pocket, since it makes single H-bond interactions affording a favourable orientation for the nucleophilic attack.

Cystic echinococcosis (CE) is a zoonotic parasitic disease endemic in southern and eastern European countries. The true prevalence of CE is difficult to estimate due to the high proportion of asymptomatic carriers who never seek medical attention and to the underreporting of diagnosed cases, factors which contribute to its neglected status. In an attempt to improve this situation, the European Register of Cystic Echinococcosis (ERCE), was launched in October 2014 in the context of the HERACLES project. ERCE is a prospective, observational, multicentre register of patients with probable or confirmed CE. The first ERCE meeting was held in November 2015 at the Italian National Institute of Health (Istituto Superiore di Sanita, ISS) in Rome, to bring together CE experts currently involved in the Register activities, to share and discuss experiences, and future developments.Although the Register is still in its infancy, data collected at the time of writing this report, had outnumbered the total of national cases reported by the European endemic countries and published by the European Centre for Disease Prevention and Control in 2015. This confirms the need for an improved reporting system of CE at the European level. The collection of standardized clinical data and samples is expected to support a more rational, stage-specific approach to clinical management, and to help public authorities harmonize reporting of CE. A better understanding of CE burden in Europe will encourage the planning and implementation of public health policies toward its control.

The solid-state structure and behavior of tartrate (MT-o) and succinate (MS-m) metoprolol salts have been studied with a combined experimental (X-ray diffraction by both single crystal and microcrystalline powder and differential scanning calorimetry) and modeling approach (molecular dynamics and molecular orbital calculations). In spite of their close similarity at the molecular level in the corresponding crystal lattices, calorimetric data suggest for MS-m a slightly greater cohesive energy. In addition and more importantly, they show significantly different "macroscopic" behaviors: MS-m undergoes a reversible anisotropic lattice expansion/contraction upon temperature change and once melted quickly recrystallizes to the starting crystal phase. On the other hand, MT-o expands/contracts isotropically, and upon cooling from the melt gives an amorphous solid, which, at ambient conditions, takes 6 days to completely revert to the starting crystal form. Both findings are relevant in the field of the pharmaceutical drug development; i.e., when the phase purity of these active pharmaceutical ingredients is assessed, discussed, and possibly related to drug product formulations and manufacturing methods.