Overcoming the Drawbacks of Sulpiride by Means of New Crystal Forms

This study aims at developing new multicomponent crystal forms of sulpiride, an antipsychotic drug. The main goal was to improve its solubility since it belongs to class IV of the BCS. Nine new adducts were obtained by combining the active pharmaceutical ingredient with acid coformers: a salt cocrystal and eight molecular salts. In addition, three novel co-drugs, of which two are molecular salts and one is a cocrystal, were also achieved. All samples were characterized in the solid state by complementary techniques (i.e., infrared spectroscopy, powder X-ray diffraction and solid-state NMR). For systems for which it was possible to obtain good-quality single crystals, the structure was solved by single crystal X-ray diffraction (SCXRD). SCXRD combined with solid-state NMR were used to evaluate the ionic or neutral character of the adducts. In vitro dissolution tests of the new crystal forms were performed and all the adducts display remarkable dissolution properties with respect to pure sulpiride

Engineering plastic phase transitions via solid solutions: the case of “reordering frustration” in ionic plastic crystals of hydroxyquinuclidinium salts

A family of salts of R-(+)-(3)-hydroxyquinuclidinium [QH]+, with SO42−, BPh4−, BF4− and PF6− counter-anions, have been prepared by the metathesis of [QH]Cl and metal salts of the corresponding anions. Solid solutions of formula [QH](PF6)x(BF4)1−x for x = 0.9, 0.8, 0.7 have also been obtained. The crystalline materials have been investigated by a combination of solid-state techniques, including variable temperature XRD, thermal analyses, multinuclear (11B, 13C, 15N, 19F, and 31P) solid-state NMR spectroscopy, variable temperature wideline 19F T1 relaxation measurements, and micro-Raman spectroscopy to investigate their thermal stability and phase transition behaviors. It has been shown that the salts [QH]PF6 and [QH]BF4 undergo an order–disorder solid–solid phase transition to plastic phases, whereas [QH]2SO4·H2O and [QH]BPh4 do not display any plastic phase transition. Doping [QH]BF4 into the [QH]PF6 lattice up to 30% results in the formation of a solid solution that is plastic in an expanded thermal range, thanks to a phenomenon that we describe here for the first time as “reordering frustration”

Deep Supramolecular Language Processing for Co-crystal Prediction

Approximately 40% of marketed drugs exhibit suboptimal pharmacokinetic profiles. Co-crystallization, where pairs of molecules form a multicomponent crystal, constitutes a promising strategy to enhance physicochemical properties without compromising the pharmacological activity. However, finding promising co-crystal pairs is resource-intensive, due to the vast number of possible combinations. We present DeepCocrystal, a novel deep learning approach designed to predict co-crystal formation by processing the \u27chemical language\u27 from a supramolecular vantage point. Rigorous validation of DeepCocrystal showed a balanced accuracy of 78% in realistic scenarios, outperforming existing models. By leveraging the properties of molecular string representations, DeepCocrystal can also estimate the uncertainty of its predictions. We harness this capability in a challenging prospective study, and successfully discovered two novel co-crystal of diflunisal, an anti-inflammatory drug. This study underscores the potential of deep learning -- and in particular of chemical language processing -- to accelerate co-crystallization, and ultimately drug development, in both academic and industrial contexts

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic