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Item Variations in crystals of flufenamic acid of its methyl and tert-butyl analogues as impurities as determined by partial dissolutions(Royal Society of Chemistry, 2024-11-22) Bourke, Timothy; Chiarella, Renato A.; Moynihan, Humphrey A.; Irish Research Council; Science Foundation IrelandAchieving specified levels of impurities is one the key goals of crystallisation processes in manufacturing. The mode of impurity incorporation and the variation of impurity levels throughout crystal batches are key factors affecting the performance of crystallisations in terms of achieving purity specifications. Evaluation of the distribution of impurities in crystals of flufenamic acid (FFA) using a controlled partial dissolution approach is described. 2-(3-Tolylamino)benzoic acid (MeFA) and 2-((3-(tert-butyl)phenyl)amino)benzoic acid (tBuFA), analogues of FFA in which the trifluoromethyl group has been replaced by a methyl group or by a tert-butyl group respectively, were selected as the impurities. Thermal analysis suggests formation of a solid solution between FFA and MeFA isostructural to FFA form III. The stepwise dissolution approach was initially demonstrated on samples of pure FFA crystals and was then extended to evaluate the distribution of levels of MeFA and tBuFA impurities. The impurity levels are shown as varying with dissolution midpoint. Stepwise dissolution was usefully applied to FFA crystal of various morphologies, while for crystals with extremely needle-like morphology, a segmentation analysis approach was more practical. The work presented outlines a method for evaluating the distribution of impurities in crystalline materials using commonly available analytical and particle sizing methods.Item Exploring the crystal landscape of mandelamide and chiral resolution via cocrystallization(American Chemical Society, 2025) Huang, Shan; Fitzgerald, Deirbhile; Koledoye, Samuel A.; Collins, Stuart G.; Maguire, Anita R.; Lawrence, Simon E.; Science Foundation Ireland; Irish Research CouncilThe crystal structures of (±)-mandelamide, S-mandelamide, and enantioenriched mandelamide (94 S : 6 R) were determined. Diastereomeric cocrystal pairs of S-mandelamide with both enantiomers of mandelic acid and proline were synthesized. The diastereomeric cocrystal pairs of S-mandelamide with S/R-mandelic acid form 1:1 cocrystals in each case, while the diastereomeric cocrystal pairs of S-mandelamide with proline have different stoichiometries. Preliminary investigation of this diastereomeric cocrystal system for chiral resolution shows promise.Item Synthesis, evaluation and mechanistic insights of novel IMPDH inhibitors targeting ESKAPEE bacteria(Elsevier Ltd., 2024-10-05) Ayoub, Nour; Upadhyay, Amit; Tête, Arnaud; Pietrancosta, Nicolas; Munier-Lehmann, Hélène; O'Sullivan, Timothy P.; Irish Research Council; Science Foundation Ireland; Université Sorbonne Paris CitéAntimicrobial resistance poses a significant threat to global health, necessitating the development of novel therapeutic agents with unique mechanisms of action. Inosine 5′-monophosphate dehydrogenase (IMPDH), an essential enzyme in guanine nucleotide biosynthesis, is a promising target for the discovery of new antimicrobial agents. High-throughput screening studies have previously identified several urea-based leads as potential inhibitors, although many of these are characterised by reduced chemical stability. In this work, we describe the design and synthesis of a series of heteroaryl-susbtituted analogues and the evaluation of their inhibitory potency against IMPDHs. Our screening targets ESKAPEE pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. Several analogues with submicromolar inhibitory potency are identified and show no inhibitory potency on human IMPDH nor cytotoxic effects on human cells. Kinetic studies revealed that these molecules act as noncompetitive inhibitors with respect to the substrates and ligand virtual docking simulations provided insights into the binding interactions at the interface of the NAD+ and IMP binding sites on IMPDH.Item Synthesis and reactivity of α-diazo-β-keto sulfonamides(Georg Thieme Verlag KG, 2024-06-19) Maguire, Anita R.; Judge, Evan; O'Shaughnessy, Keith A.; Lawrence, Simon E.; Collins, Stuart G.; Science Foundation Ireland; Irish Research Council; Higher Education Authority; Synthesis and Solid State Pharmaceutical Centre; European Regional Development FundCopper mediated reactions of α-diazo-β-keto sulfonamides 1 leads to a range of products including the alkyne sulfonamides 5, the enamines 6, and the α-halosulfonamides 7 and 11 with no evidence for intramolecular C–H insertion in any of the reactions, in contrast to the reactivity of the comparable α-diazo-β-keto sulfones. Use of copper(II) triflate (5 mol%) led to isolation of a series of alkyne sulfonamides 5 (up to 12%) and enamines 6 (up to 64%). Use of copper(II) chloride (5 mol%) formed, in addition, the α-halosulfonamides 7; use of stoichiometric amounts of copper(II) chloride/bromide enables facile halogenation of the β-keto sulfonamide to form the α-halosulfonamides 7 and 11 (up to 63%).Item Application of broadband acoustic resonance dissolution spectroscopy (BARDS) to the gas release behaviour during rehydration of milk protein isolate agglomerates(Elsevier Ltd, 2019) Wu, Shaozong; Fitzpatrick, John; Cronin, Kevin; Ahmed, M. Rizwan; Fitzpatrick, Dara; Miao, Song; China Scholarship Council; TeagascThe BARDS technique was applied in this study to acoustically assess the rehydration behaviour of milk protein isolate (MPI) agglomerates and to compare with regular MPI powder. The results showed that BARDS has potential to monitor the rehydration behaviour of agglomerates. The greater porosity (>70%) of agglomerated powders introduced more compressible gas into the water. The BARDS profile showed that there was faster initial gas release from the agglomerates, indicating better wetting and dispersion ability of the agglomerates with shorter t M (time of maximum gas volume in solution). At 0.10% powder addition, agglomerated MPI reached t M within 109 s, which was significantly less than the control MPI at 140 s. MPI with lactose binder (MPI-L) had a t M of 80 s at 0.10% powder addition and, larger size MPI-L had a t M of 60 s. At 0.20% and 0.30% powder addition, more time was required to wet and disperse the powders. © 2019 Elsevier Ltd