Synthesis and Solid State Pharmaceutical Centre (SSPC) - Journal Articles

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    Pharmaceutical salts of piroxicam and meloxicam with organic counterions
    (ACS Publications, 2022-10-21) Huang, Shan; Venables, Dean S.; Lawrence, Simon E.; Science Foundation Ireland
    Piroxicam (PRM) and meloxicam (MEL) are two nonsteroidal anti-inflammatory drugs, belonging to the Biopharmaceutics Classification System Class II drugs. In this study, six novel pharmaceutical salts of PRM and MEL with three basic organic counterions, that is, 4-aminopyridine (4AP), 4-dimethylaminopyridine (4DMP), and piperazine (PPZ), were prepared by both slurrying and slow evaporation. These salts were characterized by single-crystal and powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectroscopy. All six salts, especially MEL-4DMP and MEL-4AP, showed a significantly improved apparent solubility and dissolution rate in sodium phosphate solution compared with the pure APIs. Notably, PRM-4AP and PRM-4DMP salts exhibited enhanced fluorescence, and the PRMPPZ salt showed weaker fluorescence compared with that of pure PRM due to different luminescence mechanisms.
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    Identification of BgP, a cutinase-like polyesterase from a deep-sea sponge-derived actinobacterium
    (Frontiers Media S.A., 2022-04-12) Carr, Clodagh M.; Rodrigues de Oliveira, Bruno Francesco; Jackson, Stephen A.; Laport, Marinella Silva; Clarke, David J.; Dobson, Alan D. W.; Science Foundation Ireland; Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro; Conselho Nacional de Desenvolvimento Científico e Tecnológico
    Many marine bacteria produce extracellular enzymes that degrade complex molecules to facilitate their growth in environmental conditions that are often harsh and low in nutrients. Marine bacteria, including those inhabiting sea sponges, have previously been reported to be a promising source of polyesterase enzymes, which have received recent attention due to their potential ability to degrade polyethylene terephthalate (PET) plastic. During the screening of 51 marine bacterial isolates for hydrolytic activities targeting ester and polyester substrates, a Brachybacterium ginsengisoli B129SM11 isolate from the deep-sea sponge Pheronema sp. was identified as a polyesterase producer. Sequence analysis of genomic DNA from strain B129SM11, coupled with a genome "mining" strategy, allowed the identification of potential polyesterases, using a custom database of enzymes that had previously been reported to hydrolyze PET or other synthetic polyesters. This resulted in the identification of a putative PET hydrolase gene, encoding a polyesterase-type enzyme which we named BgP that shared high overall similarity with three well-characterized PET hydrolases-LCC, TfCut2, and Cut190, all of which are key enzymes currently under investigation for the biological recycling of PET. In silico protein analyses and homology protein modeling offered structural and functional insights into BgP, and a detailed comparison with Cut190 revealed highly conserved features with implications for both catalysis and substrate binding. Polyesterase activity was confirmed using an agar-based polycaprolactone (PCL) clearing assay, following heterologous expression of BgP in Escherichia coli. This is the first report of a polyesterase being identified from a deep-sea sponge bacterium such as Brachybacterium ginsengisoli and provides further insights into marine-derived polyesterases, an important family of enzymes for PET plastic hydrolysis. Microorganisms living in association with sponges are likely to have increased exposure to plastics and microplastics given the wide-scale contamination of marine ecosystems with these plastics, and thus they may represent a worthwhile source of enzymes for use in new plastic waste management systems. This study adds to the growing knowledge of microbial polyesterases and endorses further exploration of marine host-associated microorganisms as a potentially valuable source of this family of enzymes for PET plastic hydrolysis.
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    Genome mining and characterisation of a novel transaminase with remote stereoselectivity
    (Springer Nature Switzerland AG, 2019-12-30) Gavin, Declan P.; Reen, F. Jerry; Rocha-Martin, J.; Abreu-Castilla, I.; Woods, David F.; Foley, Aoife M.; Sanchez-Murcia, P. A.; Schwarz, Maria; O'Neill, P.; Maguire, Anita R.; O'Gara, Fergal; Enterprise Ireland; Health Research Board; Irish Thoracic Society; European Commission; Science Foundation Ireland; Irish Research Council for Science, Engineering and Technology; Cystic Fibrosis Foundation; Austrian Science Fund
    Microbial enzymes from pristine niches can potentially deliver disruptive opportunities in synthetic routes to Active Pharmaceutical Ingredients and intermediates in the Pharmaceutical Industry. Advances in green chemistry technologies and the importance of stereochemical control, further underscores the application of enzyme-based solutions in chemical synthesis. The rich tapestry of microbial diversity in the oceanic ecosystem encodes a capacity for novel biotransformations arising from the chemical complexity of this largely unexplored bioactive reservoir. Here we report a novel omega-transaminase discovered in a marine sponge Pseudovibrio sp. isolate. Remote stereoselection using a transaminase has been demonstrated for the first time using this novel protein. Application to the resolution of an intermediate in the synthesis of sertraline highlights the synthetic potential of this novel biocatalyst discovered through genomic mining. Integrated chemico-genomics revealed a unique substrate profile, while molecular modelling provided structural insights into this 'first in class' selectivity at a remote chiral centre.
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    Investigating microcrystalline cellulose crystallinity using Raman spectroscopy
    (Springer Nature Switzerland AG, 2021-07-27) Queiroz, Ana Luiza P.; Kerins, Brian M.; Yadav, Jayprakash; Farag, Fatma; Faisal, Waleed; Crowley, Mary Ellen; Lawrence, Simon E.; Moynihan, Humphrey A.; Healy, Anne Marie; Vucen, Sonja; Crean, Abina M.; Science Foundation Ireland; European Regional Development Fund
    Microcrystalline cellulose (MCC) is a semi-crystalline material with inherent variable crystallinity due to raw material source and variable manufacturing conditions. MCC crystallinity variability can result in downstream process variability. The aim of this study was to develop models to determine MCC crystallinity index (%CI) from Raman spectra of 30 commercial batches using Raman probes with spot sizes of 100 µm (MR probe) and 6 mm (PhAT probe). A principal component analysis model separated Raman spectra of the same samples captured using the different probes. The %CI was determined using a previously reported univariate model based on the ratio of the peaks at 380 and 1096 cm−1. The univariate model was adjusted for each probe. The %CI was also predicted from spectral data from each probe using partial least squares regression models (where Raman spectra and univariate %CI were the dependent and independent variables, respectively). Both models showed adequate predictive power. For these models a general reference amorphous spectrum was proposed for each instrument. The development of the PLS model substantially reduced the analysis time as it eliminates the need for spectral deconvolution. A web application containing all the models was developed.
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    Exploiting continuous processing for challenging diazo transfer and telescoped copper-catalyzed asymmetric transformations
    (American Chemical Society, 2021-08-11) Crowley, Daniel C.; Brouder, Thomas A.; Kearney, Aoife M.; Lynch, Denis; Ford, Alan; Collins, Stuart G.; Maguire, Anita R.; Irish Research Council; Science Foundation Ireland; European Regional Development Fund
    Generation and use of triflyl azide in flow enables efficient synthesis of a range of α-diazocarbonyl compounds, including α-diazoketones, α-diazoamides, and an α-diazosulfonyl ester, via both Regitz-type diazo transfer and deacylative/debenzoylative diazo-transfer processes with excellent yields and offers versatility in the solvent employed, in addition to addressing the hazards associated with handling of this highly reactive sulfonyl azide. Telescoping the generation of triflyl azide and diazo-transfer process with highly enantioselective copper-mediated intramolecular aromatic addition and C–H insertion processes demonstrates that the reaction stream containing the α-diazocarbonyl compound can be obtained in sufficient purity to pass directly over the immobilized copper bis(oxazoline) catalyst without detrimentally impacting the catalyst enantioselectivity.