Synthesis and Solid State Pharmaceutical Centre (SSPC) - Journal Articles
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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(MeFA) and 2-((3-(tert-butyl)phenyl)amino)benzoic acid (tBuFA), analogues of FFA in which the trifluoromethyl group has been replaced by a methyl group or by a tert-butyl group respectively, were selected as the impurities.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 Uncovering the biotechnological importance of Geotrichum candidum(MDPI, 2023) Kamilari, Eleni; Stanton, Catherine; Reen, F. Jerry; Ross, R. PaulFungi make a fundamental contribution to several biotechnological processes, including brewing, winemaking, and the production of enzymes, organic acids, alcohols, antibiotics, and pharmaceuticals. The present review explores the biotechnological importance of the filamentous yeast-like fungus Geotrichum candidum, a ubiquitous species known for its use as a starter in the dairy industry. To uncover G. candidum’s biotechnological role, we performed a search for related work through the scientific indexing internet services, Web of Science and Google Scholar. The following query was used: Geotrichum candidum, producing about 6500 scientific papers from 2017 to 2022. From these, approximately 150 that were associated with industrial applications of G. candidum were selected. Our analysis revealed that apart from its role as a starter in the dairy and brewing industries, this species has been administered as a probiotic nutritional supplement in fish, indicating improvements in developmental and immunological parameters. Strains of this species produce a plethora of biotechnologically important enzymes, including cellulases, β-glucanases, xylanases, lipases, proteases, and α-amylases. Moreover, strains that produce antimicrobial compounds and that are capable of bioremediation were identified. The findings of the present review demonstrate the importance of G. candidum for agrifood- and bio-industries and provide further insights into its potential future biotechnological roles.Item Nebulised delivery of RNA formulations to the lungs: From aerosol to cytosol(Elsevier, 2024-11-25) Neary, Michael T.; Mulder, Lianne M.; Kowalski, Piotr S.; MacLoughlin, Ronan; Crean, Abina M.; Ryan, Katie B.; Science Foundation Ireland; Health Research Board; European Research Council; Irish Research CouncilIn the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success.Item Pharmaceutical salts of piroxicam and meloxicam with organic counterions(ACS Publications, 2022-10-21) Huang, Shan; Venables, Dean S.; Lawrence, Simon E.; Science Foundation IrelandPiroxicam (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.Item 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 TecnológicoMany 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.