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Fabian L.,University College Cork | Hamill N.,Almac science | Eccles K.S.,University College Cork | Moynihan H.A.,University College Cork | And 3 more authors.
Crystal Growth and Design | Year: 2011

Cocrystal formation between nicotinamide and five fenamic acid derivative drugs (flufenamic acid, niflumic acid, tolfenamic acid, mefenamic acid and meclofenamic acid) was investigated using solution-based and solid-state preparation methods. It was anticipated that the well-known acid-aromatic nitrogen heterosynthon would provide a sufficient driving force for cocrystallization. The experiments yielded cocrystals with four of the five acids. Although the structures of these molecules are similar, they showed marked differences in both the stability and the stoichiometry of the cocrystals. A detailed analysis of the structures and properties of both the starting materials and the cocrystals allows a tentative explanation of these differences, but it also shows that even though all four cocrystals utilize one of the most predictable supramolecular synthons (COOH...N), their structures and properties remain elusive to design. © 2011 American Chemical Society.


Murrell V.,Almac science | Fabritius C.-H.,Almac science | Speed D.,Almac science | Denance M.,Almac science | And 6 more authors.
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2010

There are several literature methods for conversion of 14C precursors into [14C]-acetylenes, and a number of these involve elaboration of [14C]-aldehydes into a terminal acetylenes. One method that involves mild conditions, and in our experience is high yielding and tolerant of a range of functional groups uses the Ohira-Bestmann reagent to effect this transformation. This document briefly describes some of the different methods that have been used for the preparation of [ 14C]-acetylenes and discusses two worked examples, the synthesis of [5-14C]-hex-5-ynoic acid and [benzene-(U)-14C]-7- methoxybenzofuran, both of which involve Ohira-Bestmann chemistry being used for the preparation of terminal [14C]-acetylenes. Copyright © 2010 John Wiley & Sons, Ltd.


Higgins C.A.,Queen's University of Belfast | Bell T.,Almac science | Delbederi Z.,Almac science | Feutren-Burton S.,Almac science | And 6 more authors.
Planta Medica | Year: 2010

A study of the components of the fruits of Kigelia pinnata was undertaken to identify compounds with potential growth inhibitory activity against human melanoma cells, since extracts from the fruits of this plant have been described in traditional medicine to have application in the treatment of skin cancer and other skin ailments. A bioactivity-guided fractionation process yielded a number of crude fractions, which demonstrated cytotoxicity in vitro against human melanoma cells. Compounds isolated and identified included the isocoumarins, demethylkigelin (1) and kigelin (2), fatty acids, oleic (3) and heneicosanoic acids (4), the furonaphthoquinone, 2-(1-hydroxyethyl)-naphtho[2,3- b]furan-4,9-dione (5), and ferulic acid (6). A number of structurally related synthetic compounds were also tested using the MTT assay. The most potent series of these compounds, the furonaphthoquinones, also demonstrated a cytotoxic effect in two human breast cancer cell lines tested. © Georg Thieme Verlag KG Stuttgart · New York.


Guo M.,De Montfort University | Wang K.,De Montfort University | Hamill N.,Almac Science | Lorimer K.,Almac Science | Li M.,De Montfort University
Molecular Pharmaceutics | Year: 2016

The development of enabling formulations is a key stage when demonstrating the effectiveness of pharmaceutical cocrystals to maximize the oral bioavailability for poorly water soluble drugs. Inhibition of drug crystallization from a supersaturated cocrystal solution through a fundamental understanding of the nucleation and crystal growth is important. In this study, the influence of the three polymers of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2-pyrrodidone (60%) and vinyl acetate (40%) (PVP-VA) on the flufenamic acid (FFA) crystallization from three different supersaturated solutions of the pure FFA and two cocrystals of FFA-NIC CO and FFA-TP CO has been investigated by measuring nucleation induction times and desupersaturation rates in the presence and absence of seed crystals. It was found that the competition of intermolecular hydrogen bonding among drug/coformer, drug/polymer, and coformer/polymer was a key factor responsible for maintaining supersaturation through nucleation inhibition and crystal growth modification in a cocrystal solution. The supersaturated cocrystal solutions with predissolved PEG demonstrated more effective stabilization in comparison to the pure FFA in the presence of the same polymer. In contrast, neither of the two cocrystal solutions, in the presence of PVP or PVP-VA, exhibited a better performance than the pure FFA with the same predissolved polymer. The study suggests that the selection of a polymeric excipient in a cocrystal formulation should not be solely dependent on the interplay of the parent drug and polymer without considering the coformer effects. © 2016 American Chemical Society.


Maltman B.A.,Elvingston Science Center | Dunsmore C.J.,Elvingston Science Center | Couturier S.C.M.,Almac science | Tirnaveanu A.E.,Elvingston Science Center | And 5 more authors.
Chemical Communications | Year: 2010

A novel long lifetime fluorescence reporter based on 9-aminoacridine was designed, the lifetime of which can be modulated in a defined manner when in proximity to a tryptophan residue enabling fluorescence lifetime based biochemical assays to be configured. © 2010 The Royal Society of Chemistry.


Hamill N.A.,Almac science | Howells M.E.,Novozymes AS
ACS Symposium Series | Year: 2014

The safe management of hazardous reagents is a key part of the transition from medicinal chemistry syntheses to pilot scale processes. The detection, investigation and circumvention of the risks associated with their use at scale are elucidated through six case studies from the contract manufacturing sector. An approach for the successful scale up using hazardous reagents is described, involving the combination of chemical hazard assessment and 'holistic process design', where the integration of hazard reduction measures and the maintenance of product quality should be viewed with equal importance. © 2014 American Chemical Society.


Zlateski V.,ETH Zurich | Fuhrer R.,ETH Zurich | Koehler F.M.,ETH Zurich | Wharry S.,Almac science | And 5 more authors.
Bioconjugate Chemistry | Year: 2014

In the pursuit of robust and reusable biocatalysts for industrial synthetic chemistry, nanobiotechnology is currently taking a significant part. Recently, enzymes have been immobilized on different nanoscaffold supports. Carbon coated metallic nanoparticles were found to be a practically useful support for enzyme immobilization due to their large surface area, high magnetic saturation, and manipulatable surface chemistry. In this study carbon coated cobalt nanoparticles were chemically functionalized (diazonium chemistry), activated for bioconjugation (N,N-disuccinimidyl carbonate), and subsequently used in enzyme immobilization. Three enzymes, β-glucosidase, α-chymotrypsin, and lipase B were successfully covalently immobilized on the magnetic nonsupport. The enzyme-particle conjugates formed retained their activity and stability after immobilization and were efficiently recycled from milliliter to liter scales in short recycle times. © 2014 American Chemical Society.


PubMed | De Montfort University and Almac Science
Type: Journal Article | Journal: Molecular pharmaceutics | Year: 2016

The development of enabling formulations is a key stage when demonstrating the effectiveness of pharmaceutical cocrystals to maximize the oral bioavailability for poorly water soluble drugs. Inhibition of drug crystallization from a supersaturated cocrystal solution through a fundamental understanding of the nucleation and crystal growth is important. In this study, the influence of the three polymers of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2-pyrrodidone (60%) and vinyl acetate (40%) (PVP-VA) on the flufenamic acid (FFA) crystallization from three different supersaturated solutions of the pure FFA and two cocrystals of FFA-NIC CO and FFA-TP CO has been investigated by measuring nucleation induction times and desupersaturation rates in the presence and absence of seed crystals. It was found that the competition of intermolecular hydrogen bonding among drug/coformer, drug/polymer, and coformer/polymer was a key factor responsible for maintaining supersaturation through nucleation inhibition and crystal growth modification in a cocrystal solution. The supersaturated cocrystal solutions with predissolved PEG demonstrated more effective stabilization in comparison to the pure FFA in the presence of the same polymer. In contrast, neither of the two cocrystal solutions, in the presence of PVP or PVP-VA, exhibited a better performance than the pure FFA with the same predissolved polymer. The study suggests that the selection of a polymeric excipient in a cocrystal formulation should not be solely dependent on the interplay of the parent drug and polymer without considering the coformer effects.

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