Analytical & Biological Chemistry Research Facility

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1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with diazoalkanes
(RSC Publishing, 2010-06-21) Kissane, Marie; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology
2-Thio-3-chloroacrylamides undergo 1,3-dipolar cycloadditions with diazoalkanes leading to a series of novel pyrazolines and pyrazoles. The mechanistic and synthetic features of the cycloadditions to the 2-thio-3-chloroacrylamides at both the sulfide and sulfoxide levels of oxidation are rationalised on the basis of the nature of the substituents.
1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and nitrones
(Elsevier, 2010-06-19) Kissane, Marie; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology
1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and nitrones is described. A series of novel isoxazolines are isolated from the nitrile oxide cycloadditions, whilst the isoxazolines generated from the nitrone cycloadditions undergo further ring opening to yield piperidines.
Access to modified geiparvarins using Pd(0)-mediated C-C bond forming reactions
(University College Cork, 2014) Lynch, Denis; McCarthy, Daniel G.; Cork County Council; Irish Research Council for Science Engineering and Technology
Geiparvarin is a natural product which contains both a 3(2H)-furanone and a coumarin moiety in its structure. The aim of this project was to investigate the use of Pd(0)-mediated C–C bondforming reactions to produce structurally modified geiparvarins. Chapter 1 consists of a review of the relevant literature, including that pertaining to the syntheses of selected naturally occurring 3(2H)-furanones. The known syntheses of geiparvarin and closely related analogues are examined, along with the documented biological activity of these compounds. The synthetic routes which allow access to 4-substituted-3(2H)-furanones are also described. Chapter 2 describes in detail the synthesis of a variety of novel structurally modified geiparvarins by two complementary routes, both approaches utilising Pd(0)-mediated crosscoupling reactions, and discusses the characterisation of these compounds. The preparation of 5-ethyl-3(2H)-furanones is described, as is their incorporation into geiparvarin and the corresponding 5″-alkylgeiparvarin analogues via formation and dehydration of intermediate alcohols. Halogenation of 5-ethyl-3(2H)-furanones and the corresponding geiparvarin derivatives is discussed, along with further reactions of the resulting halides. Preparation of 3″-arylgeiparvarins involving both Suzuki–Miyura and Stille reactions, using the appropriate intermediate iodides and bromides, is described. The application of Stille and Heck conditions to give 3″-ethenylgeiparvarin analogues and Sonogashira conditions to produce 3″-ethynylgeiparvarin analogues, using the relevant intermediate iodides, is also extensively outlined. Chapter 3 contains all of the experimental data and details of the synthetic methods employed for the compounds prepared during the course of this research. All novel compounds prepared were fully characterised using NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; the details of which are included.
Addition-substitution reactions of 2-thio-3-chloroacrylamides with carbon, nitrogen, oxygen, sulfur and selenium nucleophiles
(RSC Publishing, 2011-04-07) Kissane, Marie; Murphy, Maureen; O'Brien, Elisabeth; Chopra, Jay; Murphy, Linda.; Collins, Stuart G.; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology; Forbairt; Merck, United States; University College Cork
Synthetically versatile conjugate addition of a range of carbon, nitrogen, oxygen, sulfur and selenium nucleophiles to the highly functionalised 2-thio-3-chloroacrylamides is described. The stereochemical and synthetic features of this transformation are discussed in detail. In most instances, the nucleophile replaces the chloro substituent with retention of stereochemistry. With the oxygen nucleophiles, a second addition can occur leading to acetals, while with the nitrogen nucleophiles, E-Z isomerism occurs in the resulting enamine derivatives. The ratio of the E/Z isomers can be rationalised on the basis of the substituent and the level of oxidation.
Advances in the synthesis of acyclic peroxides
(Royal Society of Chemistry, 2017-03-31) O'Sullivan, Timothy P.; Gandhi, Hirenkumar; O'Reilly, Kate; Gupta, Manoj K.; Horgan, Conor C.; O'Leary, Eileen M.; Irish Research Council; European Commission; Seventh Framework Programme
Peroxide-containing compounds are an attractive synthetic target, given their widespread abundance in nature, with many displaying potent antimalarial and antimicrobial properties. This review summarises the many developments in the synthesis of acyclic peroxides, with a particular focus on the past 20 years, and seeks to update organic chemists about these new approaches. The synthetic methodologies have been subdivided into metal-catalysed reactions, organocatalytic reactions, direct oxidation reactions, miscellaneous reactions and enzymatic routes to acyclic peroxides.
Alpha-carboxynucleoside phosphonates: direct-acting inhibitors of viral DNA polymerases
(Future Science, 2019-01-16) Balzarini, Jan; Ford, Alan; Maguire, Nuala M.; John, Jubi; Das, Kalyan; Arnold, Eddy; Dehaen, Wim; Maguire, Anita R.; KU Leuven; National Institutes of Health; Science Foundation Ireland
Acyclic nucleoside phosphonates represent a well-defined class of clinically used nucleoside analogs. All acyclic nucleoside phosphonates need intracellular phosphorylation before they can bind viral DNA polymerases. Recently, a novel class of alpha-carboxynucleoside phosphonates have been designed to mimic the natural 2′-deoxynucleotide 5′-triphosphate substrates of DNA polymerases. They contain a carboxyl group in the phosphonate moiety linked to the nucleobase through a cyclic or acyclic bridge. Alpha-carboxynucleoside phosphonates act as viral DNA polymerase inhibitors without any prior requirement of metabolic conversion. Selective inhibitory activity against retroviral reverse transcriptase and herpesvirus DNA polymerases have been demonstrated. These compounds have a unique mechanism of inhibition of viral DNA polymerases, and provide possibilities for further modifications to optimize and fine tune their antiviral DNA polymerase spectrum.
The application of molecular tethers in controlling axial chirality
(Bentham Science Publishers, 2016-06) Reen, Michael; O'Sullivan, Timothy P.
Atropisomeric biaryl compounds are an attractive target in organic chemistry due to their abundance in nature and their utility as ligands in catalysis. Among the methods available for their synthesis, the use of chiral tethers offers very high levels of stereocontrol. In this article, we review the application of molecular tethers in controlling axial chirality across a range of different ligands and natural products.
Applications development of broadband acoustic resonance dissolution spectroscopy (BARDS) in the pharmaceutical, food and animal nutrition industries
(University College Cork, 2018) Ahmed, M. Rizwan; Fitzpatrick, Dara; Irish Research Council
Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) is a novel analytical tool for the characterisation of powders, blends, tablets and a myriad of formulations. It is based on a phenomenon which occurs during the dissolution of solid material in solution. When the sample is added the solution undergoes changes in its compressibility due to gas evolution in solution. This has the effect of slowing down a resonant frequency which is induced in the dissolution vessel. These frequency changes are very reproducible and can be used as a signature for the sample in question. This also infers that what may have been previously understood to be a random and chaotic dissolution of a sample, is in fact highly ordered in terms of gas evolution and loss. The results chapters will highlight new and exciting applications which have been developed using BARDS for several industries. These include the analysis of a variety of milk protein concentrates, whey protein concentrates and isolates. An example of this is a new method to track the hydration of milk protein concentrates which has been developed and modelled. In addition, tracking the agglomeration of milk protein isolates has also been developed which takes a fraction of the time and cost of current approaches. Data generated in collaboration with industry partners have also shown that BARDS can be used to track the degree of hydrosylation of soy proteins. It is also demonstrated that profiles could be established for yeast and soy protein-based supplement products with different manufacturing provenance. Samples showed excellent intra-batch consistency whilst inter-batch comparisons were clearly discernible depending on the manufacturing site. The research in this thesis has also lead to the major discovery of a new approach to determine pH and acid base reactions which is probeless, contactless and non-titrimetric. Additionally, synthesis of gold nanoparticles due to reduction reaction between acid and base were also monitored. Important pharmaceutical applications have also been developed for continuous batch manufacturing relating to wettability of lubricated and unlubricated blends. Results show the degree of blending of lubricants and their likely effect on tablet hardness. The speed of conveyancing of powder material is also assessed as are the final compressed tablets using BARDS. Finally, applications to parameterise yeast metabolism have also been developed which produce data for the uptake rate of carbon sources and the rate of CO2 production. The relationship between CO2 production and ethanol production have also been achieved. A quantitative value for gas production by individual cells has been established by BARDS experiments. In conclusion, multiple applications with extreme novelty of this platform technology have been demonstrated with scope for many more to be developed. The broader impacts of the research are both academically and commercially.
Applications of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) in pharmaceutical analysis
(University College Cork, 2022-02-08) O'Mahoney, Niamh; Fitzpatrick, Dara; National University of Ireland
Dissolution testing is one of the most time-consuming, costly, and laborious tasks in the pharmaceutical industry, and yet it is a cornerstone of quality control testing and product release. Dissolution testing is a prerequisite for the quality control and release to market of nearly every prescription and over the counter product. It is one of the few technologies which has not undergone disruption of any kind. Practices have changed little in decades, with liquid samples being taken at regular intervals over several hours and tested using expensive analytical instruments. Most routine testing can take upwards of a day to perform. Speeding up these processes is vital. This thesis highlights a modern complementary approach to existing dissolution testing practices for powder, pellet, tablet and liquid formulations called Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS is an innovative technique that can economise production processes for drug formulations. BARDS is based on reproducible changes in a solvent's compressibility as a sample dissolves. It is a rapid and straightforward method that utilises a magnetic stir bar to mix added solute and induce a vessel's acoustic resonance containing a fixed volume of solvent. As a sample is wetted and subsequently dissolved, gas is released from the solvent, altering the resonance frequency. Adding a solute to a solvent reduces the solubility of dissolved gases in solution, leading to gas oversaturation and outgassing of the solvent, changing the solvent system's compressibility, and reducing the velocity of sound in the solvent. In the results section of this thesis, Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) is used to characterise several pharmaceutical formulations, including enteric-coated microspheres, tablets and multiple-unit pellet systems (MUPS). Effervescent tablets, chewable tablets and liquid formulations were also analysed. A single replicate BARDS measurement can provide data relevant to multiple dissolution processes in a time-efficient manner by tracking the Erosion of the enteric coating, Disintegration, Deaggregation and overall Dissolution of the formulations while assessing the formulation's integrity using an EDDDI Plot. BARDS can determine the thickness of the drug and enteric coatings, characterise various dosage forms and test formulation integrity. Ultra Violet -Visable Spectroscopy (UV-Vis) has been used in the cross-validation of the technique. Tablets, pellets, and multiple-unit pellet system (MUPS) formulations were examined to investigate the effect of polymer coating and formulation core degradation over time. BARDS can enable the rapid development of solid drug formulation dissolution and disintegration testing as an In-Process and In-Line Control test and drug stability analysis. In combination with minimal Ultra Violet - Visible Spectroscopy usage, BARDS can effectively track these changes, therefore assessing a formulation's stability. BARDS data also indicates which aspect of a formulation may be unstable, whether a coating, sub-coating or core. Paediatric and geriatric formulations were studied in detail in this thesis. Chewable, effervescent and liquid dosage forms were characterised for formulation attributes using BARDS. Nutraceutical and pharmaceutical chewable and effervescent formulations were investigated in tablet form to examine how the formulation disintegrates and dissolves. The data show that a solid oral dose formulation has an intrinsic acoustic signature specific to the method of manufacture and excipient composition. Effervescent tablets disintegrate rapidly due to a chemical reaction. The reaction causes carbon dioxide gas production and subsequent release, resulting in the characteristic effervescent fizz, which can be tracked acoustically using BARDS. This thesis will highlight BARDS as a rapid characterisation technique to track the chemical reaction associated with effervescent dosage forms. BARDS can be used as an analytical tool to quantify the dissolution of liquid formulations. This has been demonstrated by a test model using two different liquid formulation types, suspension formulations and syrup formulations. Similarities between different brands were apparent when tested. BARDS can qualitatively discriminate between Active Pharmaceutical Ingredient (API) dosage, API type, and discriminate whether an API has been partially dissolved in the suspension media before addition to the BARDS instrument. In conclusion, various applications with the tremendous novelty of this platform technology have been proven. This project can potentially impact the methodology for dissolution testing with a high capability to influence regulatory policies and practices worldwide. BARDS can enable the rapid development of solid drug formulation dissolution and disintegration testing as an in-process control test and drug stability analysis. The data shows that a dosage formulation has an intrinsic acoustic signature specific to the method of manufacture, excipient composition and elapsed time since the production of a product. In addition, BARDS is a time-efficient, cost-effective and green approach to formulation characterisation.
The arylation of 2-pyrones and related heterocycles
(University College Cork, 2018) Prendergast, Aisling M.; Mcglacken, Gerard P.; Science Foundation Ireland
2-Pyrones, and related heterocycles such as 2-pyridones, 2-coumarins and 2- quinolones, are useful model substrates to test a novel methodology due to their varied chemical properties. In addition, these moieties possess broad spectrum biological activity. Chapter 1 provides a review of C–H activation methodology as it has been applied to 2-pyrones and related heterocycles. Direct arylation via C–H activation of 2-pyrone, 2-pyridone and 2-coumarin compounds is described in Chapter 2. Protocols for the palladium-catalysed direct arylation of these molecules were developed and applied to a library of substrates. C–H activation at both the C–3 and C–5 positions of the 2-pyrone scaffold was achieved. The C–5 direct arylation methodology proceeded with retention of a C–Cl bond to give a cyclised 3-chloro-2-pyrone. In Chapter 3, the development of cross-coupling conditions for the cyclised 3-chloro-2-pyrone is discussed. Following on from this, more generally applicable, environmentally friendly cross-coupling conditions evolved to allow the application of green chemistry principles to the Suzuki-Miyaura cross-coupling of 2-coumarins, 2-pyrones, 2-pyridones and 2-quinolones, with yields of up to 99%. In parallel to the synthetic aspects of this project, investigations were also performed to understand the mechanisms through which 2-coumarins and related heterocycles undergo C–H activation and direct arylation reactions. In Chapter 4 the experiments which were performed as part of these investigations are described, and the results are presented. Based upon these results from three different sets of reaction conditions, it was proposed that C–H activation of these substrates occurs via concerted metallation-deprotonation.
Asymmetric 1,3-dipolar cycloadditions of acrylamides
(RSC Publishing, 2009) Kissane, Marie; Maguire, Anita R.
This critical review, which is relevant to researchers in synthetic organic chemistry, focuses on asymmetric 1,3-dipolar cycloadditions with acrylamides. The use of chiral acrylamides as dipolarophiles leads to high levels of stereocontrol, due to conformational constraint in the acrylamides. Employment of chiral tertiary acrylamides containing nitrogen heterocycles is particularly effective in controlling the stereoselectivity. Following a general overview of 1,3-dipolar cycloadditions, the main body of the review focuses on asymmetric 1,3-dipolar cycloadditions of acrylamides with nitrile oxides, nitrones, diazoalkanes and azomethine ylides, with particular emphasis on the rationale for the observed stereocontrol (215 references).
Asymmetric oxidation of sulfides
(Taylor and Francis, 2012-10-16) O'Mahony, Graham E.; Ford, Alan; Maguire, Anita R.
This review discusses synthesis of enantiopure sulfoxides through the asymmetric oxidation of prochiral sulfides. The use of metal complexes to promote asymmetric sulfoxidation is described in detail, with a particular emphasis on the synthesis of biologically active sulfoxides. The use of non-metal-based systems, such as oxaziridines, chiral hydroperoxides and peracids, as well as enzyme-catalyzed sulfoxidations is also examined.
Asymmetric peroxidation of α,β-unsaturated aldehydes under diarylprolinol ether catalysis
(Bentham Science Publishers, 2017) O'Reilly, Kate; Gupta, Manoj K.; Gandhi, Hirenkumar; Kumar, Vydyula P.; O'Sullivan, Timothy P.; Irish Research Council; Horizon 2020
Background: Chiral peroxides, many of which are biologically active, are an attractive target in organic synthesis. Organocatalysts have been used for some time in the asymmetric epoxidation of α,β- unsaturated carbonyls. More recently, cinchona-derived organocatalysts have been adapted to effect the asymmetric peroxidation of unsaturated ketones. We successfully applied this catalyst system to the stereoselective peroxidation of more challenging α,β-unsaturated aldehydes with moderate enantioselectivity observed. Herein we describe our efforts to improve upon the overall stereoselectivity using prolinol-derived organocatalysts. Objective: To determine whether diarylprolinol silyl ethers are effective catalysts in the asymmetric peroxidation of α,β-unsaturated aldehydes. Methods: Using trans-2-butenal as the test substrate, peroxidation with tert-butyl hydroperoxide was attempted in a range of different solvents. The resulting β-peroxyaldehydes were oxidised in situ to afford stable β-peroxyesters. The reaction was further optimised by varying the co-catalyst and by changing the silyl ether group on the prolinol catalyst. A number of short-chain substrates were subjected to peroxidation under optimised conditions. Results: Diarylprolinol ethers were found to be effective catalysts for the enantioselective peroxidation of unsaturated aldehydes. The degree of enantioselectivity was influenced both by the choice of solvent and acid cocatalyst. Furthermore, a clear trend emerged where the level of enantioselectivity increased with increasing steric bulk of the silyl group. Conclusion: Diarylprolinol ethers are effective catalysts for the asymmetric peroxidation of α,β-unsaturated aldehydes. Under optimised conditions, short-chain substrates may be converted to the corresponding β- peroxyesters in good yields and excellent enantioselectivities.
Asymmetric transformations of enolates and azaenolates
(University College Cork, 2023-04-29) Alcock, Emma; Mcglacken, Gerard P.; Irish Research Council; Higher Education Authority
Chapter I - The asymmetric α-alkylation of a ketone represents one of the most fundamental reactions in organic chemistry. In 2014, a chiral ligand strategy to furnish enantioenriched α-alkylated ketones was published by the McGlacken group. The yields and enantioselectivities achieved for this transformation were modest. The first section of this thesis outlines efforts to further expand the scope of this methodology and improve the enantioselectivity of this chiral ligand protocol. Whilst a 10% ee was observed for the direct α-alkylation of a ketone, future optimisations focused on the use of N,N-dimethylhydrazones as ketone surrogates. A number of previously unexplored solvents, chiral ligands, hydrazones and electrophiles were examined. However, attempts to improve the enantioselectivity proved unsuccessful. The latter section of this chapter details a number of asymmetric transformations with 2-alkyl pyridines (azaenolate equivalents). Investigations were undertaken to develop new asymmetric aldol and Michael-type reactions for these substrates using chiral amines. Modest enantio- and diastereoselectivities were observed for the aldol reaction. Chapter II - Outlines efforts to develop a continuous flow chemistry protocol for the α-alkylation of a range of simple ketone substrates. Extensive optimisation studies are detailed within this chapter. Continuous flow chemistry proved to be a superior alternative to traditional batch chemistry for this transformation. Advantages of the continuous approach include: i) significantly higher yields; ii) reduced reaction times; iii) increased product purity; iv) more scalable reaction temperatures and v) an increased safety profile associated with the use of hazardous alkyl lithium and alkylating agents. Chapter III - Describes methodology for the synthesis of 3-amino-1,5-diol derivatives with concurrent introduction of up to five contiguous chiral centres in one-pot. Highly functionalised amino alcohol derivatives of challenging substrates such as butanone, 3-pentanone and cyclobutanone were synthesised via an aldol, aldol-Tishchenko reaction of (S)-tert-butanesulfinyl imine derivatives. Modest yields (up to 55%) and excellent diastereoselectivites (up to > 99:1) were achieved for this transformation. The synthetic utility of the compounds synthesised was examined by selective cleavage of the ester and sulfinyl moiety. Finally, the absolute stereochemistry of the major diastereomer was elucidated by X-ray crystallography and mechanistic insight is provided using DFT calculations, through collaboration with Prof Ken Houk.
Biocatalysis in organic synthesis
(University College Cork, 2019) Foley, Aoife M.; Maguire, Anita R.; Science Foundation Ireland
The first chapter provides an overview of the use of biocatalysis for the synthesis of pharmaceutical intermediates and natural products. This review focuses, in particular, on the impact of recent developments in technologies which enable the increased use of biocatalysts. These developments include: • the immobilisation of biocatalysts to enhance stability and ease of use, and enabling use in combination with metal and organocatalysts leading to dynamic kinetic resolution, as well as in continuous flow. • discovery and development of novel enzymes using molecular biology for enzyme engineering and metagenomics. The second chapter describes the lipase-mediated kinetic resolution of 2-phenylalkanols by tuning the steric properties of the acyl group to control the efficiency and selectivity of the resolution. In contrast to literature reports, efficient resolution was achieved using short-chain acyl groups through careful process control and substrate modification. The effect of increased steric demand at the stereocentre was also explored. Chapter three describes proof of concept that a hydrolase-catalysed dynamic kinetic resolution of a lactol is possible. By taking advantage of the spontaneous racemisation of the unreacted starting material, the dynamic kinetic resolution was carried out without the need for a separate racemisation catalyst. While the kinetic resolution was effective in a model system, the biotransformation was inhibited by the introduction of a second, remote stereocentre. Chapter four describes a dynamic kinetic resolution of synthetically versatile nitroalcohols by combination of a lipase-mediated resolution and the reversible intramolecular nitroaldol (Henry) reaction. Significant challenges in effecting the combination of the base-mediated racemisation step and the lipase-mediated resolution step were encountered. Reaction engineering allowed design of a sequential one-pot reaction system which furnished the products with excellent enantioselectivity, and good diastereoselectivity. Chapter five describes the use of novel transaminases in the kinetic resolution of model amine substrates and pharmaceutical intermediates by oxidative deamination, including exploration of the substrate scope of these novel biocatalysts. While transaminase-mediated reductive amination is an attractive method for asymmetric synthesis of chiral amines, the reductive amination is generally thermodynamically disfavoured. Preliminary investigation of approaches to favour the reductive amination is described. The final chapter contains the full experimental details, including spectroscopic and analytical data of all the compounds synthesised in this project; details of chiral phase HPLC analysis are included in the appendix.
Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): a novel approach to investigate the wettability of pharmaceutical powder blends
(American Chemical Society, 2017-09-19) Peddapatla, Raghu V. G.; Ahmed, M. Rizwan; Blackshields, Caroline A.; Sousa-Gallagher, Maria J.; McSweeney, Sean; Kruse, Jacob; Crean, Abina M.; Fitzpatrick, Dara; Enterprise Ireland
The ability of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) to assess the wettability of powder blends is investigated. BARDS is a novel analytical technology developed based on the change in acoustic phenomenon observed when material is added into a solvent under resonance. Addition of solid material to the solvent results in the introduction of gas (air) into the solvent, changing the compressibility of the solvent system and reducing the velocity of sound in the solvent. As a material is wetted and dissolved, the gas is released from the solvent and resonance frequency is altered. The main purpose of this work is to demonstrate the ability of BARDS to assess differences in the wetting behaviour of tablet excipients (microcrystalline cellulose (MCC) and magnesium stearate (MgSt)) and a model drug (metoclopramide hydrochloride) as single component powders and multi-component powder blends. BARDS acoustic responses showed a prolonged release of gas for the powdered blends with lubricant compared to un-lubricated blends. As the elimination of gas from the solvent was assumed to follow first order elimination kinetics, a compressible gas elimination rate constant was calculated from the log plots of the gas volume profiles. The gas elimination rate constant was used as a parameter to compare the release of gas from the powder introduced to the solvent and hence the powder wetting behavior. A lower gas elimination rate constant was measured for lubricated blends compared to non-lubricated blends, suggesting the prolonged hydration of lubricated blends. Standard wetting techniques such as contact angle measurements and wetting time analysis were also used to analyze the blends and confirmed differences in wetting behavior determined by BARDS. The study results demonstrate the capability of BARDS as a rapid, analytical tool to determine the wetting behavior of the pharmaceutical powder blends and the potential of BARDS as a process analytical technology (PAT) tool.
Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): a rapid test for enteric coating thickness and integrity of controlled release pellet formulations
(Elsevier B.V., 2018-04-12) Dillon, Amy; Alfarsi, Anas; McSweeney, Seán; Krüse, Jacob; Griffin, Brendan T.; Devine, Ken J.; Sherry, Patricia; Henken, Stephan; Fitzpatrick, Stephen; Fitzpatrick, Dara; Ministry of Education, Saudi Arabia
There are no rapid dissolution based tests for determining coating thickness, integrity and drug concentration in controlled release pellets either during production or post-production. The manufacture of pellets requires several coating steps depending on the formulation. The sub-coating and enteric coating steps typically take up to six hours each followed by additional drying steps. Post production regulatory dissolution testing also takes up to six hours to determine if the batch can be released for commercial sale. The thickness of the enteric coating is a key factor that determines the release rate of the drug in the gastro-intestinal tract. Also, the amount of drug per unit mass decreases with increasing thickness of the enteric coating. In this study, the coating process is tracked from start to finish on an hourly basis by taking samples of pellets during production and testing those using BARDS (Broadband Acoustic Resonance Dissolution Spectroscopy). BARDS offers a rapid approach to characterising enteric coatings with measurements based on reproducible changes in the compressibility of a solvent due to the evolution of air during dissolution. This is monitored acoustically via associated changes in the frequency of induced acoustic resonances. A steady state acoustic lag time is associated with the disintegration of the enteric coatings in basic solution. This lag time is pH dependent and is indicative of the rate at which the coating layer dissolves. BARDS represents a possible future surrogate test for conventional USP dissolution testing as its data correlates directly with the thickness of the enteric coating, its integrity and also with the drug loading as validated by HPLC.
Catalytic asymmetric C-H insertion reactions of α-diazocarbonyl compounds
(Elsevier, 2010-08-21) Slattery, Catherine N.; Ford, Alan; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology; Eli Lilly and Company, United States
The purpose of this review is to provide an overview of the development of asymmetric catalysts for C-H insertion reactions over the past two decades, focusing on the application of these catalysts in the decomposition of α-diazocarbonyl compounds. Given the rapid pace of development in the field of enantioselective C-H insertion chemistry, an up-to-date review of this type is warranted. While recent reviews22,23 have dissected their content into intramolecular and intermolecular processes, this article is differentiated in extending this division to include classification of C-H insertion reactions according to product type. Thus, catalytic methods for the asymmetric synthesis of carbocyclic compounds, oxygen-containing heterocycles, nitrogen-containing heterocycles and sulfur-containing heterocycles are readily identifiable. Due to the diversity of compounds resulting from intermolecular C-H insertion processes, classification of reactions by product type was not attempted in this section of the review.
Characterisation, solubility and intrinsic dissolution behaviour of benzamide: dibenzyl sulfoxide cocrystal
(Elsevier, 2012-01) Grossjohann, Christine; Eccles, Kevin S.; Maguire, Anita R.; Lawrence, Simon E.; Tajber, Lidia; Corrigan, Owen I.; Healy, Anne Marie; Science Foundation Ireland
This study examined the 1:1 cocrystal benzamide: dibenzyl sulfoxide, comprising the poorly water soluble dibenzyl sulfoxide (DBSO) and the more soluble benzamide (BA), to establish if this cocrystal shows advantages in terms of solubility and dissolution in comparison to its pure components and to a physical mixture. Solubility studies were performed by measuring DBSO solubility as a function of BA concentration, and a ternary phase diagram was constructed. Dissolution was examined through intrinsic dissolution studies. Solid-state characterisation was carried out by powder X-ray diffraction (PXRD), energy-dispersive X-ray diffraction (EDX), infra-red spectroscopy (ATR-FTIR) and thermal analysis. DBSO solubility was increased by means of complexation with BA. For the cocrystal, the solubility of both components was decreased in comparison to pure components. The cocrystal was identified as metastable and incongruently saturating. Dissolution studies revealed that dissolution of DBSO from the cocrystal was not enhanced in comparison to the pure compound or a physical mix, while BA release was retarded and followed square root of time kinetics. At the disk surface a layer of DBSO was found. The extent of complexation in solution can change the stability of the complex substantially. Incongruent solubility and dissolution behaviour of a cocrystal can result in no enhancement in the dissolution of the less soluble component and retardation of release of the more soluble component.
Chemoenzymatic routes to enantiopure hydroxytetrahydrofurans: muscarine and its analogues
(University College Cork, 2015) Beecher, Denis; Maguire, Anita R.; Mccarthy, Daniel G.; Irish Research Council; University College Cork
Muscarine was identified as an active principle of the poisonous mushroom Amanita muscaria over 170 years ago and has been identified as an agonist of acetylcholine. The synthesis of all stereoisomers of muscarine have been accomplished at this stage by chemical methods and the biological activity of these compounds tested. A number of synthetic routes to enantiomerically pure muscarine and its analogues have been published. In this work, we are focussed on the use of a novel biotransformation strategy to access these compounds. Asymmetric synthesis involves targeting a synthetic pathway leading to one enantiomer of a compound and biocatalysis is one strategy used in asymmetric synthesis. Chapter 1 consists of a review of the relevant literature pertaining to the synthesis and stereoselective transformations of 3-hydroxytetrahydrofuranss. A review of synthetic routes to these compounds is presented, with a particular focus on routes to the natural product muscarine and its analogues. Chapter 2 discusses the preparative routes to the 3-hydroxytetrahydrofurans via 3(2H)- furanones. Steps amongst which include Rh(II) mediate cyclisation and kinetic resolution via baker’s yeast mediated carbonyl reduction, resulting in enantioenriched 3- hydroxytetrahydrofuran derivatives. Finally, application of this methodology to the preparation of all four enantiomers of an analogue of desmethylmuscarine and the synthesis of epimuscarine is described. Chapter 3 consists of a detailed experimental section outlining the synthetic procedures employed.

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