Molecular architecture influences on material properties of pharmaceutical compounds

Salt formation has extensively been studied as a strategy to improve drug solubility but it has not been explored as a strategy to improve mechanical properties. A better understanding of which factors of the solid state can have an influence in the mechanical properties of pharmaceutical powders can help to optimise and reduce cost of tablet manufacturing. The aim of this study was to form different series of amine salts of flurbiprofen, gemfibrozil and diclofenac and to establish predictive relationships between architectural characteristics and physicochemical and mechanical properties of the salts. For this purpose, three different carboxylic acid drugs were selected: flurbiprofen, gemfibrozil and diclofenac, similar in size but varying in flexibility and shape and three different series of counterions were also chosen: one with increasing bulk and no hydroxyl groups to limit the hydrogen bonding potential; a second one with increasing number of hydroxyl groups and finally a third series, related to the latter in number of hydroxyl groups but with different molecular shape and flexibility. Physico-chemical characterization was performed (DSC, TGA, solubility, intrinsic dissolution rate, particle size, true density) and mechanical properties measured using a compaction replicator. Strained molecular conformations produce weaker compacts as they have higher energy than preferred conformations that usually lie close to energy minimums and oppose plastic deformation. It was observed that slip planes, which correspond to regions of weakest interaction between the planes, were associated with improved plasticity and stronger compacts. Apart from hydrogen bonds, profuse van der Waals forces can result in ineffective slip planes. Salts displaying two-dimensional densely hydrogen bonded layers produced stronger compacts than salts showing one-dimensional networks of non-bonded columns, probably by reducing the attachment energy between layers. When hydrogen bonds are created intramolecularly, it is possible that the mechanical properties are compromised as they do not contribute so much to create twodimensional densely bonded layers and they can force molecules into strained conformations. Some types of hydrogen bonding network may be associated with improved mechanical properties, such as type II, or R (10) 3 4 using graph-set notation, versus type III, or R (12) 4 8 , columns. This work clearly demonstrates the potential of investigating crystal structure-mechanical property relationship in pharmaceutical materials.

Skin adhesive hydrogels for the topical delivery of active agents

This thesis illustrates the development of tailor-made, partially hydrated skin adhesive hydrogels as a vehicle for the topical delivery of moisturising agents. Maintaining an optimum hydration level of the stratum corneum ensures that the barrier properties of the skin are preserved. An unsaturated ionic monomer 2-acrylamido-2-methylpropanesulfonic acid sodium salt, glycerol, water, a photoinitiator Irgacure 184 and crosslinker Ebacryl II facilitated the production of monophasic sheet skin adhesives using photopolymerisation. The exploration and modification of the hydrogel components coupled with their influence on the adhesive and dynamic mechanical behaviour led to the development of novel monophasic and biphasic hydrogels. Biphasic pregels comprising of a hydrophobic monomer (epoxidised soybean oil acrylate, lauryl acrylate or stearyl acrylate) micellised with a non ionic surfactant Tween 60 allowed a homogeneous distribution throughout a predominantly hydrophilic phase (2-acrylamido-2-methylpropanesulfonic acid sodium salt, 4-acryloylmorpholine, glycerol and water). Further development of biphasic hydrogel technology led to the incorporation of preformed commercial O/W emulsions (Acronal, Flexbond 150, DM137 or Texicryl 13056WB) allowing the hydrophobic component to be added without prior stabilisation. The topical release of moisturising agents 2-pyrrolidone-5-carboxylic acid, lactobionic acid and d-calcium pantothenate results in the deposition onto the skin by an initial burst mechanism. The hydration level of the stratum corneum was measured using a Comeometer CM 825, Skin Reader MY810 or FT-ATR. The use of hydrophilic actives in conjunction with lipophilic agents for example Vitamin E or Jojoba oil provided an occlusive barrier, which reduced the rate of transepidermal water loss. The partition coefficients of the release agents provided invaluable information which enabled the appropriate gel technology to be selected. In summary the synthetic studies led to the understanding and generation of transferable technology. This enabled the synthesis of novel vehicles allowing an array of actives with a range of solubilities to be incorporated.

Chemistry of phospholipid oxidation

The oxidation of lipids has long been a topic of interest in biological and food sciences, and the fundamental principles of non-enzymatic free radical attack on phospholipids are well established, although questions about detail of the mechanisms remain. The number of end products that are formed following the initiation of phospholipid peroxidation is large, and is continually growing as new structures of oxidized phospholipids are elucidated. Common products are phospholipids with esterified isoprostane-like structures and chain-shortened products containing hydroxy, carbonyl or carboxylic acid groups; the carbonyl-containing compounds are reactive and readily form adducts with proteins and other biomolecules. Phospholipids can also be attacked by reactive nitrogen and chlorine species, further expanding the range of products to nitrated and chlorinated phospholipids. Key to understanding the mechanisms of oxidation is the development of advanced and sensitive technologies that enable structural elucidation. Tandem mass spectrometry has proved invaluable in this respect and is generally the method of choice for structural work. A number of studies have investigated whether individual oxidized phospholipid products occur in vivo, and mass spectrometry techniques have been instrumental in detecting a variety of oxidation products in biological samples such as atherosclerotic plaque material, brain tissue, intestinal tissue and plasma, although relatively few have achieved an absolute quantitative analysis. The levels of oxidized phospholipids in vivo is a critical question, as there is now substantial evidence that many of these compounds are bioactive and could contribute to pathology. The challenges for the future will be to adopt lipidomic approaches to map the profile of oxidized phospholipid formation in different biological conditions, and relate this to their effects in vivo. This article is part of a Special Issue entitled: Oxidized phospholipids-their properties and interactions with proteins.

Selective functionalisation of Re6 cluster anionic units:from hexa-hydroxo [Re6Q8(OH)6]4− (Q = S, Se) to neutral trans-[Re6Q8L4L′2] hybrid building blocks

The reaction of [Re6Q8(OH)6]4- (Q = S, Se) with p-tertbutylpyridine (TBP) in water leads to neutral trans-[Re6Q8(TBP)4(OH)2] whose hydroxyl reactivity with carboxylic acid and TBP exchange reaction with functional pyridine have been investigated.

Covalent attachment of chiral manganese(III) salen complexes onto functionalised hexagonal mesoporous silica and application to the asymmetric epoxidation of alkenes

Two modified Jacobsen-type catalysts were anchored onto an amine functionalised hexagonal mesoporous silica (HMS) using two distinct anchoring procedures: (i) one was anchored directly through the carboxylic acid functionalised diimine bridge fragment of the complex (CAT1) and (ii) the other through the hydroxyl group on the aldehyde fragment of the complex (CAT2), mediated by cyanuric chloride. The new heterogeneous catalyst, as well as the precedent materials, were characterised by elemental analyses, DRIFT, UV-vis, porosimetry and XPS which showed that the complexes were successfully anchored onto the hexagonal mesoporous silica. These materials acted as active heterogeneous catalysts in the epoxidation of styrene, using m-CPBA as oxidant, and α-methylstyrene, using NaOCl as oxidant. Under the latter conditions they acted also as enantioselective heterogeneous catalysts. Furthermore, when compared to the reaction run in homogeneous phase under similar experimental conditions, an increase in asymmetric induction was observed for the heterogenised CAT1, while the opposite effect was observed for the heterogenised CAT2, despite of CAT2 being more enantioselective than CAT1 in homogeneous phase. These results indicate that the covalent attachment of the Jacobsen catalyst through the diimine bridge leads to improved enantiomeric excess (%ee), whereas covalent attachment through one of the aldehyde fragments results in a negative effect in the %ee. Using α-methylstyrene and NaOCl as oxidant, heterogeneous catalyst reuse led to no significant loss of catalytic activity and enantioselectivity. © 2005 Elsevier Inc. All rights reserved.

Increasing flower longevity in Alstroemeria

The vase-life of Alstroemeria (cv. Rebecca) flowers is terminated when the tepals abscise. Abscission was accelerated by both chloroethylphosphonic acid (CEPA) and 1-aminocyclopropane-1-carboxylic acid (ACC). Petals abscised 24 h earlier compared with controls, when isolated cymes were placed in 340 nM CEPA, and earlier still when higher concentrations were used. This suggests that flowers of this Alstroemeria cultivar are very ethylene sensitive. Treatment with silver thiosulphate (STS) overcame the effects of exposure to CEPA and delayed perianth abscission of untreated isolated flowers by 3-4 days. The inclusion of 1% sucrose in the vase solution also extended longevity but not by as much as STS treatment; combined STS and sucrose treatments did not increase longevity beyond that of either treatment alone. However, removal of the young buds from the axil of the first flower was the most effective treatment to extend vase-life and encouraged the growth and development of the remaining flower. Flowers on cut inflorescences from which young axillary buds were trimmed more than doubled in fresh weight 6 days after flower opening compared with an increase of only 70-80% in those untreated or treated with STS and/or sucrose. Growth was less in isolated cymes but followed a similar pattern. The effect of STS and/or sucrose treatment was synergistic with the trimming treatment and thus the vase-life of trimmed, STS and sucrose-treated flowers was over 7 days longer than that for untreated controls. © 2003 Elsevier B.V. All rights reserved.

Organic reactions in ionic liquids:Ionic liquid promoted Knoevenagel condensation of aromatic aldehydes with (2-thio)barbituric acid

The Knoevenagel condensation of aromatic aldehydes with (2-thio)barbituric acid proceeded efficiently in reusable ionic liquids, EAN, BmimBF4, and BmimPF6 at room temperature in the absence of any catalyst with high yields.

Design and characterisation of novel blends of poly(lactic acid)

This thesis is concerned with the effect of polymer structure on miscibility of the three component blends based on poly(lactic acid) (PLA) with using blending techniques. The examination of novel PLA homologues (pre-synthesised poly(a-esters)), including a range of aliphatic and aromatic poly(a-esters) is an important aspect of the work. Because of their structural simplicity and similarity to PLA, they provide an ideal system to study the effect of polyester structures on the miscibility of PLA polymer blends. The miscibility behaviour of the PLA homologues is compared with other aliphatic polyesters (e.g. poly(e-caprolactone) (PCL), poly(hydroxybutyrate hydroxyvalerate) (P(HB-HV)), together with a series of cellulose-based polymers (e.g. cellulose acetate butyrate (CAB)). The work started with the exploration the technique used for preliminary observation of the miscibility of blends referred to as “a rapid screening method” and then the miscibility of binary blends was observed and characterised by percent transmittance together with the Coleman and Painter miscibility approach. However, it was observed that symmetrical structures (e.g. a1(dimethyl), a2(diethyl)) promote the well-packing which restrict their chains from intermingling into poly(L-lactide) (PLLA) chains and leads the blends to be immiscible, whereas, asymmetrical structures (e.g. a4(cyclohexyl)) behave to the contrary. a6(chloromethyl-methyl) should interact well with PLLA because of the polar group of chloride to form interactions, but it does not. It is difficult to disrupt the helical structure of PLLA. PLA were immiscible with PCL, P(HB-HV), or compatibiliser (e.g. G40, LLA-co-PCL), but miscible with CAB which is a hydrogen-bonded polymer. However, these binary blends provided a useful indication for the exploration the novel three component blends. In summary, the miscibility of the three-component blends are miscible even if only two polymers are miscible. This is the benefit for doing the three components blend in this thesis, which is not an attempt to produce a theoretical explanation for the miscibility of three components blend system.

Mesoporous sulfonic acid silicas for pyrolysis bio-oil upgrading via acetic acid esterification

Propylsulfonic acid derivatised SBA-15 catalysts have been prepared by post modification of SBA-15 with mercaptopropyltrimethoxysilane (MPTMS) for the upgrading of a model pyrolysis bio-oil via acetic acid esterification with benzyl alcohol in toluene. Acetic acid conversion and the rate of benzyl acetate production was proportional to the PrSO3H surface coverage, reaching a maximum for a saturation adlayer. Turnover frequencies for esterification increase with sulfonic acid surface density, suggesting a cooperative effect of adjacent PrSO3H groups. Maximal acetic acid conversion was attained under acid-rich conditions with aromatic alcohols, outperforming Amberlyst or USY zeolites, with additional excellent water tolerance.

Influence of alkyl chain length on sulfated zirconia catalysed batch and continuous esterification of carboxylic acids by light alcohols

The impact of alkyl chain length on the esterification of C2–C16 organic acids with C1–C4 alcohols has been systematically investigated over bulk and SBA-15 supported sulfated zirconias (SZs). Rates of catalytic esterification for methanol with acetic acid are directly proportional to the sulfur content for both SZ and SZ/SBA-15, with the high dispersion of SZ achievable in conformal coatings over mesoporous SBA-15 confering significant rate-enhancements. Esterification over the most active 0.24 mmol gcat−1 bulk SZ and 0.29 mmol gcat−1 SZ/SBA-15 materials was inversely proportional to the alkyl chain length of alcohol and acid reactants; being most sensitive to changes from methanol to ethanol and acetic to hexanoic acids respectively. Kinetic analyses reveal that these alkyl chain dependencies are in excellent accord with the Taft relationship for polar and steric effects in aliphatic systems and the enthalpy of alcohol adsorption, implicating a Langmuir–Hinshelwood mechanism. The first continuous production of methyl propionate over a SZ fixed-bed is also demonstrated.