Structural properties of a family of hydrogen-bonded co-crystals formed between gemfibrozil and hydroxy derivatives of t-butylamine, determined directly from powder X-ray diffraction data

We report the formation and structural properties of co-crystals containing gemfibrozil and hydroxy derivatives of t-butylamine H2NC(CH3)3-n(CH2OH)n, with n=0, 1, 2 and 3. In each case, a 1:1 co-crystal is formed, with transfer of a proton from the carboxylic acid group of gemfibrozil to the amino group of the t-butylamine derivative. All of the co-crystal materials prepared are polycrystalline powders, and do not contain single crystals of suitable size and/or quality for single crystal X-ray diffraction studies. Structure determination of these materials has been carried out directly from powder X-ray diffraction data, using the direct-space Genetic Algorithm technique for structure solution followed by Rietveld refinement. The structural chemistry of this series of co-crystal materials reveals well-defined structural trends within the first three members of the family (n=0, 1, 2), but significantly contrasting structural properties for the member with n=3. © 2007 Elsevier Inc. All rights reserved.

Experimental and theoretical studies on six-membered ring hydrogen bond systems in crystalline drug substances

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism:lessons from class B crystal structuress

The glucagon-like peptide 1 (GLP-1) receptor is a class B G protein-coupled receptor (GPCR) that is a key target for treatments for type II diabetes and obesity. This receptor, like other class B GPCRs, displays biased agonism, though the physiologic significance of this is yet to be elucidated. Previous work has implicated R2.60190 , N3.43240 , Q7.49394 , and H6.52363 as key residues involved in peptide-mediated biased agonism, with R2.60190 , N3.43240 , and Q7.49394 predicted to form a polar interaction network. In this study, we used novel insight gained from recent crystal structures of the transmembrane domains of the glucagon and corticotropin releasing factor 1 (CRF1) receptors to develop improved models of the GLP-1 receptor that predict additional key molecular interactions with these amino acids. We have introduced E6.53364 A, N3.43240 Q, Q7.49493N, and N3.43240 Q/Q7.49 Q/Q7.49493N mutations to probe the role of predicted H-bonding and charge-charge interactions in driving cAMP, calcium, or extracellular signal-regulated kinase (ERK) signaling. A polar interaction between E6.53364 and R2.60190 was predicted to be important for GLP-1- and exendin-4-, but not oxyntomodulin-mediated cAMP formation and also ERK1/2 phosphorylation. In contrast, Q7.49394 , but not R2.60190 /E6.53364 was critical for calcium mobilization for all three peptides. Mutation of N3.43240 and Q7.49394 had differential effects on individual peptides, providing evidence for molecular differences in activation transition. Collectively, this work expands our understanding of peptide-mediated signaling from the GLP-1 receptor and the key role that the central polar network plays in these events.

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.

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.

The effect of care solutions on the bulk and surface properties of soft contact lenses

Purpose: Soft contact lenses for continuous wear require the use of cleaning regimes which utilise hydrogen peroxide systems or multipurpose cleaning solutions (MPS). The compositions of MPS are becoming increasingly complex and often include disinfectants, cleaning agents, preservatives, wetting agents, demulcents, chelating and buffering agents. Recent research on solution–lens interactions has focused on specific ocular parameters such as corneal staining. However the effect of a solution on the lens, particularly silicone hydrogel lenses, itself has received less attention. The purpose of this work was to establish and understand the effects that care solutions have on selected bulk and surface material properties. Methods: Selected bulk and surface properties of each material (etafilcon A, vifilcon A, balafilcon A, senofilcon A, lotrafilcon A and lotrafilcon B, galyfilcon A) were measured after a 24 h soak in a variety of care solutions. Additionally the lenses were soaked for 24 h in hyperosmolar (680 mOsm L-1) and hyposmolar (170 mOsm L-1) PBS. A bulk property parameter the total diameter (TD) was measured using an Optimec contact lens analyser. The surface property related CoF of soaked lenses was measured on a nano-tribometer with conditions of load 30 mN, at a distance of 20 mm and speed 30 mm/min. Results: In terms of bulk properties, change is related to the EWC of the lens, the higher the EWC of the lens the greater the TD changes. Silicone hydrogel lenses have EWCs of <47% and little or no TD changes were observed; lotrafilcon A exhibited no change irrespective of the cleaning solution. Conventional contact lenses have higher EWCs (58% for etafilcon A and 55% for vifilcon A) and the TD was seen to change to a greater extent, for example the etafilcon A material in ReNu MPS had an increase to 14.45± 0.07 mm from the cited 14.2 mm. Other lenses increased or decreased in TD depending on the solution used. The osmolarity of the solution although important is not the only factor governing change in the TD, for example soaking senofilcon A in hyperosmolar PBS (680 mOsm L-1) for 24 h increased the TD of the lens (+0.25 ± 0.07 mm), however when the same lens type was soaked for 24 h in a MPS with a lower osmolarity there was a similar effect. Biotribology measurements demonstrated that some solution–lens combinations can reduce the CoF by 55%, when compared with biotribology with the native packing solution. An increase in the CoF was observed for other solution–lens combinations. Conclusions: There is a dramatic difference in bulk and surface performance of specific lens materials with particular care solutions. Individual components of the care solutions have effects on the bulk and surface properties of contact lenses. The affects are not as great with the silicone hydrogel as compared with conventional hydrogels.

Anisotropic surface energetics and wettability of macroscopic form I paracetamol crystals

Advancing (θA) and receding (θR) contact angles were measured with several probe liquids on the external facets (201), (001), (011), and (110) of macroscopic form I paracetamol crystals as well as the cleaved (internal) facet (010). For the external crystal facets, dispersive surface energies γd calculated from the contact angles were found to be similar (34 ± 1 mJ/m2), while the polar components varied significantly. Cleaving the crystals exposed a more apolar (010) surface with very different surface properties, including γd = 45 ± 1 mJ/m2. The relative surface polarity (γp/γ) of the facets in decreasing order was (001) > (011) > (201) > (110) > (010), which agreed with the fraction of exposed polar hydroxyl groups as determined from C and O 1s X-ray photoelectron spectroscopy (XPS) spectra, and could be correlated with the number of non-hydrogen-bonded hydroxyl groups per unit area present for each crystal facet, based on the known crystal structures. In conclusion, all facets of form I paracetamol crystals examined exhibited anisotropic wetting behavior and surface energetics that correlated to the presence of surface hydroxyl groups.  © 2006 American Chemical Society.

Comparative physical, mechanical and crystallographic properties of a series of gemfibrozil salts

Objectives Understanding the impact of the counterion on the properties of an acidic or basic drug may influence the choice of salt form, especially for less potent drugs with a high drug load per unit dose. The aim of this work was to determine the influence of the hydrogen bonding potential of the counterion on the crystal structure of salts of the poorly soluble, poorly compressible, acidic drug gemfibrozil and to correlate these with mechanical properties. Methods Compacts of the parent drug and the salts were used to determine Young's modulus of elasticity using beam bending tests. Crystal structures were determined previously from X-ray powder diffraction data. Key findings The free acid, tert-butylamine, 2-amino-2-methylpropan-1-ol and 2-amino-2-methylpropan-1, 3-diol salts had a common crystal packing motif of infinite hydrogen-bonded chains with cross-linking between pairs of adjacent chains. The tromethamine (trsi) salt, with different mechanical properties, had a two-dimensional sheet-like network of hydrogen bonds, with slip planes, forming a stiffer compact. Conclusions The type of counter ion is important in determining mechanical properties and could be selected to afford slip and plastic deformation. © 2010 Royal Pharmaceutical Society of Great Britain.

Investigation of bonded hydrogen defects in nanocrystalline diamond films grown with nitrogen/methane/hydrogen plasma at high power conditions

In this work, we investigate the influence of some growth parameters such as high microwave power ranging from 3.0 to 4.0 kW and N2 additive on the incorporation of bonded hydrogen defects in nanocrystalline diamond (NCD) films grown through a small amount of pure N2 addition into conventional 4% CH4/H2 plasma using a 5 kW microwave plasma CVD system. Incorporation form and content of hydrogen point defects in the NCD films produced with pure N2 addition was analyzed by employing Fourier-transform infrared (FTIR) spectroscopy for the first time. A large amount of hydrogen related defects was detected in all the produced NCD films with N2 additive ranging from 29 to 87 µm thick with grain size from 47 nm to 31 nm. Furthermore, a specific new H related sharp absorption peak appears in all the NCD films grown with pure N2/CH4/H2 plasma at high powers and becomes stronger at powers higher than 3.0 kW and is even stronger than the 2920 cm−1 peak, which is commonly found in CVD diamond films. Based on these experimental findings, the role of high power and pure nitrogen addition on the growth of NCD films including hydrogen defect formation is analyzed and discussed.

The separation of hydrogen and carbon monoxide using polymer membranes

This work studies the development of polymer membranes for the separation of hydrogen and carbon monoxide from a syngas produced by the partial oxidation of natural gas. The CO product is then used for the large scale manufacture of acetic acid by reaction with methanol. A method of economic evaluation has been developed for the process as a whole and a comparison is made between separation of the H2/CO mixture by a membrane system and the conventional method of cryogenic distillation. Costs are based on bids obtained from suppliers for several different specifications for the purity of the CO fed to the acetic acid reactor. When the purity of the CO is set at that obtained by cryogenic distillation it is shown that the membrane separator offers only a marginal cost advantage. Cost parameters for the membrane separation systems have been defined in terms of effective selectivity and cost permeability. These new parameters, obtained from an analysis of the bids, are then used in a procedure which defines the optimum degree of separation and recovery of carbon monoxide for a minimum cost of manufacture of acetic acid. It is shown that a significant cost reduction is achieved with a membrane separator at the optimum process conditions. A method of "targeting" the properties of new membranes has been developed. This involves defining the properties for new (hypothetical -yet to be developed) membranes such that their use for the hydrogen/carbon monoxide separation will produce a reduced cost of acetic acid manufacture. The use of the targeting method is illustrated in the development of new membranes for the separation of hydrogen and carbon monoxide. The selection of polymeric materials for new membranes is based on molecular design methods which predict the polymer properties from the molecular groups making up the polymer molecule. Two approaches have been used. One method develops the analogy between gas solubility in liquids and that in polymers. The UNIFAC group contribution method is then used to predict gas solubility in liquids. In the second method the polymer Permachor number, developed by Salame, has been correlated with hydrogen and carbon monoxide permeabilities. These correlations are used to predict the permeabilities of gases through polymers. Materials have been tested for hydrogen and carbon monoxide permeabilities and improvements in expected economic performance have been achieved.

Chapter 1 : nucleobases with designed patterns of hydrogen bonding

The chemistry used in key bond-forming steps to prepare nucleobases with designed patterns of hydrogen bonding is surveyed. Incorporation of the nucleobases into DNA and RNA oligomers is achieved either chemically using building blocks such as nucleoside phosphoramidites or enzymatically using nucleotide triphosphates. By varying the hydrogen bonding pattern within nucleobases, and by incorporating additional substituents, new structures have been designed that "reach over" so that contacts with both strands in targeted duplex DNA can be made in antigene strategies to control gene expression. Various new base-pairing systems have been evaluated that expand the genetic alphabet beyond Watson-Crick base pairs A.T and G.C. For example, benzo-homologated analogs of the natural DNA bases represent a new genetic set of orthogonal, size-expanded derivatives that have been shown to encode amino acids of a protein in a living organism.

Effect of methane concentration in hydrogen plasma on hydrogen impurity incorporation in thick large-grained polycrystalline diamond films

We investigate the impact of methane concentration in hydrogen plasma on the growth of large-grained polycrystalline diamond (PCD) films and its hydrogen impurity incorporation. The diamond samples were produced using high CH4 concentration in H2 plasma and high power up to 4350 W and high pressure (either 105 or 110 Torr) in a microwave plasma chemical vapor deposition (MPCVD) system. The thickness of the free-standing diamond films varies from 165 µm to 430 µm. Scanning electron microscopy (SEM), micro-Raman spectroscopy and Fourier-transform infrared (FTIR) spectroscopy were used to characterize the morphology, crystalline and optical quality of the diamond samples, and bonded hydrogen impurity in the diamond films, respectively. Under the conditions employed here, when methane concentration in the gas phase increases from 3.75% to 7.5%, the growth rate of the PCD films rises from around 3.0 µm/h up to 8.5 µm/h, and the optical active bonded hydrogen impurity content also increases more than one times, especially the two CVD diamond specific H related infrared absorption peaks at 2818 and 2828 cm−1 rise strongly; while the crystalline and optical quality of the MCD films decreases significantly, namely structural defects and non-diamond carbon phase content also increases a lot with increasing of methane concentration. Based on the results, the relationship between methane concentration and diamond growth rate and hydrogen impurity incorporation including the form of bonded infrared active hydrogen impurity in CVD diamonds was analyzed and discussed. The effect of substrate temperature on diamond growth was also briefly discussed. The experimental findings indicate that bonded hydrogen impurity in CVD diamond films mainly comes from methane rather than hydrogen in the gas source, and thus can provide experimental evidence for the theoretical study of the standard methyl species dominated growth mechanism of CVD diamonds grown with methane/hydrogen mixtures.

Impact of high microwave power on hydrogen impurity trapping in nanocrystalline diamond films grown with simultaneous nitrogen and oxygen addition into methane/hydrogen plasma

In this work, we study for the first time the influence of microwave power higher than 2.0 kW on bonded hydrogen impurity incorporation (form and content) in nanocrystalline diamond (NCD) films grown in a 5 kW MPCVD reactor. The NCD samples of different thickness ranging from 25 to 205 μm were obtained through a small amount of simultaneous nitrogen and oxygen addition into conventional about 4% methane in hydrogen reactants by keeping the other operating parameters in the same range as that typically used for the growth of large-grained polycrystalline diamond films. Specific hydrogen point defect in the NCD films is analyzed by using Fourier-transform infrared (FTIR) spectroscopy. When the other operating parameters are kept constant (mainly the input gases), with increasing of microwave power from 2.0 to 3.2 kW (the pressure was increased slightly in order to stabilize the plasma ball of the same size), which simultaneously resulting in the rise of substrate temperature more than 100 °C, the growth rate of the NCD films increases one order of magnitude from 0.3 to 3.0 μm/h, while the content of hydrogen impurity trapped in the NCD films during the growth process decreases with power. It has also been found that a new H related infrared absorption peak appears at 2834 cm-1 in the NCD films grown with a small amount of nitrogen and oxygen addition at power higher than 2.0 kW and increases with power higher than 3.0 kW. According to these new experimental results, the role of high microwave power on diamond growth and hydrogen impurity incorporation is discussed based on the standard growth mechanism of CVD diamonds using CH4/H2 gas mixtures. Our current experimental findings shed light into the incorporation mechanism of hydrogen impurity in NCD films grown with a small amount of nitrogen and oxygen addition into methane/hydrogen plasma.

Significant quantum effects in hydrogen activation

Dissociation of molecular hydrogen is an important step in a wide variety of chemical, biological, and physical processes. Due to the light mass of hydrogen, it is recognized that quantum effects are often important to its reactivity. However, understanding how quantum effects impact the reactivity of hydrogen is still in its infancy. Here, we examine this issue using a well-defined Pd/Cu(111) alloy that allows the activation of hydrogen and deuterium molecules to be examined at individual Pd atom surface sites over a wide range of temperatures. Experiments comparing the uptake of hydrogen and deuterium as a function of temperature reveal completely different behavior of the two species. The rate of hydrogen activation increases at lower sample temperature, whereas deuterium activation slows as the temperature is lowered. Density functional theory simulations in which quantum nuclear effects are accounted for reveal that tunneling through the dissociation barrier is prevalent for H2 up to ∼190 K and for D2 up to ∼140 K. Kinetic Monte Carlo simulations indicate that the effective barrier to H2 dissociation is so low that hydrogen uptake on the surface is limited merely by thermodynamics, whereas the D2 dissociation process is controlled by kinetics. These data illustrate the complexity and inherent quantum nature of this ubiquitous and seemingly simple chemical process. Examining these effects in other systems with a similar range of approaches may uncover temperature regimes where quantum effects can be harnessed, yielding greater control of bond-breaking processes at surfaces and uncovering useful chemistries such as selective bond activation or isotope separation.