1,721,017 research outputs found
Vibrational spectroscopy to monitor controlled drug release from hydrophilic matrices
Get PDFApproximately 40% of drugs currently marketed and 90% of all drugs under development
show poor and varied aqueous solubility at the different pH values encountered along
the gastrointestinal tract. The pH-dependent release profile exhibited by these drugs
often leads to poor bioavailability and ultimately means that many do not make it to
licence. To mitigate against this and to inform future drug development, it is important to
understand the dissolution behaviour of these types of drugs at a molecular level.
This thesis explores the use of ATR-FTIR imaging to gain an insight into the within-tablet
dynamics of a sparingly soluble, weakly basic drug that has been incorporated into a
hydrophilic matrix. This approach provides a chemical insight into the nature of drug,
polymer matrix, excipients and water in a formulation undergoing dynamic changes
including ionisation, dissolution, hydration, swelling and particle dislocation. Specifically,
this work uses tablets manufactured using an HPMC polymer matrix incorporating 20%
w/w itraconazole as the model drug which has a pKa of 3.7 and is practically insoluble
at pH 7, both with and without the addition of the organic acid modifiers (citric acid,
betaine HCl, cysteine HCl and glycine HCl) to control the local pH.
In placebo HPMC tablets, ATR-FTIR imaging, supplemented by optical imaging, showed
that hydration and swelling was independent of the pH of the media. However, when the
ionic strength of the hydrating medium was adjusted, rapid formation of the gel layer was
observed at low ionic strength, while increased ionic strength was shown to interfere with
HPMC hydration, resulting in the suppression of the expansion of the gel layer.
Hydration and dissolution studies conducted on HPMC tablets loaded with 20% w/w IT
were limited to the use of low ionic strength media only. From the dissolution studies, the
release of IT from these tablets was shown to be significantly greater at pH 1.5 when
compared with that at pH 7. Optical measurements showed that the swelling of 20% w/w
IT loaded HPMC tablets was greater at pH 1.5 over the period of the hydration in
comparison to the pH 7 environment. ATR-FTIR imaging data revealed that at pH 1.5
the IT was ionised, becoming soluble and there was evidence of IT particle translocation
into the diffusion front and eventually out into the surrounding medium. However, at pH
7, the IT remained in the free base form, largely within the tablet core and the swelling
front, with less evidence of IT particle translocation. From both the optical measurements
and ATR-FTIR imaging studies, it was shown that the swelling capacity of the gel layer
in IT loaded tablets was reduced at pH 7 in comparison to pH 1.5 indicating that the poor
solubility of IT retarded hydration.
Exploring the impact of organic pH modifiers on the release of IT from the HPMC matrix
at a 10% w/w and 30% w/w loading, enhanced dissolution at pH 7 of the IT was observed
in comparison to tablets without any modifier. From both the optical imaging and ATRFTIR
imaging data, the gel layer expansion was shown to be greater at higher pH
modifier loading for all systems. However, the magnitude of swelling differed between
the modifier systems over the hydration period and a greater amount of swelling was
observed with the betaine HCl and citric acid in comparison to the cysteine HCl and
glycine HCl. The results indicated that, of the organic acid modifiers selected, tablets
containing cysteine HCl provided the greatest enhancement of release of IT. These
findings were consistent with the ATR-FTIR imaging results, where the greatest
reduction in the intensity of the spectral band assigned to the free base form of IT, was
also observed in tablets containing the cysteine HCl modifier
The use of ATR-FTIR to probe the release mechanism from hydrophilic matrices.
No full textHydrophilic matrices are widely used in the pharmaceutical industry as control release agents in solid oral
dosage formulations. One of the key parameters that controls release in such systems is the distribution of
exipients within the formulation, which in turn is governed by the processing and manufacturing
procedures. This thesis explores the effect of processing on the distribution of excipients in binary and
tertiary formulations obtained using different mixing procedures, (manual shaking, tumble blending and
grinding) with a range of particle size distributions. Samples were prepared by compacting processed
powder mixtures directly onto a diamond attenuated total reflectance (ATR) crystal using an in-house built
compaction cell which proved to be a successful tool for small scale tablet manufacturing. For this study
the following exipients were used; the hydrophilic matrix HPMC grade K4M, the drug 6-hydroxy
buspirone hydrochloride and citric acid. The homogeneity of the formulations were determined by the
reproducibility of the spectra obtained from the tablets after compaction and the concentration of exipients
within the samples was successfully predicted using Partial Least Squares (PLS) data analysis. The
distribution of the components was confirmed using Near Infrared imaging with principal components
analysis (PCA). Standard dissolution tests of the binary and tertiary systems gave an indication about the
release behaviour of the formulations in different dissolution media. Total dissolution of the drug was
observed in 0.1N HCl for binary mixtures and in both pH 6.8 buffer and 0.1 N HCl for tertiary formulations
highlighting the impact of citric acid on the dissolution results and confirming the pH dependence of the
system. The release of drug was also studied using the complementary technique of ATR-FTIR by
performing hydration experiments on the compacted tablets. Both standard data analysis approaches, such
as peak area changes, and multivariate curve resolution (MCR) were applied to these datasets. The MCR
studies showed some promise, but also highlighted a need for further development. The standard data
analysis showed that the rate of release of the API and citric acid was higher than the rate of solvation of
HPMC, indicating a diffusion controlled release mechanism. Standard dissolution experiments and infrared
spectroscopy measurements were combined, by developing a hyphenated system, whereby dissolution
media was circulated through the ATR compaction cell and out through a UV/vis flow detector in a closed
loop. These results were in good agreement with the data from both the standard dissolution tests and the
ATR-FTIR hydration studies
Mid-IR Imaging and Multivariate Analysis of Dynamic Processes in Pharmaceutically Relevant Microparticles
No full textSustained release microparticles used for parenteral drug delivery must be well characterized in terms of their size range, morphology and function. It is widely understood that the chemistry and morphology of microparticles have a degree of interdependence which strongly affects drug release behaviour from microparticles.
This thesis investigates, for the first time, the use of mid-IR imaging along with the development and optimisation of relevant multivariate image analysis methods for studying the real-time degradation of pharmaceutically relevant biodegradable polymer microparticles and the real-time release of protein based drugs from such microparticle
systems.
The application of attenuated total reflection - Fourier transform infrared spectroscopic(ATR-FTIR) imaging and analysis to monitor the degradation of a single microparticle is optimised and the developed methodology is detailed. A series of time resolved images of a PLGA microparticle undergoing hydrolysis at 70 °C are obtained using ATR-FTIR imaging for the first time. A novel partially supervised non-linear curve fitting (NLCF) tool is developed and the output from the NLCF is evaluated by direct quantitative comparison with a traditional peak height (PH) data analysis approach and multivariate curve resolution alternating least squares (MCR-ALS) analysis for the same images, in order to develop an image analysis strategy. The NLCF method is shown to facilitate the calculation of hydrolysis rate constants for both the glycolic (kG)and lactic (kL) segments of the PLGA copolymer. This results in improved spatial resolution on time-resolved microparticle images, so providing better insight into the dimensions of hydration layers and particle dimension changes during hydrolysis when
compared to images derived from both PH measurements and MCR-ALS. The MCRALS routine is shown to be faster than NLCF and its images are found to provide sufficient contrast to be used for qualitative comparison.
The optimised mid-IR-ATR procedures are then applied to investigate several factors influencing the hydrolytic degradation of a family of PLGA microparticles. Degradation
rate constants for glycolic and lactic units are shown to increase (whilist maintaining a ~1.3 ratio between each other) with increasing initial glycolic content of the copolymer,temperature or γ-radiation exposure. Differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) results indicate a chain scission based degradation in PLGA upon γ exposure. The distribution of lactic acid is probed with IR during the hydrolysis of a PLA microparticle for the first time, showing a diffusional pathway from the degrading microparticle outwards into surrounding water.
Utilising the chemical selectivity of the infrared methodology, ATR-FTIR imaging is applied for the first time to monitor the redistribution and release of human growth
hormone (hGH) from a range of CriticalMixTM processed PLGA/PLA microparticles during a set of dissolution experiments at 37 °C in D2O. Increasing the γ dose is shown
to have a profound influence on the release mechanism, with higher γ doses leading to a dramatic increase in the initial burst release followed by retardation in the sustained release and a lower total level of hGH release over the dissolution experiment. These changes are shown to be the result of: (i) protein aggregation as a function of applied γ-dose as studied by size exclusion chromatography; (ii) decrease in overall porosity as studied by SEM; (iii) decrease in Mw of all of the component polymers post γ irradiation indicating a chain scission mechanism as studied by GPC and DSC; and (iv) the increase in the number of oxygenated components in the Poloxamer 407 excipient,
thereby increasing the strength of interaction between the microparticle and the entrapped hGH. These findings suggest that any γ sterilisation dose should be less than
25 kGy and that other sterilisation methods may need to be considered, due to the stability of the studied formulations
The synthesis, characterisation and rheological properties of clay-polymer nanocomposites
Get PDFThis study aims to investigate the effect of different crosslinking agent and different
crosslinking agent content on the material properties of the clay-polymer
nanocomposite. A lot of materials were tried to be mixed to form a fully-reacted
clay-polymer nanocomposite for the first time, which is a part of the novelty for this
work. The overall properties governed by clay properties and clay/polymer
relationship are prime aspects of this study. The Enhancement of significant
properties of nanocomposites is a measure of clay platelets dispersion within the
polymer matrix. Different approaches were adopted to understand the influence of
clay properties on the nanocomposite; (i) by examining and comparing different
clays as raw, dry, powder material using spectroscopy and thermogravimetric
analysis (ii) mechanical examination of clay/water suspension of different clay
types/grads, and different concentrations varying from 0.5 % - 10 % using
rheological studies (iii) chemical and mechanical and morphological examination of
Clay/Polymer nanocomposite with different clay types/grades, concentration, and
polymers.
The synthesis of such material addresses issues including heterogeneity,
processability, injectability, crosslinking and mechanical stability. The synthesis
requires no purification steps no specialist equipment, and basic typical
components of crosslinked nanocomposite/hydrogels (water, monomer, clay and
initiator).
Morphological, pore size and scaffolding general arrangement which shows the
effect of different crosslinking agents and crosslinking density were examined by
Scanning Electron Microscope (SEM) to acquire information on wide/small pores
are, diffusion kinetics in the system if required for further applications. The nature
and elemental composition of the clay-polymer nanocomposites were determined
by X-ray diffraction (XRD), X-ray fluorescence (XRF), and Fourier Transfer Infrared
(FTIR) spectroscopy. The water content in the dry clay-polymer nanocomposite was
determined and examined by Thermogravimetric analysis (TGA). Mechanical and
rheological properties of the result were examined using a rheometer that operates
on different modes (as a Dynamic Mechanical Analysis (DMA) technique) to
evaluate the structure, performance, strength, and mechanical modules of these
nanocomposites under different rotational and oscillatory loads. This offers the
opportunity to relate the differences to the clays and polymers the hydrogels were
synthesised from
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Remediation of heavy metals from water using Modified Clay-Chitosan Composites
Get PDFWater contamination with pollutants such as heavy metals is of significant concern because the toxicity exhibited by these metals can pose a severe threat to human health and the environment. Adsorption with the combined use of geological materials (such as clays) and biodegradable polymers (such as chitosan) seems to be a promising technique for purification of water contaminated with toxic metals. These materials not only provide a cost-benefit but are also materials derived from sustainable sources and are thus environmentally friendly. This study focuses on the preparation of functional composites (from bentonite clay and chitosan biopolymer) as cheaper, and sustainable adsorbents for effective removal of heavy metals from water. The work carried out in this thesis investigated the efficiency of mixing bentonite with two different chitosans via different preparation methods. The different forms of bentonite-chitosan (Bt-Ch), composites and beads, were prepared in the weight ratios of 90%/10%, 70%/30% and 50%/50%, and via solution blending and precipitation methods, respectively. The beads were further subdivided, identified as “beads-A” and “beads-B”, and were formed by adding either bentonite suspension or bentonite powder, respectively, to solubilised chitosan solution. The composites and beads were characterised by thermogravimetric analysis (TGA), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Subsequently, the different forms of the prepared clay-chitosan composites were investigated for their ability to remove metal ions (Pb, Pb-Cu and As) from aqueous solutions. Batch adsorption procedures (via statistical design of experiments) were used to study the removal of these metal ions. Results showed that Pb (or Pb-Cu) ions can be removed from aqueous solutions effectively. The amount of chitosan present in the adsorbent and its distribution within or outside the interlayer space of the bentonite clay was shown to have pronounced effects on the Pb (or Pb-Cu) uptake by these clay-chitosan composites, and the adsorption of Pb was significantly affected by the presence of other multi-competing ions. However, these composites showed a poor loading capacity (very low removal efficiencies) towards As ions. This led to modification of bentonite clay with chitosan and Fe(III) cations; the Fe-modified composites have demonstrated effective removal of As ions from aqueous solution. The developed Bt-Ch and Fe-modified composites exhibited good potential for re-use after five cycles of regeneration, thus, indicating their potential as cost-effective adsorbents for removal of these metal ions from both drinking and wastewater. Overall, this study provides insights and new valuable knowledge for inexpensive remediation of metal-contaminated water, especially when using composites made from cheap and sustainable materials
The synthesis and development of novel, easily processable poly (n-isopropylacrylamide)-based hyrdogels.
Get PDFThis work describes the invention of a synthetic method which allows a fully-reacted PNIPAM/clay nanocomposite system to remain a watery liquid until it is cooled to a predetermined temperature. Beyond this temperature, the polymer/clay precursor hydrogel liquid (PCPH) spontaneously forms a cross-linked hydrogel that does not re-liquefy upon re-heating, but instead, possesses all of the highly utilisable stimuli-responsive properties typical of PNIPAM-based nanocomposite hydrogels synthesised in situ. This novel methodology simultaneously addresses issues including cytotoxicity, processability, injectability, cross-linking and mechanical stability. In addition, PCPH synthesis requires no specialist equipment, inexpensive and basic components typical of cross-linked hydrogels (water, monomer, clay and initiator), requires no purification steps and can be maintained as a fully-reacted liquid at evaluated temperatures for up to several weeks with no apparent loss of eventual functionality. The ability to create a fully polymerised hydrogel polymer with a liquid intermediate state has allowed the incorporation of biologically active dopants which can be dispersed and distributed homogeneously throughout the matrix prior to "phase transition triggered nanoparticle anchored gelation" (or PTTNAG) of the hydrogel.Human mesenchymal stem cells (MSCs), have been incorporated into the gel by i) placing them on the assembled gel surface - the cells responded by migrating and proliferating throughout the matrix of the gel, and more interestingly, ii) combining the MSCs with the PCPH in the liquid phase and allowing PTTNAG of the polymer matrix to occur around the cells. In both cases, cell viability was excellent throughout a series of 14-28 day experiments. The work was expanded by the exploration of PTTNAG temperature tailorability. This was achieved with the incorporation of the relatively polar comonomer dimethylacrylamide (DMAc), and non-polar comonomer glycedyl methacrylate (GMAc) which respectively increased and decreased the PTTNAG and lower-critical solution temperature (LCST) of the resulting gels. Crucially, it was found that the PTTNAG temperature can be tailored precisely and incorporation of DMAc did not affect cell viability. The process also opened several novel avenues for gel processing possibilities, including facile casting, extruding and electrospinning. Well defined and uniform electrospun fibres with diameters ~300nm are presented. The production of continuous, uniform flat PNIPAM/ clay sheets of 300pm -1000pm achieved using an industrial film extrusion line is detailed. This work represents an innovation in the way in which such hydrogels can be manufactured and produced safely and cleanly, with no additives, no energy input and no toxic by-products.Interactions between polymer and water are examined by monitoring the dehydration of 3 separate hydrogel formulations using ATR-FTIR. The pseudo diffusion coefficient (in this instance, the diffusion of water out of the polymer matrix) was not affected by dopant composition, but instead, the intercept of the slope was altered markedly. Cross-link type, cross-link density, initiation method and addition of dopants have a strong influence on the swelling/ deswelling behaviour of the hydrogels under study. PNIPAM/ clay gels exhibit much larger volume changes than those prepared with chemical cross-linking agent methylenebisacrylamide (BIS). Deswelling magnitude increases with decreasing cross-linker content for all gel types examined. Thermal deswelling is hindered in dopant-incorporated networks. The aqueous dilution of the nanocomposite in the liquid phase affects gel deswelling behaviour when clay concentration is low. De/reswelling of PNIPAM/ clay, PNIPAM/BIS and gelatine-doped PNIPAM/ clay gels can be induced by adjusting the alcohol volume fraction of the media. BIS cross-linked gels exert restricted swelling/deswelling behaviours compared to those cross-linked with clay. Cross-link density within systems does not have a significant impact on cononsolvency behaviour, although the incorporation of gelatine imposes some restriction on it, directly relative to gelatine concentration.X-ray diffraction (XRD) data proved the exfoliation of clay in the nanocomposite system post-PTTNAG. DMA data revealed that the viscoelasticity of the gels can be tailored with varying the nature and quantity of dopant materials. Gels doped with hyaluronic acid (HA) most closely resemble the mechanical properties of bovine NP tissue
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