Symposium on
Synchrotron
Applications
in Pharma Innovation
and Research
11 – 12 October, 2016
PGN Conference, AstraZeneca
Gothenburg
Title: Possibilities with SAXS in biology
ABSTRACTS
Presenters in
alphabetical order
Abstract: SAXS is a great complementary method in many areas of science. With new advances in the technique biological
sciences has started to become more and more interested. Using SAXS we can study the very core properties of for example
proteins, properties like radius of gyration, maximum dimension, excluded volume, and molecular weight. Given that there is
more than limited knowledge of a protein system it is also possible to study the dynamics of protein domains, and proteinprotein interaction in for example self-assembling systems. I will be presenting the method and its possibilities with a focus on
pharmaceutical applications in the available literature.
Clare Strachan
Andrew Fitch
Andy Fitch has been an instrument scientist at the ESRF since 1992 where he is responsible for
the high resolution powder diffraction program, i.e. beamline ID22 and its predecessors, ID31
and BM16.
Title: Powder diffraction studies using synchrotron radiation
Abstract: Synchrotron radiation allows the design of powder diffractometers that have higher angular resolution (narrower peaks)
than is possible using a laboratory source, hence enhancing the extraction of structural information from a complex diffraction
profile of closely spaced and overlapping diffraction peaks from a low-symmetry crystal structure. Moreover, by appropriate
design of the optics, various aberrations that affect peak positions can be eliminated, meaning that peak positions are accurate,
and can be used to index unit cells of previously unknown crystal structures. From high quality data, it is possible to solve and
refine all sorts of crystal structures, including those of organic molecules of interest to the pharmaceutical community, when a
single crystal of the material is not available for standard crystallographic analysis. Shorter wavelengths are generally available
at the synchrotron, allowing diffraction measurements to be made to high values of the scattering vector, and the extraction of
the pair distribution function to characterize structurally materials that may be in a poorly crystalline or amorphous state. I will
attempt to illustrate some of the advantages of using synchrotron radiation for structural characterization for the characterization
of materials, and particularly those of interest in pharmaceutical research.
IClare Strachan originates from New Zealand where she completed a PhD in 2005 on the
spectroscopic characterisation of solid state drugs at the School of Pharmacy and Department
of Chemistry, University of Otago. During this time she was also based at TeraView Ltd and the
Cavendish Laboratory, University of Cambridge, where she employed terahertz spectroscopy for
solid state pharmaceutical analysis. Since then she has oscillated between Finland and New
Zealand, and is currently Assistant Professor (tenure track) at the University of Helsinki where
she heads the Formulation and Industrial Pharmacy Unit within the Division of Pharmaceutical Chemistry and Technology.
Clare Strachan’s research focuses on the formulation of poorly water–soluble drugs and spectroscopic analysis of solid drugs
and dosage forms. She has a particular focus on advanced vibrational spectroscopy and imaging approaches (especially Raman,
CARS and other forms of non-linear optical imaging) to provide insights into solid drug and dosage form behaviour in different
contexts (manufacturing, storage, and administration). She collaborates internationally with academic and industrial partners, as
well as regulatory agencies (e.g. Food and Drug Administration), and has given invited presentations in Europe, the USA, Asia and
Australasia. She has published approximately 95 articles in international peer-reviewed scientific journals as well as several book
chapters, and has supervised 17 PhD students.
Title: Solid state analysis – making the link to critical quality attributes
Abstract: Solid state characterisation, in particular that involving crystallinity/amorphousness analysis, is an intrinsic component
of solid preformulation and formulation development. However, two challenges include a) a lack of congruence between different
analytical techniques as well as critical quality attributes.
The talk will consider some recent and current research involving solid state analysis of the amorphous form and amorphousness.
Specific topics will be drawn from the following areas: 1) comparison of vibrational spectroscopy with other methods (e.g. thermal
analysis and x-ray powder diffraction) for analysis of amorphousness and the importance of linking the data to critical quality
attributes, 2) spatially resolved analysis and the detection of low levels of crystallinity, 3) recent developments for solid state
analysis (e.g. low frequency and time-resolved Raman spectroscopies).
Christopher Söderberg
I finished my PhD in Molecular Biophysics, September 2013, working with self-assembling
protein systems. From there I moved on to a two year post-doc at MAX-Lab working with
BioSAXS development at the beamline. After the post-doc I got my current position at MAX IV,
working at the CoSAXS beamline to develop BioSAXS and IT-solutions for when the beamline
opens its doors in 2018.
Tomas Lundqvist
Dean Murphy
I have worked within in various drug development functions within AstraZeneca (UK) since
leaving University. Most of my AstraZeneca career has been focussed within the analytical/
characterisation sciences, primarily in the area of particle characterisation (size and morphology)
and more latterly the applicaton of Micro x-ray computed tomography (µCT) imaging. I have
the opportunity to work across the drug development portfolio, from early stage to commercial
products, both regionally with AZ and also with our external partners. I find investigating the use
of new technologies and ways of working to solve project problems the most stimulating aspect of my role and feel fortunate to
work with great people across with business.
Title: Seeing is Believing: Use of X-Ray µCT for Drug Development
Abstract: Micro x-ray computed tomography (µCT) imaging has proven to be a powerful characterisation tool for increasing
our understanding of pharma products and their behaviour. The technology has enabled the non-destructive visualisation and
assessment of the internal 3D structure of AstraZeneca (AZ) oral dosage forms, devices, drug product dosed in tissue and drug
substance crystals.
The ability to evaluate solid oral dosage form characteristics and in-process behaviour e.g. over/under compression, blending
efficiency, homogeneity, porosity, cracking / internal fracturing or bubbles/voids has been demonstrated. This technology is being
incorporated into our drug development process to help establish new functional relationships between product manufacture and
behaviour/performance, improving design, understanding and reduced batch failure.
A mechanistic understanding of product performance, the geometry or spatial distribution of drug product or its components post
administration, may influence in vivo release from controlled delivery systems. Both synchrotron and lab source x-ray µCT have
demonstrated the ability to detect the post administration spacial distribution of drug product components within multiple tissue
types. For example, the accumulation of nano-particle probes within tumours has enhanced both our knowledge of tumour biology
and the behaviour of potential nano-particle drug products.
Tomas Lundqvist is Director at the MAX IV Laboratory with responsibility for Life Science and
Industrial relations. Tomas has a career within structural biology and early drug discovery.
He got his Ph.D. in molecular and structural biology at the Department of Molecular Biology
in Uppsala, Sweden. After two post-doc periods, DuPont CR&D (Wilmington, USA) and MRC
Laboratory of Molecular Biology (Cambridge, UK) he returned to Sweden 1992 to set up the
protein crystallography group at Pharmacia in Stockholm. In 1996 he joined AstraZeneca to build
a similar function at the research site in Mölndal. Over the next 18 years he held various position including as a Director within
Discovery Sciences, a global function supporting drug discovery projects particularly in the early phase, before he joined the MAX
IV project in 2014.
Tomas has over the years served as an industrial representative in various bodies related to the use and the strategic development
of synchrotrons and other large-scale facilities; most lately as a member of the Industrial Advisory Board (AIB) for the Calipso and
NMI3 European networks and he still holds a seat on the Scientific Advisory Committee (SAC) for the European Spallation Source
(ESS).
Title: Advanced characterisation for the future: Introducing ESRF and MaxIV
Abstract: The creation and tailoring of new drugs, delivery methods, and medical devices are at the heart of pharma and biotech
industry challenges. New drugs and materials must meet ever more stringent requirements of performance and regulations
in a highly competitive landscape. Their properties depend heavily upon their composition and their micro- or even nano- and
atomic-structure. Their “ultimate” characterisation is possible using the tools available at large-scale facilities such as neutron
and synchrotron X-ray sources.
Such facilities could arguably be described as the means of our age for the ultimate characterisation of materials: such facilities
provide the ability to visualise the atomic, nano-, and macro-structure of a huge range of complex materials, often under processing
or end-use conditions and in real time. This capability lends itself to an equally wide range of industrial R&D problems which, in
particular, have been adopted by the healthcare industry.
Nowadays, synchrotron protein crystallography is a tool used day-to-day by drug discovery teams in pharma, and synchrotron
sources have evolved to provide reliable, high-throughput, and routine systems for protein diffraction data and processing. Beyond
drug discovery, these large-scale facilities like the European Synchrotron and MAXIV are active in providing analysis for drug
development and formulation, implants, medical devices and amongst others.
This introduction will present and discuss the increasingly critical role of such large-scale facilities in delivering both ultimate and
routine materials characterisation for innovative industrial and applied R&D.
Edward Mitchell
Edward Mitchell is Head of Business Development at the European Synchrotron Radiation Facility
ESRF in Grenoble, France. He has spent over 20 years working with synchrotron radiation, firstly
designing and operating X-ray stations for structural biology. After being General Manager for
the international Partnership for Structural Biology in Grenoble, he coordinated the preparation
phase of the 250MEuro ESRF Upgrade Programme (an ESFRI roadmap project). Since 2010, he
manages the relations between ESRF and industry, which today participates in one third of the
science done at the ESRF. He remains active in research with structural biology projects related to HIV and malaria. In 2011 he
was made honorary professor at the Research Institute for the Environment, Physical Sciences and Applied Mathematics of Keele
University.
Elodie Boller
Elodie Boller is an engineer, specialist in Materials Sciences. She has been working at ESRF
for 19 years as a liaison for industry and developing the ID19 beamline, mainly dedicated to
microtomogrpahy.
Title: Synchrotron multi-scale and time-resolved microtomography: a powerful imaging
technique to study microstructures
Abstract: Since 20 years, micro-computing tomography (micro-CT) instruments were developed at the European Synchrotron
Radiation Facility (ESRF in France). Micro-CT is now the main imaging technique of the 150 m-long beamline ID19. Within the
context of the ESRF general upgrade (Phase 1: 2008-2015), ID19 has benefiting from a consequent refurbishment: both medium
and high resolution are optimized, trying to use as best the specificities of a 6 GeV 3rd generation synchrotron, like coherence
and high energies, comparing to other synchrotron source and laboratory instruments. New samples stages have been designed
to accept very large objects (up to half-meter range). Micro-CT is successfully applied to characterise various specimens and
numerous experiments are done weekly (pixel sizes from 0.2 to 50 microns, down to 10nm on ID16). The main applications are
originating from materials sciences, palaeontology and biomedical research. Synchrotron radiation provides high photon flux
density, especially in the so-called pink beam (polychromatic) mode, using single-harmonic undulators (19 and 26 keV) or filtered
white beam.
Katarina Logg
Katarina Logg works as a research engineer at Chalmers Materials Analysis Laboratory - a user
facility that offers access to basic and state-of-the-art instruments with relevance to materials
science. I have a MSc in Physics and a PhD in Bioscience. I am responsible mainly for the optical
instruments in the lab.
This possibility leads to develop in situ experiments to add a fourth dimension to studies (time, temperature, …). Samples can
be investigated in situ, employing different sample environments like tensile stress, compression, fatigue devices, low or high
temperature, hygrometry control, and more recently high temperature under controlled atmosphere (scan time down to 0.2s per
3D image with 1.1 micron pixel size, using commercial CMOS-based camera).
A focus on pharmaceutical applications will be presented.
Stefan Gustafsson
TStefan Gustafsson works as a research engineer at CMAL - Chalmers Materials Analysis
Laboratory. He is a PhD in materials science and has a special expertise in the field of high
resolution analytical electron microscopy – transmission electron microscopy (TEM) and
scanning electron microscopy (SEM).
Title: Chalmers Materials Analysis Laboratory - a resource for materials science researchers
Kajsa Sigfridsson Clauss
Kajsa Sigfridsson Clauss is a beamline scientist at the Balder beamline, MAX IV Laboratory and
have her PhD in Chemistry, Molecular Biomimetics from Uppsala University. After postdoctoral
years at the Experimental Physics department at Freie Universität-Berlin and additional
postdoctoral years at I811 XAFS beamline in the old MAX-lab, she is now a versatile X-ray
spectroscopist with a special scientific interest in metalloproteins and bio-catalysis.
Title: Hard X-ray spectroscopy - application in pharma research
Abstract: Hard X-ray spectroscopy is an element specific tool to access the local atomic and electronic structure of transition
metals and heavier elements. The method is applicable to essentially all scientific fields, not at least to structural biology to access
structural and chemical information of metal sites in proteins and how ligands might exchange during experiments. The sample
can be in any physical form (solid, liquid, gaseous, crystalline) and be studied and followed under reaction conditions (in situ).
Examples of X-ray absorption spectroscopy (XAS) and X-ray emission spectroscopy (XES) studies with applications to life science
and pharma will be presented, as will the research possibilities at the Balder beamline for XAS and XES at MAX IV. Balder will be
suitable for study of time-resolved in situ catalytic reactions and dilute, sensitive systems.
Abstract: Chalmers Materials Analysis Laboratory (CMAL) is a research and user facility providing basic and state-of-the-art
instruments with relevance to materials science. The laboratory operates as a Chalmers research infrastructure is open to all
Chalmers researchers as well as to researchers from other academia and from industry. It is our vision that the multitude of
advanced and basic instruments, professional technical support staff and an excellent research environment will provide unique
possibilities for conducting world-class materials research.
Today CMAL offers access to a number of instruments and analysis methods such as:
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2 Scanning electron microscopes (SEM)
3 Transmission electron microscopes (TEM)
2 Focused ion-beam work stations
A high-end spectrofluorometer
A UV-Vis spectrophotometer
An atom probe tomograph (APT)
A surface plasmon resonance instrument (SPR).
Several new instruments will be installed during 2017 including a SAXS instrument, a FTIR microscope, a confocal laser scanning
microscope (CLSM) and an instrument for combustional elementary analysis. In addition, several new state-of-the-art electron
microscopes will be installed during 2017-2018.
The instrumentation at CMAL provides imaging and chemical analysis capabilities at a variety of length scales and is an important
and necessary complement to large scale infrastructure facilities like ESS (European Spallation Source) and MAX IV in developing
materials for the future.
Keisuke Saito, Ph.D.
Marjolein Thunnissen
Received Ph.D. degree for engineering from Tokyo Institute of Technology, Tokyo, by oxides thin film
characterization using high-resolution X-ray diffraction (2003) and M.B.A. degree from Business
Break Through University, Tokyo (2016). Joined Rigaku in 2011 and since then responsible for
marketing for EMEA market (2011), global marketing (2012) and head of application laboratory
and marketing for European operation (2014).
Marjolein Thunnissen, Science Coordinator Structural Biology MAX IV Laboratory, did her
undergraduate and PhD studies in chemistry at the University of Groningen, the Nether- lands.
In 2001 she came to Lund, to coordinate the construction and development of the specialised
protein crystallography beamline I911 at MAX-Lab.
Title: Advances in laboratory based XRD instrumentation
Abstract: Laboratory based X-ray powder diffraction (XRPD) is commonly and widely used in pharmaceutical development, for
example for polymorph screening, quantification of amorphous phase and structure refinement or determination. Especially in the
last 20 years, each components including X-ray source, optics, detectors, sample stages and software have been largely improved.
A multipurpose XRPD from Rigaku called “SmartLab” offers continued refinement of the original ease of use features awarded
the R&D 100 Award in 2006: automatic alignment, component recognition and cross beam optics. Automatic alignment controls
and optimizes the positions of all system components. The complete optical path comprised of X-ray source, optics, sample stage
and detector is automatically aligned in fifteen minutes. Award winning guidance software recognizes installed components and
seamlessly integrates them into data collection and data analysis methods. Cross beam optics offers permanently mounted,
permanently aligned and user selectable optical geometries for various diffraction experiments. As an example, you can choose a
Bragg-Brentano and focusing transmission combination to measure organic materials in both transmission and reflection modes.
The newest additions to the SmartLab is the HyPix-3000 0, 1, and 2D detection system. This is hybrid pixel array detector, the type
currently being used at most Synchrotron beamlines and offer the highest resolution and count rates available today. They are fully
manufactured and integrated into the SmartLab system by Rigaku and, as such, offer the superior ease of use pioneered by Rigaku
in the original SmartLab system model. In the presentation, some of the unique applications on the SmartLab for pharmaceutical
research, such as differential scanning calorimetry (DSC) sample stage, Johansson type Kα1 optics that enables to be switched
between reflection and transmission geometry, CALSA ultra high-resolution spiral single crystal analyser, USAXS-SAXS-WAXS and
GISAXS utilizing the HyPix-3000 detector will be discussed.
Currently she is the User Office Coordinator at MAX IV working with user related questions, such
as access, organizing outreach activities towards scientists, training and education and more.
Title: Possibilities for Protein Crystallography at MAX IV
Abstract: MAX IV is the next generation synchrotron radiation facility in Sweden. It replaces the old MAX-lab that has served a
wide scientific community for nearly 30 years. The new synchrotron consists of two new storage rings (1.5 GeV and 3 GeV) using
a 7-bend achromat design that leads to exceptionally low emittance and an unprecedented brilliance for a synchrotron source.
BioMAX is the first beamline at MAX IV dedicated to macromolecular crystallography. The beamline is designed to be a stable
and reliable micro-focus beamline offering excellent facilities for most of the demands of the structural biology community.
The hardware and software environment of the beamline will be presented. A second planned beamline for more challenging
crystallography, MicroMAX will also be discussed.
Dr. Michael Sztucki, ESRF
Michael is expert in Small- and Wide-Angle X-ray Scattering (SAXS and WAXS) techniques and
data modelling for Soft Matter industrial applications. He has more than 15 years’ experience at
the ESRF and is currently working on the High Brilliance SAXS/WAXS/USAXS Beamline ID02 and
the Micro- and Nano-diffraction beamline ID13.
Magnus Larsson
Magnus Larsson is Industrial Liaison Officer at MAX IV Laboratory, the Swedish synchrotron
light facility situated in Lund, Sweden. He is managing the relations between MAX IV and the
industry and is focusing on opening up the facility for industry to come as a user of synchrotron
light techniques. Magnus has his recent background in industry, working as program manager
at Topsoe Fuel Cell, Denmark in charge of external collaborations and customer development
projects. His academic background lies within nanotechnology working with transmission
electron microscopy of nanowires, and he holds a Ph.D. in inorganic chemistry at Lund University.
Title: X-ray scattering techniques for pharmaceutical R&D
Abstract: Small- and Wide-Angle X-ray Scattering (SAXS/WAXS) are well-established techniques to probe nanoscale structures
of samples of pharmaceutical relevance such as tablets, suspensions, or freeze-dried powders. The scattering of X-rays at small
angles is (like light scattering) a non-invasive technique which originates from the spatial fluctuations of the electron density within
the material. Modern synchrotron SAXS instruments cover more than four orders of magnitude in length scales, corresponding to
real-space dimension from the μm down to the Å range. This allows investigating nanoparticles, molecular ordering/packing on
the sub-nanometer scale and in addition permits to identify the physical form of API/polymorphs and excipients in drug products.
Small amounts of aggregates or crystalline material can be detected and amorphous, liquid crystalline, and crystalline structures
be distinguished.
Furthermore, the high photon flux and collimation provide high angular resolution and allow time-resolved experiments down
to millisecond range, even in dilute samples. The technique can be combined with various sample environments (e.g., varying
temperature, humidity, pressure, or rapid mixing) for in-situ experiments (e.g. to follow real-time mixing, crystallization/dissolution
kinetics, or phase transitions during processing). Sub-micron beams can also provide high real-space spatial resolution.
Many synchrotron SAXS beamlines are adopting also automation and robotics, particularly those specializing in biological samples
(BIOSAXS). The aim of such systems is to facilitate measurements of many samples under different conditions with speed
and reliability. These state-of-the-art sample changers allow full data collection of a complete concentration series, including
background buffer measurements, in a little over 5 min. – opening the way to qualitative comparison studies across (for example)
formulation matrices.
The presentation will concentrate on recent examples of relevance for pharmaceutical R&D.
Title: DiffMAX, a diffraction beamline at MAX IV Laboratory
Abstract: The DiffMAX beamline will provide two stations designed for scattering and diffraction experiments for the material
sciences. The beamline will be a versatile tool for structural and morphological determination of matter at the atomic/nanometric
scale. The integration of sample environments will allow to study matter while it is subjected to various conditions (temperature,
pressure, gas environment, electrochemical potential, mechanical loading, etc)
One station will be dedicated to powder diffraction and will be equipped with a large area detector or a strip detector and a robotic
sample changer. The second station will be equipped with a heavy duty , accurate sample positioning system and a moveable
detector system. The optics of the beamline will provide tuneable energy in the range 5-40 keV, with possibility for energy scans.
The available space and flexibility of the beamline will facilitate the use of any sample environment up to a size of 1m radius and
around 200kg.
Niklas Lorén
Niklas Lorén is working in the section of Soft Materials Science at SP Food and Bioscience in
Göteborg, Sweden, as researcher and project leader. He is also adjunct professor in the Eva Olsson
Group at the Department of Physics, Chalmers University of Technology. The focus of his research is
within microstructure-property relationships in soft heterogeneous materials. Areas of expertise are
microscopy, image analysis, modelling, food science, food physics, microstructures and properties
of hydrogels, emulsions, phase separated systems, fat-based systems and interfaces.
Paul Handa
I received my PhD in 2007 from Chalmers University of Technology and the department of
Chemistry and Chemical Engineering. Since 2008 I have been employed at Promimic working
with surface modification of dental and orthopedic implants in order to facilitate and accelerate
osseointegration.
Title: RISE at MAX IV and ESS
Title: Characterization of Nanometer Thin Hydroxyapatite Coatings
Abstract: RISE Research Institutes of Sweden is a group of research and technology organisations. In global co-operation with
academia, enterprise and society, we create value, growth and competitiveness through research excellence and innovation. RISE
is actively working with MAX IV and ESS to establish routes for strong collaborations. The aim is to integrate x-ray and neutron
based imaging, scattering and spectroscopy techniques into applied research and business activities at RISE. MAX IV, ESS and RISE
complement each other very nicely with regard to applied research and business. Several steps and competences are needed to solve
industrial and societal challenges. These includes problem formulation, experimental design, sample preparation, complementary
measurements, x-ray and or neutron measurements at synchrotron or spallation source, data storage, data evaluation, and
interpretation of all combined data to solve the formulated problem. In most cases, data from x-ray and neutron techniques needs to
be combined with complementary measurements to obtain optimal results. For applied research and industrial customers, RISE can
provide the required infrastructure, materials competences and the whole loop ranging from problem formulation to interpretation in
many application areas such as pharmaceutics, foods, forestry, soft matter, and metals etc.
Abstract: The mineral Hydroxyapatite (Ca5(PO4)3OH) is one of the main components comprising human bone and has been
widely used as surface coatings in order to promote osseointegration (integration of bone and implantable devices) of implants.
Traditionally, surface coatings using Hydroxyapatite have been in the micrometer range. However, thicker coating are often
associated with issues, such as cracking and particles loosening which may result in acute inflammation and possibly implant
failure.
The Promimic HAnano surface is based on a wet chemical procedure and is used to give a nanometer thin coating consisting of
Hydroxypatite particles in the same size and shape as found in human bone. Due to the fact that the layer merely 20-40 nanometer
thin and composed of discrete particles, the issues seen with thicker coating can be avoided. However, nanometer thin layers also
presents challenges in terms of characterization.
Small Angle X-ray Scattering (SAXS) was used to monitor the phase behavior of the liquid crystalline phase used for synthesizing
nanometer sized Hydroxyapatite particles over time. Synchotron measurements were performed in order to assess the crystallinity
of the Hydroxyapatite particles when applied as a surface coating.
Olivier Balmes
Olivier Balmes has worked at the MAX IV Laboratory since September 2013 as beamline
manager, hard x-ray group manager and now planning the DiffMAX beamline. He has previously
worked more than 7 years at the European Synchrotron Radiation Facility (ESRF) on the surface
diffraction beamline ID03.
Rajmund Mokso
Richard Storey
Rajmund Mokso achieved his PhD at the European Synchrotron Radiation Facility in Grenoble,
France. Between 2008 and 2015 was scientist at the Paul Scherrer Institut in Switzerland. There
the main focus of the work was on improving the temporal resolution in tomographic microscopy
and developing the methodology for in vivo imaging of lungs in rodents with micrometer spatial
resolution. From September 2015 he is leading the project of the Biomedical Imaging beamline at
the Max IV Laboratory.
RRichard Storey is a materials scientists in the Product Development section of PT&D. His role
involves interacting with both chemists and formulators to ensure the physical properties of the
input materials (API and excipients) are assessed as part of the development process so the
“right particles” are utilised in the formulation.
Title: Dynamics of Life under an X-ray microscope
Abstract: The new highly collimated and coherent X-ray sources are starting to emerge and with this we are now entering a new
era of imaging at micrometer resolution in life sciences. There is good hopes that in vivo tomographic microscopy will develop to a
widely used tool of functional anatomy. I will discuss the state of the art in dynamic micrometer scale tomographic microscopy applied
to biological systems and through examples I will open a discussion on the perspectives of dynamic X-ray imaging at synchrotrons.
Title: Use of Pairwise Distribution Function (PDF) to assess amorphous stability in pharmaceuticals
Abstract: Amorphous materials offer a great opportunity for the improvement of dissolution and hence bioperformance of poorly
soluble materials. The enhancement in dissolution is produced by destruction of the crystal lattice commonly performed by melt
extrusion or freeze or spray drying. Due to the unstable nature of amorphous materials they have a tendency to recrystallize hence
they are commonly formulated with other ingredients such as polymers or sugars. An understanding of the crystallisation kinetics
is critical to the stability and hence performance of these high energy materials.
Due to the “lack” of structure in these materials analysis is complex and X-ray diffraction offers limited information about the
structure. However, there is information in the otherwise featureless X-ray powder diffraction pattern that can be interpreted using
PDF. This technique can be used to determine the presence (or absence) of structure in the amorphous materials which are the
pre-cursors to crystallisation. A case study showing where this has been used as part of polymer selection will be presented.
Both lab source and synchrotron radiation can be used to investigate structure in amorphous materials by PDF. The UK facility
Diamond is currently building a beamline, with collaboration of AZ scientists, to provide state of the art information on these
complex materials.
Richard Neutze
Richard Neutze is Professor of Biochemistry at the Department of Chemistry and Molecular
Biology at the University of Gothenburg. He has been working for two decades with membrane
protein structural biology and has been active in applying synchrotron and X-ray free electron
laser generated radiation to the study of membrane protein structure and dynamics.
Title: Time-Resolved serial femtosecond crystallography studies of bacteriorhodopsin - a light-driven proton pump
Abstract: XFEL radiation has revolutionized experimental approaches to structural biology. One area where XFEL radiation is
having a large impact is time-resolved structural studies of protein conformational changes. Bacteriorhodopsin is a light-driven
proton pump which has long been used as a model system in biophysics. The mechanism by which light-driven isomerization
of a retinal chromophore is coupled to the transport of protons “up-hill” against a transmembrane proton concentration gradient
involves protein structural changes. I will describe collaborative studies performed at SACLA that have investigated the nature and
time-scale of these structural changes at high resolution. We used Time-Resolved Serial Femtosecond Crystallography (TR-SFX) to
probe structural changes in microcrystals on a time-scale from nanoseconds to milliseconds. Structural results from these studies
enabled a complete picture of structural changes occurring during proton pumping by bacteriorhodopsin to be recovered. These
results provide new chemical insight into one mechanism by which the energy of sunlight is directed into the biosphere.
Stefan Norberg
PhD in inorganic chemistry at Chalmers University of Technology. Spent 2 years as post-doc at
Ceramics Research Laboratory (Tajimi, Japan) and 3 years at ISIS Neutron Facility (Chilton, UK).
Associate Professor 2010. Faculty position at Chalmers from 2010 to 2016.
Title: Neutron total scattering analysed with reversed Monte Carlo
Abstract: Neutron total scattering analysed with reversed Monte Carlo (RMC) is a state-of-the-art technique for determining local
atomic order/disorder in crystalline and amorphous materials. The ISIS Neutron Facility at Rutherford Appleton Laboratory, UK, is
a short-pulsed spallation source uniquely situated for collecting high quality neutron total scattering data to a very low d-spacing.
The presentation will give a short overview of the ISIS Neutron Facility and demonstrate the use of RMC on inorganic materials.
functional theory (DFT) to provide reliable and highly precise modelling of physical properties through highly precise understanding
of intermolecular bonding in solid forms. I will then contrast NEXAFS spectra of solutions with those of the solid state, revealing
strong sensitivity of NEXAFS to the local chemical and structural environment in solution, creating a powerful tool for characterising
crystallisation processes. In combination with computational modelling by DFT calculations incisive analysis of solute-solvent and
solute-solute interactions can be achieved. Combining NEXAFS and resonant as well as non-resonant X-ray scattering reveals
solvent-dependent variations in crystallising systems including novel methods for quantitative bond length determination based
on σ* shape resonance analysis in NEXAFS.
Stéphanie Monaco-Malbet
After a PhD at EMBL-Grenoble with S. Cusack and in collaboration with BioMérieux (Lyon) on
structural studies of human HIV-1 P24 in complex with a Fab using crystallography, Stéphanie
Monaco-Malbet did a post-doc at ESRF on yeast Sec12p with S. Wakatsuki. For the last 15
years, she has been the ESRF liaison for industrial clients at ESRF in structural biology. She is
also strongly involved in the automation of the structural biology beamlines at the European
Synchrotron, adapting to the evolution of the field and building new features responding to industrial demands.
Title: Large and Small: How the ESRF MX beamlines support drug discovery
Tove Sjögren
Abstract: The European Synchrotron Radiation Facility (ESRF) provides the ability to visualise the atomic, nano-, and macrostructure of a huge range of complex materials, often under processing or end-use conditions and in real time.
Tove Sjögren hold a position as Associate Director in the department of Structure and Biophysics
in Discovery Sciences, AstraZeneca R&D. She manages a team of protein structure scientists
delivering 3-dimensional information on protein-ligand complexes to projects across the
AstraZeneca discovery portfolio. She joined AstraZeneca in 2001.
This presentation will focus on how synchrotron sources and in particular the ESRF supports drug development research by
providing structural information for small and large molecules. Study cases will be presented as well as the unique technology
tools that are available at ESRF to facilitate these studies.
Title: Protein X-ray crystallography at AstraZeneca- A synchrotron love story
Abstract: X-ray crystallography is the most effective tool for the elucidation of macromolecular structure. It has been widely
used to elucidate detailed mechanism by which these macromolecules carry out their functions in living cells. The structural
chemistry lab in AstraZeneca was opened in 1997 and today X-ray crystallography supports most small-molecule drug projects
with a soluble target. Structures of the protein target and newly synthesized drug candidates are delivered in an iterative manner
to support the design-cycles during the lead discovery phase. Synchrotron radiation is critical to generate sufficient quality data
for most projects. In order to match the timelines of the projects an efficient work flow has to be put in place. I will describe how
this is done in AstraZeneca and also discuss some of our future challenges.
Sven Schroeder
Sven has more than 20 years’ experience in translational research in applied physical chemistry
using national central research facilities. He holds the Royal Academy of Engineering Bragg
Centenary Chair in Engineering Applications of Synchrotron Radiation (SR), a joint appointment
between The University of Leeds, Diamond Light Source Ltd and Infineum Ltd., UK. His pioneering
approach has underpinned DFG, EU, NFS, EPSRC, AHRC and industrial funding totalling more than
£10M. Recent industrial collaborators have included the oil and gas, energy, pharmaceuticals, consumer products and heritage
sectors. Besides UK facilities his research makes also use of leading international facilities such as the NSLS (Brookhaven Nat’l
Lab, USA), BESSY (Germany) and the APS (Argonne national Laboratory USA). In 2011 he proposed a Phase III high-throughput
X-ray spectroscopy facility for the UK at Diamond Light Source, which is now under construction at the VERSOX beamline.
....
Title: X-ray Spectroscopies in Pharmaceutical Formulation Research: High-Precision Probing of Intermolecular Interactions
Title: Neutron methods for the life sciences: from macromolecular interactions to therapy
Abstract: I will discuss the application of synchrotron core level spectroscopies for the control of pharmaceutical solid dosage
forms, including examples addressing powder processing problems, the origin of variations in bioavailability and formulation
stability, and here especially interactions with excipients in tablets. Through the development of sample environments for liquids
and near ambient pressure operation X-ray core level spectroscopies are emerging as versatile and extremely sensitive probes
of local electronic and geometric structure in pharmaceutical systems, especially for the characterisation and control of solid
dosage forms. I will present recent examples that illustrate the possibilities for characterising organic molecular species in the
solid state and as solutes in solution. First, I will show how X-ray photoelectron spectroscopy (XPS) readily distinguishes proton
transfer from H-bonding in the organic solid state, complementing X-ray diffraction and solid-state NMR methods. Next I will
demonstrate how XPS and near-edge X-ray absorption fine-structure (NEXAFS) measurements can be combined with density
Trevor Forsyth
Abstract: Neutron applications span a wide range of disciplines in the life sciences, in many cases relating directly industrial
interests. Novel techniques for the study of molecules in solutions, crystals, and at interfaces, provide information that is not
accessible using other techniques. All of these approaches are in one way or the other best exploited in combination with
selective or non-selective deuteration of the systems involved. Small-angle neutron scattering techniques provide the ability to
selectively image different parts of a macromolecule. At high resolution, neutron crystallography allows information on protonation
states and hydration to be obtained – information that may be of central interest for the study of protein stability and ligand
binding. Additionally, neutron techniques for the production of medical isotopes are used widely in diagnosis and in therapy. These
applications will be described and illustrated with examples.