International synchrotron facilities for crystal structure determination
Submitting InstitutionNewcastle University
Unit of AssessmentChemistry
Summary Impact TypeTechnological
Research Subject Area(s)
Chemical Sciences: Inorganic Chemistry, Physical Chemistry (incl. Structural)
Summary of the impact
This case study describes impact from the Newcastle-led research project
to construct the world's first dedicated single-crystal diffraction
synchrotron beamline for chemistry and materials science at Daresbury
Laboratory Synchrotron Radiation Source (SRS). The result was an
innovative and productive facility that has served as the model for the
development of other facilities internationally, especially at Diamond
Light Source (UK) and the Advanced Light Source (USA). The original
Newcastle University research has helped produce scientists now employed
by industry and public service sectors around the world. Major new and
beneficial drugs and catalysts have been developed with the aid of the
synchrotron beamlines and work conducted at these facilities has been
critically important for the advancement of the global chemical and
pharmaceutical industries and US Government energy development programmes.
Crystal structure determination is crucial to our understanding of the
properties of materials and is of fundamental importance in physical and
life sciences. The technique faces ever-increasing demands for the study
of more complex molecular systems. The years 1994-1997 were the main
period of a major Newcastle-led research project to design, construct and
commission a single-crystal diffraction beamline (Station 9.8) at the SRS,
recognising the need for a facility that could greatly extend the range of
materials not otherwise amenable to conventional laboratory equipment.
Before Station 9.8 was built there were no dedicated facilities available
for the study of crystals with one or more dimensions on the micron scale
or other very weak scatterers, as laboratory facilities were not
sufficient, and so many important structural insights were lost.
The project team, led by Clegg, designed and set up Station 9.8 using a
modified laboratory diffractometer and detector system with X-ray optical
components in a novel combination to ensure that the equipment would
function successfully with the synchrotron source and also to combat
constraints of the available space. Other challenges overcome were the
needs for appropriate control and processing procedures and software, and
requirements for handling a wide range of samples, including air-sensitive
materials, to ensure maximum applicability [P1]. A primary objective was
to offer a familiar setup to a non-specialist first-time synchrotron user.
Overall project leadership and direction was maintained throughout by
Clegg, on site half-time at Daresbury from 1995 to 1998 through formal
Joint Appointments financed as research grants to Newcastle University to
cover 50% of salary costs; he was responsible for key decisions regarding
the choice of equipment, software and postdoctoral staffing as well as
conducting the extensive commissioning work using samples provided by
chemists from around the UK and abroad. Station 9.8 was the first
dedicated facility of its kind anywhere in the world [P2] and has enjoyed
immense success and productivity from the first commissioning data
measurement. In 1997, in accordance with the original plan and EPSRC grant
conditions, it was formally handed over by Newcastle University as a full
SRS user facility, on schedule, within budget, and with performance
exceeding the design specifications. It quickly became one of the most
heavily oversubscribed beamlines at Daresbury, with academic and
commercial users, generating between 10 and 20% of SRS-based publications
in subsequent years [P3, P4, P5 & P6].
Continued use of the facility beyond 1997, and of its direct successor at
Diamond Light Source after 2008, by Clegg's Newcastle research group
included the establishment of a synchrotron-based component of the EPSRC
National Crystallography Service (NCS) in 2001, which further raised the
profile of the beamline and introduced its benefits to a wide range of UK
chemists, some of whom subsequently became commercial users, while others
were carrying out research projects with industrial partners; this
attraction of a large user community contributed hugely to the success of
the proposal to construct Diamond beamline I19.
References to the research
[P1] Cernik, R. J., Clegg, W., Catlow, C. R. A., Bushnell-Wye, G.,
Flaherty, J. V., Greaves, G. N., Burrows, I., Taylor, D.J., Teat, S.J.,
& Hamichi, M. (1997). A new high-flux chemical and materials
crystallography station at the SRS Daresbury. 1. Design, construction and
test results. J. Synchrotron Rad. 4, 279-286. Corrigendum J.
Synchrotron Rad. (2000), 7, 40. The principal technical
description of the SRS facility.190 citations. [* Key reference]
[P2] Clegg, W. (2000). Synchrotron chemical crystallography. J. Chem.
Soc. Dalton Trans. 3223-3232. Describes the context of the
research, with specific references to the use of the SRS facility.
[P3] Camblor, M. A., Díaz-Cabañas, M. J., Perez-Pariente, J., Teat, S.
J., Clegg, W., Shannon, I. J., Lightfoot, P., Wright, P. A. & Morris,
R. E. (1998). SSZ-23: an odd zeolite with pore openings of seven and nine
tetrahedral atoms. Angew. Chem. Int. Ed. Engl. 37, 2122-2126. Early
publication of results from the initial project & an example of work
that has led to commercial impact. 68 citations. [* Key
[P4] Li, X.-C., Sirringhaus, H., Garnier, F., Holmes, A. B., Moratti, S.
C., Feeder, N., Clegg, W., Teat, S. J. & Friend, R. H. (1998). A
highly f070-stacked organic semiconductor for thin film transistors based
on fused thiophenes. J. Am. Chem. Soc. 120, 2206-2207. Early
publication of results from the initial project. 320 citations. [*
[P5] Hamilton, D. G., Sanders, J. K. M., Davies, J. E., Clegg, W., &
Teat, S. J. (1997). Neutral  catenanes from oxidative coupling of
f070-stacked components. Chem. Commun. 897-898. Early
publication of results from the initial project. 76 citations.
[P6] Francis, R.J., Drewitt, M. J., Halasyamani, P. S., Ranganathachar,
C., O'Hare, D., Clegg, W. & Teat, S. J. (1998). Organically templated
layered uranium(VI) phosphates: hydrothermal syntheses and structures of
Chem. Commun. 279-280. Early publication of results from the
initial project. 52 citations.
Key grants awarded to Newcastle University:
W. Clegg (PI), C. R. A. Catlow (CI; Royal Institution). A high-flux
synchrotron station for single-crystal diffraction. EPSRC. 1994-1997.
W. Clegg. CLRC Joint Appointment. CCLRC. 1995-1998. £68,500.
W. Clegg. National X-ray Crystallography Service: a synchrotron
component. EPSRC. 2001-2006. £527,964.
W. Clegg. Joint Appointment at Daresbury Laboratory. CCLRC. 2001-2007.
W. Clegg. National Crystallography Service 2006 renewal. EPSRC.
All the EPSRC grant final reports were recognised as Outstanding and
Internationally Leading; the NCS synchrotron component was singled out by
reviewers for special commendation.
Details of the impact
Station 9.8, with its unique design developed by Newcastle University
researchers, was the first dedicated facility of its kind in the world.
Its rapid and large oversubscription prompted the decision by SRS to
establish a second similar station by reallocation of an underused powder
diffraction beamline (16.2) a few years later. Both facilities operated
until mid-2008 and provided the model, inspiration and (through high
demand from users) justification for current facilities in the UK and
worldwide. Impact from commercial work using these facilities typically
develops over many subsequent years, as illustrated by specific examples
Impact on the development of other synchrotron facilities
The success of Station 9.8 led to the design principles being used
subsequently in plans for other similar facilities worldwide, particularly
the beamline I19 at Diamond Light Source (DLS), effectively a direct UK
replacement for Station 9.8 from 2008 [E1], and the Advanced Light Source
in California, USA (ALS, conversion of beamline 11.3.1 from threatened
closure in 2006 to the most productive beamline from 2009), and to the
successful cases for development of these facilities as a result of its
immense popularity and success. These two are the only current dedicated
beamlines of their kind in the world and are unrivalled in their output by
any shared- use facilities [E2, E3]; such other facilities include
beamlines at APS (USA) and Soleil (France), themselves influenced
indirectly by the design principles and the success of Station 9.8.
DLS is the largest UK Government-funded science project in a generation,
costing around £400M in its construction to date and with an annual
operating budget rising from the initial £23M in 2007-2008 as beamlines
are added; it provides a high level of employment and contribution to the
local economy. The I19 beamline had a construction budget of around £5M
and its annual operating budget is £430K excluding support for an average
of 3 PhD students per year; it has a full-time staff of 4 scientists and
technical support equivalent to 1.25 FTE.
In addition to providing the model for such facilities, the original
research has also produced leading scientists to manage and operate them.
Of grant-funded research staff employed for the construction and
commissioning stages of SRS 9.8, one is now Staff Scientist for ALS 11.3.1
(Dr Simon Teat, previously beamline scientist at SRS and Principal
Beamline Scientist for DLS I19), and another is a director of the
EPSRC-funded NCS (Dr Simon Coles). Major users/beneficiaries of SRS 9.8
who are now in commercial and public service employment include Dr David
Allan (Principal Beamline Scientist for DLS I19), Dr Neil Feeder (Pfizer
then CCDC), and Dr Elizabeth Shotton (Industrial Liaison Manager, DLS).
Clegg has also helped provide training for over 150 staff and users of
synchrotron facilities from many countries through Synchrotron Radiation
Summer Schools, formerly at Chester/Daresbury [E4 p.69] and currently at
Impact through commercial use of facilities
Around 10 commercial companies made use of SRS Station 9.8 up to 2008,
including all the major UK pharmaceutical firms; 5 companies from the
pharmaceutical and chemical sectors of UK industry currently use DLS
beamline I19 (one reason for the lower number is company mergers). These
companies are prepared to pay full-cost-recovery commercial rates for
access, since there is usually no other feasible way for them to obtain
vital structural information for the development and marketing of their
products when the available materials are poorly diffracting [E5].
Confidentiality agreements between the facilities and commercial customers
make it impossible to provide details of such usage, but we give some
examples here where results have been published or approved by company
representatives, or where the work is commercially-sponsored research by
academic partner teams; they are undoubtedly typical of other work. At
DLS, as previously at SRS, several days of beamtime in each 6-month
operating schedule are allocated to commercial work and a day of beamtime
can deliver up to 10 or more data sets, as an indication of overall usage.
Without the original Newcastle underpinning research, these opportunities
would probably not exist and the key structures would remain unknown.
For example, Organon (now Merck) used SRS 9.8 to investigate the
structure of a cyclodextrin complexed with a drug used as a neuromuscular
blocker, to confirm its mode of action. Sugammadex is now marketed as
Bridion; it was approved for use in the EU in 2008 and sales to date have
been around £300M [E6; E4 pp. 7 & 93].
Roche Discovery Welwyn, part of Hoffman LaRoche, carried out structural
studies at SRS 9.8, concentrating on active pharmaceutical ingredients,
intermediates and impurities in support of anti-inflammatory and
anti-viral programmes. This work contributed to the development of the
influenza neuraminidase inhibitor Tamiflu (oseltamivir phosphate) and the
first-generation HIV protease inhibitor Invirase (saquinavir mesylate),
both originally licensed for use in the 1990s and in continued use today
[E7]. Tamiflu has had particularly high public profile and impact in
recent years as a major treatment during several big flu outbreaks around
the world. In the UK alone the NHS has spent an average of around £70M per
year maintaining stocks of Tamiflu; annual worldwide sales peaked in 2009
and 2010 at around £550M, then reduced by over 50%.
Commercial use of the SRS facilities was taken over by DLS I19 beamline
from 2009. Anhydrous sodium diclofenac was a key structure obtained by
SAFC Pharmorphix (Sigma-Aldrich) using DLS I19, enabling a thorough study
of relative stability of hydrates and other crystalline forms of this
common painkiller, which is one of the top 100 drugs in international use,
with an estimated annual value of about £820M in 2009 [E7, E8 p.5, E9].
This work is typical of polymorphism and solvate studies carried out by
pharmaceutical companies, requiring synchrotron facilities for unstable
and poorly crystalline forms of important drugs and drug candidates in
order to secure and protect intellectual property rights attributable to
particular solid forms [E7].
Other major pharmaceutical firms who have confirmed their use of these
facilities in order to obtain or improve vital drug development structures
and to support regulatory and patent processes are Pfizer and
Impact through commercialisation or Government use of academic
Zeolites and metal-organic framework materials studied by St Andrews
chemists at SRS, DLS and ALS have led to Chevron Texaco patents on two
materials, SSZ-23 and SSZ-51, for use in oil refineries, three patents
related to storage and release of nitric oxide, and two spin-out
companies, Zeomedix LLC (started in 2009 with over $1M of external
investment to date) and MOFgen Ltd (started in 2013 with 14 commercial
agreements with other companies) [P3, E4 p.51, E10]. Metal-organic
frameworks have become popular research projects, of interest for
potential in hydrogen and other gas storage and energy applications. Work
is often industrially sponsored, such as that by Nottingham University
supported by General Motors [E7, p.17].
ALS 11.3.1 is used in projects of the US Department of Energy, including
gas separations for clean air technology, extraction of uranium from sea
water, and nuclear reprocessing [E2].
Sources to corroborate the impact
S. A., Christensen, K. E., Teat, S. J. & Allan, D. R. (2012). I19, the
small-molecule single-crystal diffraction beamline at Diamond Light
Source. J. Synchrotron Rad. 19, 435-441
[E2] Supporting statement: Staff Scientist at Advanced Light Source
(formerly Principal Beamline Scientist at SRS and at Diamond Light Source)
[E3] Supporting statement: Principal Beamline Scientist at DLS
[E4] New Light on Science: The Social & Economic Impact of the
Daresbury Synchrotron Radiation Source 1981-2008. Science & Technology
Facilities Council (2010). https://www.stfc.ac.uk/resources/PDF/SRSImpact.pdf
[E5] Supporting statement: Industrial Liaison Manager at DLS (and
previously at SRS)
[E6] Bom, A., Bradley, M., Cameron, K., Clark, J. K., van Egmond, J.,
Feilden, H., MacLean, E. J., Muir, A. W., Palin, R., Rees, D. C. &
Zhang, M.-Q. (2002). A novel concept of reversing neuromuscular block:
chemical encapsulation of rocuronium bromide by a cyclodextrin-based
synthetic host. Angew. Chem. Int. Ed. Engl. 41, 265-270
[E7] Supporting statement: Chief Scientific Officer at SAFC Pharmorphix
[E8] Diamond Industrial Liaison Office case studies. DLS, 2013. http://www.diamond.ac.uk/Home/industry/casestudies.html
[E9] Top 200 Pharmaceutical Products by Worldwide Sales in 2009. Poster.
(Diclofenac is 86th) http://cbc.arizona.edu/njardarson/group/sites/default/files/Top200PharmaceuticalProductsByWorld
[E10] Supporting statement from Professor of Chemistry, EASTCHEM, St