Reports on Meetings during 1997

• 19 March 97 Pharmaceutical meeting
• Sessions at BCA 97 Annual Meeting in Leeds
• 4 June 97 Diffraction at high temperatures
• 6 Nov 97 Use of XRD in Industrial problem Solving

Powder Diffraction and Computer Simulation of Pharmaceutical Materials

held at Glaxo Wellcome, Stevenage, 19th March 1997.

The meeting, which was attended by 70 people, was the first to be held under the auspices of the Industrial Group of the British Crystallographic Association. It was held to reflect the special interests of the Pharmaceutical and Organic Industries and follows a trial meeti ng held a year earlier. The meeting was opened by Dr Steve Norval of the BCA who elaborated on the aims of the association.

Dr. Robert Hammond (Heriot Watt University) then discussed a procedure for generating trial structures by systematically searching phase space, the possible packing arrangements being ranked on the basis of atom-atom interactions. The methodology was employed as an aid to determine the crystal structure from high resolution powder diffraction data for a number of speciality materials. In the future the hope is to extend these studies to include conformationally flexible systems.

Prof. Kenneth Harris (University of Birmingham) then continued the theme of solving crystal structures from powder diffraction data. Prof. Harris discussed a novel approach based on a Monte Carlo technique. In this approach a structural fragment is moved around the unit cell using a Metropolis type algorithm and the powder diffraction pattern is calculated for ea ch configuration. The agreement between the calculated structural models and the experimental data is assessed using the profile R factor. During question time the relative merits of the systematic sampling approach and the Monte Carlo based technique were discussed.

Dr. Frank Leusin (Molecular Simulation Inc) spoke on the approach used by the Cerius 2 polymorph prediction software. The software uses an ab-initio approach to produce tens of thousands of possible structures which are screene d for duplicates and clustered to yield unique structures. The trial structures are normally restricted to the 17 most common space groups that account for about 95% of known structures. Molecular Simulations Inc intend to invite Pharmaceutical companies to join a Pharmaceutical Development Consortium to pursue the development and application of such computational methods on molecules of pharmaceutical interest, including flexible and ionic molecules. Dr Robin Payne (Zeneca Pharmaceuticals), a user of the Cerius 2 polymorph predictor, then expanded on the use of the software within Zeneca. He gave a critical appraisal of the capabilities of software when it was used for molecules of varying complexity. It appears that the current forcefields still have important limitations, and that application to flexible molecules can be challenging.

Prof. Roger Davey (UMIST) explained his current area of research namely the use of graph sets in the discrimination of hydrogen bonded polymorphic st ructures. Using sulphathiozole as a model compound he explained how the solvent might interact with the faces of developing crystals to selectively yield a particular polymorph.

The afternoon section opened with Dr Simon Clarke (Daresbury Laboratory) who introduced Daresbury Laboratory and highlighted advantages of the synchrotron source offer over conventional laboratory equipment. These derive from the bright collimated nature of synchrotron radiation. In particular, high quality, high r esolution powder diffraction data can be collected. Such data enable more reliable indexing and structure elucidation.

Dr Jamshed Anwar (King's College London) then presented results of computer simulation of the crystallisation process starting from discreet solvent and solute units. The simulations increase our understanding of the crystallisation process and may lead to the development of designer molecules that may be used to selectively crystallise a particular polymorph.

Dr.D erk Reefman (Philips Research) introduced a new software product that should enable more accurate assays of mixtures whose components have different mass absorption coefficients and are susceptible to texture effects. The method is based on total pattern fitting methodology and does not require structural information associated with Rietveld refinement methods.

Dr.Steve Norval (ICI) spoke on NAMAS and the XRD laboratory and the future introduction of European standards. Current NIST standar ds include mica for low angle calibration, silicon and alumina which has the advantage of being supplied as a solid plate.

Dr Steve Maginn (Daresbury Materials Characterisation Service) elaborated on the new Daresbury Laboratory service that has been set up in response to the needs of industrial users. In particular, station 9.8 is able to provide a complete single crystal solution for an organic compound for approximately £4000 using crystals as small as 5x50x50mm. Additionally, sta tion 2.3 allows the collection of high quality powder diffraction data suitable for Reidveld refinement at a cost of approximately £1500.

Finally Sue Staniforth (GlaxoWellcome) gave a presentation demonstrating the complex inter-relationship that can exist between polymorphic and pseudopolymorphic forms of an organic compound. Of particular interest was the fact that three polymorphic sesqui hydrates exist for the compound examined. This was followed by Robin Shirley (Sussex) who prov ided a brief update on indexing and the type of data that yields accurate solutions.

The BCA would like to thank Molecular Simulation Inc.for supporting the meeting.

Phillip Lake (GlaxoWellcome) and Jamshed Anwar
(King's College London)
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Report on Sessions at the BCA Annual meeting, April Leeds

• Session 1 - Process and Production Applications
• Session 2 - X-ray diffraction Plus...
• Call for nominations for Industrial Crystallography Award
• Industrial Group Logo?

Session 1 - Process and Production Applications

Spring Meeting, Leeds 1997

Mary Halliwell (Philip s, Almelo) reported on the use of specialised XRD techniques as a QC tool in the fabrication of semi-conductor based optoelectronic devices. The fabrication process was described and emphasis was placed on the need for precise control of layer thickness and layer composition. The economic viability of the process is dependent on the success of the heteroexptixal growth of ternary and quaternary Indium phosphide alloys and it is here that XRD has proved itself an essential QC tool. Precise monitoring of the process at each stage can be achieved by wafer mapping procedures using dense or sparse grids, utilising either double crystal diffractometers or four reflection monochromators. Compositional and mismatch mapping techniques were described and examples of their use given.

Colin Small (Rolls Royce, Derby) expanded on the need for and techniques of texture measurement in the composition of modern wide chord fan blades as used in the RB211 and Trent 800 aero-engines. After a brief hist ory of the fan blade product development from carbon fibre to chemically hollowed titanium-honeycomb composites the hexagonal and cubic symmetry of the modern product+s texture and its analysis was discussed. The use of pole figures and the success achieved in fingerprinting the production process was highlighted. The talk will long be remembered for its stage props, the concept of Rolls Royce engineers simulating bird strikes and the lengthy acronym SPFPB WCFB.

Christopher Frampton (Roche , Welwyn) discussed the subject of polymorphism and phase analysis outlining its importance in the pharmaceutical development sector. With the different physical properties exhibited by polymorphism of the same molecule the need for an appreciation of their formation and detection was emphasised and solubility, dissolution rates, hygroscopicity, and stability were highlighted as properties that require strict control in the formulation of drug delivery systems. The XRD analysis of 1-Hydroxy-7-azaben zotriazole utilising powder and single crystal methods (SMART CCD), in concert with thermal analysis and solid state NMR, was demonstrated and the two forms of H-bonded crystalline lattice, C2/c and P21/c, were shown.

G.J.McPherson
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Session 2 X-Ray Diffraction plus ... Simultaneous Methods

The formation of crystalline ceramics represented by zirconia was illustrated as the first example of the lecture. On heating from ambient to 1300 C changes in the structure from a 2 dimensional amorphous hydroxy precursor to a three dimensional crystalline oxide were followed by this multi technique approach. Key steps identified using this combination of techniques include the initial loss of peripheral waters followed by amorphous oxide hydroxide ¡rafts ¢ are believed to condense together. Oxidation of the amorphous material to form metastable 8-coordinate tetragonal zirconia then occurs. On cooling from 1300 C, 7-coordinate monoclinic zirconia is formed.

By a similar methodology the hydration of cements has been studied. An intermediate phase not previously detected due to ¡time smearing¢ has been identified. This is important as in large concrete structures, such as bridges, temperatures of 70 -80 C can be attained from e xothermic reactions during building.

A video presentation of computer modelling of methane/nitrogen separation in K substituted Ca- Clinoptilolite was the final example of the lecture. Potassium is shown to act as a ¡double cation valve¢ for selective adsorption within the main zeolite channel. Prof. Barnes finished the lecture with a few reminisce of Alun Bowen, the ¡Professor of Preferred Orientation¢, who had the ability to explain the complex subject of texture/ o rientation clearly to anyone.

The following Industrial Group Session was chaired by Craig Adam. Helen Gleeson, (University of Manchester) spoke on ¡Simultaneous X-Ray and Raman scattering studies of liquid crystals¢. At Daresbury small and wide angle scattering has been undertaken concurrently with Raman spectroscopy. Response times for optical and X-Rays have been measured for various devices and new liquid crystalline compounds from simultaneous experiments.

Ian Hanle y, (University of Leeds) spoke on ¡Correlating material properties of polymers with structure: a new rheometer for X-ray scattering studies¢. A Rheometrics RSAII rheometer has been modified to allow the passage of X-Rays for small angle scattering experiments at the SRS, Daresbury. Copolymer gels such as polyoxyethylene and polyoxobutylene form micelles. Shear induced ordering of copolymer melts is found: Bragg peaks are found to correlate with rheological properties.

Tony Ryan, (UMIST) lectured on ¡Structure Development During Polymer Film Extrusion¢. Whereas the growth of polymer crystals is well understood, the understanding of the nucleation process is less clear. Dr Ryan lectured on rapid crystallisations by melt extrusion of a tape on a synchrotron beamline with SAXS/WAXS area detectors. This steady state arrangement allows for long data collection times for short crystallisation processes. The conclusions are that the nucleation event in homopolymers is a spinodal decomposition of chain segments.

Tim Hyde,
Johnson Matthey
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Report on the Industrial Group Workshop

Diffraction at Elevated Temperatures

held at Pilkingtons, Lathom June 4th 1997

David Taylor organised this one day workshop which was hosted at Pilkington Technology Centre and attended by over 30 participants.

David Taylor (Pilkin gton plc) opened the round table event with an overview of the technique. He mentioned that while other complementary techniques such as TGA(Thermo Gravimetric Analysis) or DTA (Differential Thermal Analysis) identify a temperature at which a change occurs, it is usually only X-ray diffraction that can identify the reaction occurring.

Steve Norval (ICI, Wilton) continued with an overview of commercially available hardware. He compared and contrasted respective manufacturers approaches to th e major problems encountered with any heating design of thermal gradients and alignment. He described furnaces and reaction chambers of various specifications including high pressure (to 60 bar), and high temperature (to 2,400 C) variants.

With the formal session now completed, a more informal round table session developed. Participants brought overheads to describe their own hardware/software, adaptations and applications. Simon Redfern (University of Cambridge) described his in-house des igned horseshoe heater. He also passed on the handy tip that under vacuum conditions peak widths can be up to 50% larger due to pump vibrations.

Paul Rainsford (Zeneca) described his in-house heating stage. It cost only £1,500 to design and build and readily fits into a standard sample holder position on a Siemens diffractometer. For temperatures of up to 200 C hydration/dehydration studies and melt/recrystallisations have been readily studied. V. Ruddick (BNFL Springfields) introduce d work done using a PSD and HTK 600 at BNFL. Tim Hyde (Johnson Matthey) talked about the crystallisation of zirconias using HTK10 equipment. Different commercial suppliers of the same zirconia precursors were found to give differing crystallization temperatures on formation of crystalline zirconia, an effect which was found to correlate with overall commercial product durability.

The afternoon workshop session then considered methods to maximise intensity. Simple solutions such as the remo val of the secondary soller slit which usually leads to a doubling of count rate, together with more costly solutions such as installation of a focusing mirror were discussed.

The second main topic reviewed was temperature validation. It has been established that up to a 200 C variation in temperature between top and bottom surfaces and 30 C variation across the surface of a ribbon heater can exist. Calibration materials/methods brought significant contributions as attendees gave details o f specific standards they employ. Materials of high thermal coefficient of expansion such as aluminum enable one standard to calibrate a wide temperature range.

The meeting closed with some more general topics such as specimen preparation, sample holders, liquids, internal standards and tips for beginners were covered.

Tim Hyde,
Johnson Matthey

Report on Industrial Group Autumn Meeting 1997

The Industrial Group's Autumn Meeting took place on 6th November in the pleasant surroundings of the Whitworth Conference Centre at Cranfield University, Shrivenham, Swindon with an attendance of over 50. The meeting opened with a welcome by the Vice Principal, Professor A Brown, who outlined the role of the establishment as a services university.

Ian Langford (Birmingham University) gave the first paper entitled An Historical Perspective of X-ray Powder Crystallography. This embraced t he foundations by Debye and Scherrer in Europe and Hull in the USA, through milestones such as the data base by Hanawalt et al which led to the PDF, the Guinier camera, the introduction of the diffractometer by Parrish, the various theoretical developments by Bertaut, Guinier, Warren and Wilson and the Rietveld method.

Chris Hall (Schlumberger Cambridge Research) then described a technique using synchrotron source with an energy dispersive diffractometer and a very finely collimated beam. Diffraction occurs from a volume of a few microns cube which can be located inside a large sample. He showed how, by scanning the sample composition profiles can be obtained in rocks, concrete, clays etc with spatial resolutions of better than 10 microns.

Under the heading Pole Figures Explained, Jo Jutson (BICC Cables) offered a simple way of understanding pole figures. She used a variety of models to explain how data was collected and a pole figure plotted. She then gave each of us an indexed celluloid cube and a pole figure so that we could each learn how to interpret it. Kath Clay (Hexmat) then extended the discussion to the hexagonal system with examples of results from a variety of materials.

As an alternative to XRD pole figures, H S Uhbi (DRA-Farnborough) then described how an electron backscattered diffraction pattern can be obtained in a scanning electron microscope. This can be a nalysed by an on-line computer to produce orientation data grain by grain. Results compare well with X-ray pole figures but it is also possible to assess variations across a cross section.

After lunch Steve Norval (ICI) outlined the European X-ray Powder Diffraction Standardization project, for which he is the UK representative. The main items covered are - Terminology, General Principles, Procedures, Samples and Instrumentation. It is expected to be compl eted in early 1999 and would then become the basis for laboratory accreditation.

The second Chris Hall of the day, (SRS Daresbury) then talked about The Potential of X-ray Diffraction within the National Health Service. He outlined some applications including phases in renal and gall bladder stones. Measurements on calciferous deposits and samples of breast tissue show possibilities of identifying precancerous stages. Preferred orientation measurement has a role in corneal grafts as correct orientation is essential for success. Chris concluded with a vision of a diffractometer in every hospital.

A new Industrial Group venture was a session My Problem- What solution in which all present were invited to submit their problems in the hope that the collected wisdom would provide some answers. Topics raised included low angle measurements, texture from powder patterns, non-uniform strain from line broadening, thin films, pyrophori c nickel and microtoming of polymers.

In what was possibly the first time that the President of the BCA had addressed an IG meeting, Mike Glazer (Oxford University) made a cautious attempt to predict future developments in XRD. As well as the obvious advances in computers, he considered that developments in detectors and environmental stages were overdue. He then discussed some of the latest experiments which push the technique to its limits such a high power laser sources which produce diffraction patterns in picoseconds and also improved X-ray sources.

At the conclusion of the meeting thanks were offered to the local team, led by Keith Rogers, for their successful organisation.

Trevor Carter