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Reports - Spring Meeting, Loughborough 21st to 23rd April 2009
IG XRF/XRD Plenary and associated session.Industrial Group Plenary Lecture - Wed 9th April The Plenary was followed by an associated session on XRF/XRF Environmental applications. See the XRF meeting page for these two reports: ....link. 
Joint IG/BACG Sessions: Monitoring crystals, crystallization and transformationsChairs: Nick Blagden & Anne Kavanagh
Session 1.Chick Wilson opened this session with an overview of 'crystallisation phase space' in which he posed the question: should we expect the unexpected? And answered: yes, particularly polymorphism. Chick explored the question of whether favourable (even tunable) solid state properties of molecular materials can be achieved by understanding how those properties are determined by crystal structure, and how these desirable structures can be achieved. To do this, the structural chemist attempts to understand and control intermolecular bonds, particularly hydrogen bonds, using crystallisation, crystallography, solid state analysis and quantum chemical calculations. Paul Barnes looked back at how in-situ synchrotron X-Ray diffraction has been applied, to study both the formation and the performance of functional materials. Time-resolved powder diffraction has been used to study rapid changes taking place in response to changes in temperature, pressure and chemical conditions in systems as diverse as gypsum (dehydration), cement sintering, nd catalyst studies. TEDDI (Tomographic Energy Dispersive Diffraction Imaging) has allowed spatially-resolved information to be gained in systems such as crystallisation of zeolite A on a ceramic base,(in which the crystallisation occurred in an unexpected place: the underside of the platform!). The last part of Paul's talk explored how the current limitation of TEDDI: data collection speed and limited analysis volume might be overcome in the future. Robert Hammond described how crystallisation control techniques can be used to produce 'the right stuff'for the pharmaceutical industry: crystals of the desired polymorph, crystal habit and size distribution. Control of polymorph is an essential in production of pharmaceuticals, but crystal habit and particle size distribution can also be important, since they affect secondary processing, such as filtration and powder flow. Robert explained how inline monitoring of particle size, polymorph and supersaturation can be achieved, and also described the use of 'closed loop' crystallisation of glutamic acid, in which low supersaturation, and seeding, were used to ensure the production of well-facetted crystals. Session 2.Roger Davey gave the first talk in this session, on work aimed at understanding how structure evolves during the nucleation process. He investigated the relationship between the structure in the liquid crystal phase of p-azoxyanisole (pAA), and the structure of the crystalline phase which nucleated from the liquid crystal on cooling. He found that one polymorph, Form 1, was always formed, and Form 3 was never formed directly from the liquid crystalline phase. Roger concluded that the structure of the crystalline phase is dictated by the ordering within the supersaturated liquid crystalline phase, but that an energy barrier to nucleation still exists, since crystallisation was not observed, even after several weeks, at temperatures above 80°C. Andrew Fogg described the use of in-situ synchrotron XRPD to follow the extent of reactions with time, and hence obtain invaluable information, such as activation energies, reaction order and nucleation models. Andrew gave an overview of some of the systems which have been studied. These included layered double hydroxides used as ion exchange materials, in which the stacking sequence and the formation of intermediates was investigated, and lanthanide intercalation compounds in which the original two dimensional structure was seen to convert to a three-dimensional structure, this observation being confirmed by high resolution electron microscopy. The finale of the session was the announcement of the winner of the Industrial Group Prize for the best, industrially-relevant talk to be given in the Young Crystallographers Meeting. The prize was awarded to Anne Stevenson from Bath University, who described her work on novel metal-organic framework compounds. These compounds contain pores whose size can be controlled, and also high surface area, and these features make them of interest for a variety of applications including gas storage and purification, catalysis, and even medical applications. Anne received a cash prize and a bottle of bubbly from the IG Committee. Anne Kavanagh
Understanding API Phase Transitions
Thermal Properties of Tolbutamide and Paracetamol by Real-Time Variable Temperature Raman Microscopy In the first IG presentation of the morning Paolo Avalle really hit the theme of the conference for dynamic crystallography, by demonstrating how, by applying Raman spectroscopy in real time, you can gain some insightful information into what is really happening during an API Phase Transition. Paolo described how the individual peaks in the Raman pattern could be assigned to specific areas of the molecule. He then demonstrated how these peaks could be tracked in real time during the heating of samples of paracetamol or tolbutamide. Then during phase transitions, he demonstrated how these peaks shifted. By looking at the crystal structures of the molecules he could then gain information about how the molecules were reorganising during the polymorphic transitions. By the use of principal component analysis he could plot the phase transitions with temperature and determine how many distinct phases were present during the transitions.
Co-Crystals and Crystal Growth The second presentation of the morning saw a change to the scheduled program. J.Y. Khoo was unable to attend the conference so Nicholas Blagden heroically stepped in at the last minute to take the slot. Nick managed to put together an excellent presentation in only a couple of hours and even managed to aim towards the conference and session themes too. Nick described some of the theories of co-crystals and crystal growth. Demonstrating how co-crystal pairs could be selected by how strong their inter-molecular interactions are likely to be, in a crystal engineering approach. He then demonstrated how you could screen for co-crystal formation using the Kofler contact method. He showed an example video of co-crystal growth at the interface between isonicotinamide and benzoic acid by hot stage polarised microscopy. He also demonstrated how ternary phase diagrams could be applied to solvent based co-crystallisation studies. Identification of Driving Forces in High Pressure Phase Transitions Using the PIXEL Method. In the last talk of the session Russell Johnstone applied real pressure! Up to 10 GPa in fact by the use of a Merrill-Bassett Diamond Anvil Cell. Russell described how crystals could be subjected to very high pressures while collecting single crystal X-ray or neutron powder data. He then described the phase transition that occurs at high temperature for L-serine monohydrate, showing the changes that occur to the crystal structure and intermolecular bond lengths. He also demonstrated how the PIXEL method can be used to understand why pressure-induced phase transitions occur. Brett Cooper
Crystallography in the Pharmaceutical pipeline
As crystallographers we have a great understanding and appreciation for molecular structures and the interactions that occur at this scale. Utilising this understanding, shifting the knowledge so that it can be applied constructively to problems beyond crystal structures, within the pharmaceutical industry, is the great challenge. This session focused on the application of crystallographic data to problems outside the usual comfort zone of collecting and determining a crystal structure. Crystallography in Drug Development Cheryl gave an excellent talk presenting two case studies illustrating two uses of crystallography in the pipeline. The first case study described how computational methods such as polymorph prediction and molecular dynamics can be used to influence a polymorph screen by focusing the experiments to engineer a desired drug form with the correct hydrogen bonding. The second case study utilised non-ambient humidity conditions to collect crystal structures of a variable hydrate to understand the mechanism by which the compound could dehydrate and rehydrate. The information gathered from these crystal structures and solid state NMR, identified disordering of the flourophenyl group as a potential channel for solvent movement, flipping of the ring acting as a revolving door. The Crystal Structure is the Gold Standard for Proving of the Structure of a Drug Substance. What can be achieved for the Drug Product? David's talk focused on the drug product, an area of research which in the past has had little interaction with the crystallographer, but with the advances of computational modelling software, computer hardware and imaging techniques that can probe to sub-micron levels, the molecular and the macroscales are merging. The first case study used mesoscale simulations to rationalize the behaviour of complex polymer-based drug formulations and help to understand changes which occur during stability studies. The modelling showed how the drug interacted within the formulation, self-assembling to form a shell of drug forms around the propylene oxide rich regions, which is driven by the hydrophobic nature of the drug. The second study looked at tablet blends formulated by wet granulation and how accurate mapping of the surfaces by methods such as Raman and TOF SIMS mass spectrometry can be used to define the location of components and the degree of mixing. The sub-micron resolution of these techniques gives immense information regarding the interactions of the components and by utilising this knowledge it may be possible to speculate which components will mix favourably.
From the Industrial via the Academic laboratory to the Court Room: Ciclovirs - A Pharmaceutical PXRD Case Study Jeremy's talk covered the court room and the synchrotron, two different areas of pharmaceutical endeavour. He presented the case of Roche versus Ranbaxy over valganciclovir and his personal account of his involvement in the case: from testing powder samples under non-ambient conditions, trhough producing documents to the court, to the final court appearance. Ranbaxy argued that the amorphous form they manufactured did not infringe on the crystalline patent of Roche. Jeremy demonstrated by quantitative analysis of amorphous content of the samples by XRPD, that the samples were X-ray diffraction amorphous and therefore demonstrated the the information disclosed in the Ranbaxy patent to be true. The case is still in the court.
Matthew Johnson
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