Report Industrial Group Autumn
Meeting 5 November 2008
Pharmaceutical Special Interest Group - 5th November 2008
AstraZeneca, Charnwood.
Speakers: Left to Right are - Matt Tucker (ISIS), Graeme Day (University of Cambridge), Xue Wang (University of Leeds), Robert Docherty (Pfizer),
Claire Thompson (GSK), Frank Leusen (IPI, University of Bradford), Amy Robertson (AstraZeneca), Matthew Johnson (GSK), Talbir Austin (AstraZeneca)
The Pharamceutical Special Interest Group held its Autumn meeting on the 5th November 2008 at Astra Zeneca, Loughborough. Seven speakers presented an excellent range of topics including computational techniques such as polymorph prediction, Process Analytical Technology (PAT) focusing particularly on in-situ monitoring of crystal growth and finally techniques for characterising amorphous materials in the pharmaceutical industry, introducing Pair-wise Distribution Functions (PDF) for the understanding of amorphous structure at a molecular level. The chairs for the morning and afternoon sessions were Matthew Johnson (GSK) and Brett Cooper (MSD) respectively.
Bob Docherty (Pfizer) started the morning session with a review of the Pfizer vision for computational techniques within the pharmaceutical pipeline, highlighting a molecule to market approach which starts at the molecular level and builds up with each stage of development through formulation to manufacture and launch. Computational techniques, he explained, linked the crystal structure of the drug product to the physical properties of the drug, its surface characteristics and therefore the interaction characteristics of that surface to other materials, which will directly influence such processes as milling, drying and formulation. By utilising computational techniques he believes it will be possible to produce a stable drug product faster and cheaper than ever before.
Graham Day (University of Cambridge) followed Bob's review by focusing on polymorph prediction and the benefits this could have on the pipeline. Polymorph prediction can be used to generate subsequently unknown crystal structures of a molecule and rank them by energy to determine the most stable polymorph. This has obvious benefits to the pipeline in that allows more focused screening to be developed to crystallise, via certain solvent combinations, the stable polymorph. He presented the case study of Carbamazepine, a combination of experimental and computational approaches, where he identified that Form 2 could only be stabilised during crystallisation by the addition of toluene in the channels of the crystal structure. This was independently confirmed by Fabbiani et al in 2007 by the collection of the single crystal structure containing channel toluene.
View Presentation ( 2.2mb PDF file)
Frank Leusen (IPI, University of Bradford) followed on from Graham on the topic of polymorph prediction, summarising the CCDC blind tests from 1999-2007, particular highlighting the large Dutch movement in this field! Frank described the new approach and results obtained by himself and Marcus Neumann of Avant-garde Materials Simulation. In the 2007 CCDC blind test they predicted four out of four structures, with each of the structures being ranked as the first structure prediction. This talk really highlighted the level of complexity involved in polymorph prediction, but also showed the current state of the art and the potential for the future.
View Presentation ( 2mb PDF file)
Moving away from computational chemistry Xue Wang (University of Leeds) gave an excellent talk summarising the use of PAT for morphological population balance modelling and 2D/3D on-line monitoring of crystal growth. The case studies he presented demonstrated the effect of size and shape on bioavailability and processing and that once defined it is possible to control these variables on large scale (e.g. 200L reactors) by completing the suggested simulations to produce an optimised cooling regime.
View Presentation ( 5mb PDF file)
In the first presentation after lunch Amy Robertson (Astra Zeneca) gave a fascinating overview of how AZ applies PAT to really understand the crystallisation process. She highlighted the importance of monitoring the crystallisation process to ensure the correct particle size and morphology, which are key to the final product performance within the Quality by Design framework. She described the application of Focus Beam Reflectance Measurement (FBRM) and Particle Vision Monitoring (PVM) to show how crystal size, shape and growth could be monitored during the process. Finally, she described the use of FTIR and Raman probes to demonstrate how form turnovers could be monitored and how processing could be controlled to ensure delivery of the correct form with the desired properties.
View Presentation ( 2.8mb PDF file)
In the second afternoon presentation Claire Thompson (GSK) highlighted the importance of monitoring how much amorphous material was present in batches of API, especially when developing inhalation formulations. She highlighted how amorphous material can form during milling and what could happen to the particle size distribution should the amorphous material crystallise and fuse together particles of API. Claire then highlighted the "Plethora" of analytical techniques that could be used to study amorphous content. She discussed their relative sensitivities and discussed the approaches for quantifying amorphous content in the API batches.
View Presentation ( 0.9mb PDF file)
In the last talk of the afternoon session Matt Tucker (ISIS) highlighted the benefits of total scattering or PDF method. Matt described how synchrotron X-ray or neutron data could be normalised to an absolute scale to provide information on local, medium and long range atomic structure. He then went on to describe how this could be applied to monitor pressure induced amorphisation in the negative thermal expansion of ZrW2O8 at the molecular level, identifying the structure of the nano-zones of amorphous. Finally he challenged the Pharma audience to think of ways this technique could be applied to the challenges faced during pharmaceutical development.
We would like to thank Anne Kavanagh (Astra Zeneca) and Tal Austin (Astra Zeneca) for all their help organising the event at Astra Zeneca, Loughborough.
Conference Feedback
When asked about the meeting overall, the content, organisation and the venue the rating assigned by responders was "Excellent". When asked if they would attend future Pharma meetings or the BCA Spring meeting the majority of responders said "definitely" or "probably". When asked how far people had come or where they prefer to have meetings, it seemed clear that the Midlands to the South would be the best location to hold meetings. When asked what they would like to see at future meetings the majority of responses were "more of the same please". So we will try to do our best next year.
Matthew Johnson (GSK) and Brett Cooper (Merck)
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