Reports on Industrial Group Meetings 2005

Autumn Meetings 18^th & 19^th October 2005

• Workshop on Patents in Crystallography 18^th October 2005
• Autumn Meeting Patents & Crystallography in Industry 19^th October 2005

Workshop on Patents in Crystallography 18th October 2005 School of Crystallography, Birkbeck College, London.

Samantha Towlson (Pilkington PLC)provided a refreshingly clear overview of patents covering the complete field from what a patent is, the benefits of owning one, what can be patented, how the process works, and concluding with some examples.

Jeremy Cockcroft (UCL/Birkbeck) lecture titled “Crystallography for Patents” covered information types in the context of patents and contrasted the information rich single crystal data, routinely collected at 150K, with the 1 dimensional data sets that may be obtained by XRPD. He highlighted the fact that the intensity information obtained using flat plate presentations is often inaccurate due to preferred orientation effects and that data collected using a transmission geometry was much more reliable. He advocated the sole use of peak position data in instances where the intensity data was unreliable and the use of indexing to confirm that the presented data was consistent with a single phase and pointed out that crystallographer often chose the unit cell on the basis of one whose angles are 90 degrees rather than necessarily the smallest volume.

Gareth Lewis (Astra Zeneca) provided an overview of the lead optimisation as applied within their company indicating that their preference was to develop a crystalline compound based on a literature search that showed that of the 4700 drugs on the market only 7 are amorphous. He highlighted the importance of identifying the most stable crystalline modifications that a compound may exist in during the compounds early development. A small (and manual) polymorph screen is carried out internally and typically consists of 10-100 experiments. During late development it was then important to identify all the potential crystalline modifications:-

A final polymorph screen of the most pure material from the final route of synthesis concludes the solid state form screen. Such screen appears to be carried out externally and typically consist of 100-1000 experiments. The methodology employed includes full structural characterisation using single crystal, XRPD and IR and then DSC TGA and hot stage microscopy. He explained the use of X-ray powder data to access non ambient data

X-ray is used both qualitatively and quantitatively through the use of characteristic peaks and pattern matching using le Bail/Pawley fit methods or Rietveld analysis which requires the single crystal data for the appropriate forms.

Martin Vickers(UCL/Birkbeck) provided an example of the type of data included in a patent application which demonstrated that the data may be of questionable quality; as in this case one of the diffraction patterns purporting to be a different solid sate form was consistent with the material simply exhibiting preferred orientation effects.

Jeremy Cockcroft (UCL/Birkbeck) provided an example where quantitative X-ray powder diffraction data had been used in a patent case in an attempt to demonstrate that one company was infringing another’s patent on a livestock disinfectant which may contain sodium chloride at a levels as low as 0.025% as a result of the synthetic route based on the use of sodium dichloroisocyanurate. Using a method of standard additions it is possible to determine the concentration of the un-spiked material providing peak overlaps do not preclude this. Various presentation methods were considered and capillary was ruled out due to the relatively high background produced by the glass tube. Care in smoothing data is also indicated as his experience has shown that this may generate false peaks.

Mike Glazer (University of Oxford) lectured on crystallographic patents and seeding. He related his experience of being an expert witness and supplied his rules:

1. Do not lie.
2. Do not actively help the opposition.
3. Be aware of yourself and do not be tempted into discussion topics that you are not completely familiar with.
4. Talk slowly and consider carefully before making a statement.
5. Keep things simple.
6. Do not take with you to court any notes, papers or anything that you do not want the opposition to know about.
7. Do not make copious notes.
8. You are the expert.

He then cited a case in which the manufacture of a particular solid state form of Cephadroxyl monohydrate which is covered by a patent, that relates to a new method of synthesis, and material manufactured by the old process for which the patent has lapsed. The work demonstrated that care has to be exercised in quoting characteristic peaks as if this is too loosely defined it is possible for the opposition to claim that they are making the original solid state form and not infringing your patent.
The highlight of the talk was a double act with Bob Gould re-enacting a transcript from an american court case, emphasizing the points made and demonstrating the aggressive nature of cross examination.

Philip Lake
GSK.

Autumn Meeting "Patents & Crystallography in Industry" 19^th Oct 2005

School of Crystallography, Birkbeck College, London.

Morning session - Patents.

Chris Frampton (Pharmophix) talked on “Case Studies by an Expert Witness”. Despite claiming not to be an expert at being an ‘expert witness’, Chris gave some excellent general advice on the duties and obligations of an expert witness. This included GLP (good laboratory practice), confidentiality, reporting and being prepared for unpleasant cross examination by the QC. Also how to give opinion within the boundaries of your remit, and being representative of peers in the XRPD industry, whilst avoiding the trap of being inventive yourself. He gave a couple of pharmaceutical examples, one of which was the classic tale of Paraxetine Hydrochloride, and the disappearing polymorph. It was noted that solvate forms, of which hydrates are a subset, are not polymorphs.

Roger Savidge (Consultant) then gave an insight into “Patents and Crystallography” from the users perspective, and cleared up some of the misconceptions. There are only national patents, although these can be applied for through regional (eg. European) or World (PCT) patent offices. The 20 year timescale was described, and the importance of keeping all the parts of your invention confidential until final application. In terms of exploitation, a granted patent does not give the inventor the exclusive right to exercise his invention, merely the right to prevent others. Thus in practice the patent holder, may require licenses from other inventors whose patents overlap in some way, and he may also grant a licence to others to use the invention commercially. You are not allowed in any way to threaten potential customers by suggesting that your competition may be infringing a patent. You are well advised to go through your solicitor.

Andrew Hodge
BP Chemicals.

Afternoon session - Crystallography in Industry

Low angle Round Robin preliminary results, David Taylor, consultant

David opened by explaining that the purpose of the Round Robin was to test the suitability of Silver Behenate to become a certified low angle intensity standard. The Round Robin would also provide direct intensity comparison between different equipment and set-ups and would provide participants with feedback on instrument performance. 21 users signed up for the Round Robin, to date 14 had returned data obtained from 17 instruments (1-Bede, 7-Bruker, 8-PANalytical and 1-Stoe). 22 data sets had been collected including 1 from Holland and 1 from Taiwan. All the data sets were obtained using copper tubes.

For comparing intensities, the data was normalised for 40mA current. 'Figure of Merits' were calculated for each data set. David said that some interesting information was coming through for example some users had quite high background counts at low angles. More data analysis will be carried out to explore affects due to slit size (variable VS fixed) and counting time. A full report will be published in due course and added to the Industrial Group's web pages.
View Presentation.

Standards, Steve Norval, ICI plc

Steve updated the meeting on progress towards publishing the new European standards ubder the banner "Non-Destructive Testing - X-ray Diffraction from polycrystalline and amorphous materials".
Those so far published include:

• EN13925-1 - General Principles
• EN13925-2 - General Procedure
• EN13925-3 - Instruments

EN1330-11 - Terminology - is due to be published next year.
Future subjects include reference materials and phase identification and quantitative analysis.

Steve explained that XRPD in industry is used for understand materials, development of new materials, solving problems, identification, specification and attributing blame. Laboratories and departments need to communicate with customers and suppliers and need to conform to regulations and legislation. Thus, everyone needs to understand the technical language and XRPD users need to conform to international standards to obtain credibility. At a minimum there is a need for common concepts and terminology, well defined instruments, agreed reference materials, acceptable procedures and adequate reporting.

The committee is trying to produce structured standards with standards for overview/common issues, industrial techniques and specific applications. The three published standards to date cover general principles (basic concepts, Bragg equation etc), procedures and instruments. Terminology and Reference Materials standards are in progress and work on phase identification and quantitative analysis is starting. Standards could form the basis of laboratory accreditation and validation of patent data.

Neutron Diffraction - Introduction, Jeremy Cockcroft, Birkbeck College
[The intended speaker Peter Laggner, Institute of Biophysics and X-ray Structure Research, Austrian Acadmey of Sciences was unwell and unable to attend. Jeremy stepped in to present a talk with the same title based on his presentation to the 2005 BCA Durham School].

Jeremy began by describing the properties of a neutron (mass 1, no charge, spin ½, strong interaction with nucleus, weaker interaction with unpaired electrons). Its kinetic energy is related to its velocity and temperature. Its coherent scattering cross-section gives rise to diffraction data - incoherent scattering contributes to the background signal.

Since neutrons interact with nuclei the point scatterers are very small compared with the wavelength, unlike X-rays which interact with the electron cloud - Form Factor. The neutron pattern does exhibit decreasing intensity with 1/d. For neutron shielding, B₄C doped rubber, plastics or cadmium metal sheet is used. ⁶Li is very good but is rarely used since in is normally extracted from the lithium containing ore for military use!

Detection relies on the absorption by the atomic nucleus with the simultaneous emission of a gamma-ray. ILL Grenoble is still Europe's highest flux neutron source. The reactor consists of 10g of ²³⁵U surrounded by heavy water cooled to 35C. 'Hot' and 'Cold' sources produce long wavelength and short wavelength neutrons respectively. The neutrons are transmitted along nickel coated curved guides - Guide Halls. The beam from the reactor is a 'white' beam (continuous range of wavelengths). Selected wavelengths can be obtained by use of monochromators. The sample holders are high temperature quartz tubes.
Overall, Jeremy gave a very interesting and comprehensive overview of the subject of Neutron Diffraction.

An in-situ study of a redox catalyst analysed by Rietveld refinement, Olivier Leynaud, Birkbeck College

In-situ diffraction arises from the need to understand what is happening inside the sample such as identification of intermediary compounds in a chemical reactions. Needs greater X-ray flux than produced by laboratory instruments so that quick reactions can be studied - Time resolved X-ray Diffraction. Olivier said that in order to meet these requirements, experiments are carried at Daresbury Laboratory's synchrotron source. The MPW 6.2PD station with RAPID 2 multi-wire detector (60degree range) is used. The small oven can be heated up to 950C and is water and air cooled. Vacuum experiments can also be carried out. The Fe-Mo-O catalyst system has been studied. An excess of MoO₃ in Fe-Mo-O has been found to be beneficial for the stability of the active phase and replenishing any sublimed Molybdenum. It allows the successful Rietveld refinement of the XRD patterns.

Structure Analysis of Novel-Templated ALPOs using CCP14 Software, Richard Stephenson, UCL, Birkbeck College

Novel-Templated ALPOs are a class of crystalline micro porous materials. Three synthetic mixtures produced the same layered structure. Introducing a cation e.g. Cobalt produced a different 3D structure i.e. poor reproducibility. Richard said that if single crystals are produced then it is possible to get comprehensive information from the refinement of their diffraction patterns. However, a particular issue is that the crystal is not representative of the bulk material. The refinement programs used can be viewed at the ccp14 web site (www.ccp14.ac.uk or www.ccp14.ac.uk/solution/xtalrefine/).

Crystals Software: Has an in-built wizard and there is guided structure refinement. A 'Supervisor' routine makes recommendations for further improvement. The refinement process can be followed with in-built graphics and electron density maps can be generated.

WINGX Suite for Windows: It is compatible with the Shelx range of programs. Resulting density maps can be viewed in Contour and Map view.

For structural refinement of powder diffraction data there is a large range of programs. However, they are not as sophisticated as those for single crystal data. They have the EXPQUI Interface for Rietveld programs such as Rietica, Ortex (image and movie animations) and Struplo for Windows (polyhedral structure drawings).

Mark Farnworth
Pilkington plc.

Last updated 12-December-2005

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