NATAS/GGPF Spring Symposium - Recent Developments in Microanlaytical Techniques, March 5


Register For Spring Symposium Only, March 5


General Information

The NATAS/GGPF Spring Symposium, "Recent Developments in Microanalytical Techniques," brings together seven distinguished international scientists. See program below.

$145 for registration prior to February 10.

For information on student and retired/unemployed rates or for other inquiries contact Bruce Prime at

This event will take place at Michael's at Shoreline Park, 2960 N. Shoreline Blvd., Mountain View, CA. Michael's is a short distance from Hwy 101, about 12 miles north of the San Jose airport and 30 miles south of the San Francisco airport. From 101 in Mountain View, take the Shoreline Boulevard. Exit, turning toward the bay. Drive past the Shoreline Amphitheater and go straight ahead, entering into Shoreline Park. After a mile or so inside the park, a sign for Michael's will direct you to turn left into the parking lot. Restaurant phone: 650-962-1014 (do not call restaurant for registration).

A block of rooms has been reserved for this event at the Sheraton Sunnyvale Hotel, 1100 North Mathilda Ave, Sunnyvale, Ca. The rate is $159 weekday/$79 weekend, single or double. Locally call 408/745-6000 or in the US and Canada call direct 1-800/566-6449 and mention the GGPF March event. The Sheraton is just off Hwy 101 about 6 miles north of the San Jose Airport, 6 miles south of Shoreline and 36 miles south of the San Francisco airport. The Sheraton can provide transportation to/from the San Jose airport and to/from the programs at Michaels's at Shoreline.

Program for NATAS/GGPF Spring 2003 Symposium
March 5

Lothar Kleiner, Alza Pharmaceuticals,
Symposium Chair

8:45 am Keynote
Microcalorimetric Methods to Assess Powder Surfaces and Solid Interactions, Mark A. Phipps, Thermometric, Ltd


9:45 am


10:15 am
New Microcalorimetric Methods for the Determination of Kinetic Parameters for Solid State Reactions with Particular Reference to Pharmaceutical Testing, Anthony Beezer, Greenwich University


11:05 am
Microcalorimetry, Structural Relaxation in Glasses, and the Prediction of Pharmaceutical Stability, Michael Pikal, University of Connecticut


12:15 pm


1:15 pm
Some Recent Advances in Scanning Probe Techniques, Mike Reading, Loughborough University


2:05 pm
Quartz Crystal Microbalance/Heat Conduction Calorimetry: a New Isothermal Technique for Studying Sorption and Reaction in Thin Film Samples, Allan L. Smith, Masscal Corporation and Drexel University


3:00 pm


3:30 pm
Study of Interface Physics through Combination of Surface Plasmon Resonance and the Quartz Crystal Microbalance, Curt Frank, Stanford University


4:20 pm
Advancements in Infrared Micro Sampling Technology, Bonnie Leimer, Thermo Nicolet


5:10 pm
Wine and Cheese Reception, Instrument Display



Symposium Abstracts & Speaker Biographies

(Updated 2/21/03)

Microcalorimetric Methods to Assess Powder Surfaces and Solid Interactions

[Wednesday, March 5, 2003, 8:45am—9:45am]

Processes occurring either in the solid state or on solid surfaces are often hard to monitor without destructive and invasive measurements. Isothermal Microcalorimetry is one such technique that can investigate both physical and chemical processes without affecting the sample. During this presentation, it will be shown how stability, compatibility, amorphicity and water vapour interactions can be studied using Isothermal Microcalorimetry. The effect of stabilisers on the oxidative stability of polymers will be discussed using oxidative and inert atmospheres within the microcalorimeter. In addition, gas phase permeability into polymers via determination of WVTR will also be presented.
[Keynote Speaker: Dr. Mark A. Phipps, Thermometric Ltd]

New Calorimetric Methods for the Determination of Kinetic Parameters for Solid State Reactions with Particular Reference to Pharmaceutical Testing

[Wednesday, March 5, 2003, 10:15am—11:05am

Previous work from this laboratory [1] has shown that it is possible to determine kinetic and thermodynamic parameters (including values for the equilibrium constant, K, and for ÄG, ÄH and for ÄS) from isothermal heat conduction microcalorimetry. The equations that allow this were developed for single reaction processes although there has been an extension [2] to complex sequential reactions that are well separated in terms of rate constants and enthalpies. Examples of the study of commercial products (medicines) will be introduced and discussed.
Solid state reactions have proved a little more difficult to resolve largely because the exponents present in the equations are not order parameters but they are fitting parameters which describe the reaction mechanism [3]. Procedures have now been developed which provide solutions to this issue and hence make solid state reactions more tractable. These methods will be presented and discussed.
A more problematic area is that of complex simultaneous reaction systems (both solution and solid state). Significant progress has been made in dealing with such reactions and so theoretical approaches will be described and illustrated through the use of simulated data.
1.A.E.Beezer et al., J.Phys.Chem., 2001, 105, 1212-1215.
2.S.Gaisford et al., Thermochim.Acta,1999, 328, 39-45.
3.R.J.Willson et al., 1995, 99, 7108-7113.
[Speaker: Prof. Anthony Beezer, Greenwich University]

Microcalorimetry, Structural Relaxation in Glasses, and the Prediction of Pharmaceutical Stability

[Wednesday, March 5, 2003, 11:05am—12:15pm]

The objective of this presentation is to discuss methodology by which structural relaxation kinetics may be studied by isothermal calorimetry and to review the evidence supporting the hypothesis that pharmaceutical degradations are correlated with structural relaxation dynamics in the glassy solid. Pharmaceutical stability is extremely formulation sensitive, and our hypothesis is that differences in dynamics in the glassy state, as reflected by differences in the structural relaxation time, are partially responsible for formulation specific stability behavior of materials stored well below their Tg's.
Heat capacity and glass transition behavior were studied with Modulated DSC (TA Instruments 2920). Isothermal microcalorimetry (Thermometric 2277, or the “TAM”) was used to study relaxation dynamics. A Nicolet Magna 560 FTIR Spectrophotometer was used to characterize the secondary structure of proteins by 2nd derivative analysis of the Amide I region. To explore the relationship between glass transition width and fragility, theoretical modeling of enthalpy relaxation during a DSC scan was carried out, and modeling studies were also used to examine the impact of a time dependent relaxation time on the experimental determination of relaxation time by calorimetric aging experiments.
We find that relaxation times measured using isothermal microcalorimetry (TAM) are in satisfactory agreement with data accumulated in the conventional manner by doing enthalpy recovery experiments with a DSC. Generally, the modified stretched exponential function (MSE) provides more precise relaxation data than the simple Kohlrausch Williams Watts (KWW) equation. Further, we find that increases in relaxation time during the aging experiment can dramatically increase the measured relaxation time, t, and decrease the measured stretched exponential constant, b. However, the measured value of the relaxation time constant, tb is not affected. We also find that tb is less subject to random error than t. For these reasons, we normally report relaxation data as tb.
Using theoretical concepts and experimental structural relaxation time data, it will be demonstrated that dynamics in a glass at fixed T/Tg is a complex function of the nature (i.e., glass transition temperature and fragility) and of the thermal history of a glass (i.e., fictive temperature). These relaxation data are then compared with stability data obtained by chemical assay (HPLC) of samples stored at various temperatures and times. Experimental stability data suggest stability and structural relaxation are coupled in many cases. We present data for stability in cephalosporin antibiotics, degradation of aspartame, dimer formation in small molecule systems, and both chemical decomposition and aggregation in proteins. We also find evidence that stability may be improved by annealing, presumably as a result of the decrease in free volume and increase in structural rigidity that accompanies annealing.
In general, stability correlates well with both FTIR structure in the solid (for proteins) and with glass dynamics as measured by the structural relaxation time. We conclude that glass dynamics is an important factor in determining stability of small molecules and proteins in the amorphous solid state. However, other mechanisms also may be important, so the ability to predict stability solely from glass dynamics is limited.

Speaker: Prof. Michael Pikal, University of Connecticut]

Some Recent Advances in Scanning Probe Techniques

[Wednesday, March 5, 2003, 1:15pm—2:05pm]

The introduction of scanning probe microscopy (SPM) has opened the door to a range of new techniques for measuring a variety of surface (or near surface) properties on a small scale. Our interest started with the use of thermal probes that could be heated and so subjected to a temperature program when placed on a point of interest on a sample surface [1]. We call this type of local thermal analysis micro-thermal analysis. Initially calorimetric then mechanical properties were measured [2-6]. Recent studies have shown that relative crystallinity can be measured using the calorimetric measurement. Mechanical properties can be measured on the nanoscale using a scanning probe microscope, either by heating the tip or by heating the sample [1-6]. The results that have been achieved using these exciting new techniques are reviewed and the prospects for future developments are discussed.
Micro-thermal analysis can be combined with photothermal FTIR microscopy so that chemical and physical characterization can be carried out at the same time [6-10]. Although this kind of microscopy is not diffraction limited and so could achieve a spatial resolution of better than 100nm, in practice this has not yet been achieved. One obstacle is the size of the probe but the thermal diffusion length gives a more fundamental limitation. One solution to this problem is thermally assisted nanosampling [11] where the tip is heated to soften the sample before being retracted. The tip is usually contaminated by the material that was in contact with it and this contaminant can then be analyzed by, amongst other techniques, IR spectroscopy. These methods of chemical analysis can be complemented by using the tip for local pyrolysis with subsequent analysis of the eve loved species by mass spectroscopy and GC-MS [6].
1. Hammiche, A., Reading, M., Pollock, H.M., Song, M. and Hourston, D.J., Localized thermal analysis using a miniaturised resistive probe, Review of Scientific Instrumentation, 6712, 1996, 4268-4273.
2. M. Reading, D. J. Hourston, M. Song, H. M. Pollock and A, Hammiche, Thermal analysis for the 21st century, American Laboratory, 1998, 30(1), 13-17
3. A. Hammiche, D. M. Price, E. Dupas, G. Mills, A. Kulik, M. Reading, J. M. Weaver and H. M. Pollock, Two new microscopic applications of thermomechanical modulation: scanning thermal expansion microscopy and dynamic localised thermomechanical analysis. Journal of Microscopy, 2000, 199, 180-190
4. D. Grandy, D. Hourston, D. M. Price, M. Reading, G. Goulart Silva, M. Song and P. A. Sykes, Micro-thermal characterization of segmented polyurethane elastomers and a polystyrene-poly(methyl methacrylate) polymer blend using variable-temperature pulsed force mode atomic force microscopy. Macromolecules, 2000, 33, 9348-9359
5. F. Oulevey, N. A. Burnham, G. Gremaud, A. J. Kulik, H. M. Pollock, A. Hammiche, M. Reading, M. Song and D. J. Hourston, Dynamic mechanical analysis at the submicron Scale, Polymer Communications, 2000, 41, 3087-3092, ISSN 0032-3861.
6. M. Reading, D. M. Price, D. Grandy, R. M. Smith, L. Bozec, M. Conroy, A. Hammiche and H. M. Pollock, Micro-thermal analysis of polymers: current capabilities and future prospects, Macromolecular Symposia, 2000, 167, 45-62
7. A Hammiche, H M Pollock, M Reading, M Claybourn, P Turner and K Jewkes, Photothermal FTIR spectroscopy: a step towards FTIR microscopy at a resolution better than the diffraction limit, Applied Spectroscopy, 1999, 53, 810-815.
8. A Hammiche, L Bozec, M Conroy, H M Pollock, G Mills, J M R Weaver, D M Price, M Reading, D J Hourston and M Song, Highly localised thermal, mechanical and spectroscopic characterisation of polymers using miniaturised thermal probes, Journal of Vacuum Science & Technology B, 2000 18(3), 1322-1332
9. L. Bozec, A. Hammiche, H. M. Pollock, M. Conroy, J. M. Chalmers, N. J. Everall, and L.Turin, Localized photothermal infrared spectroscopy using a proximal probe, Journal of Applied Physics, 2001, 90, 5159-65
10. H M Pollock and D A Smith, The use of near-field probes for vibrational spectroscopy and photothermal imaging, in Handbook of vibrational spectroscopy, J.M. Chalmers and P.R. Griffiths (eds), John Wiley & Sons Ltd, 2002, Volume 2, 1472 - 1492
11. M Reading, D Grandy, A Hammiche, L Bozec and H M Pollock, Thermally-assisted nanosampling and analysis using micro-IR spectroscopy and other analytical methods, Vibrational Spectroscopy, 2002, 29, 257-260
[Speaker: Prof. Mike Reading, IPTME, Loughborough University, Loughborough LE11 3TU, UK]

Quartz Crystal Microbalance/Heat Conduction Calorimetry: a New
Isothermal Technique for Studying Sorption and Reaction in Thin Film Samples

[Wednesday, March 5, 2003, 2:05pm—3:00pm]

Many chemical processes occur in a thin solid film exposed to a gas when the gas either adsorbs on the surface or dissolves in the film. In the first generation of quartz crystal microbalance/heat conduction calorimetry (QCM/HCC), a QCM is coated with a thin (0.1-10 mm) sample, and reference combinations of a QCM in intimate thermal contact with a heat flow sensor are held at constant temperature and exposed to the same slow flow of (probe gas)/N2 mixture at ambient pressure. Three quantities are measured simultaneously: (a) the mass change m(t) (to ± 2 ng/cm2), (b) the thermal power P(t) (to ± 50 nW), and (c) the change in motional resistance R(t) when the sample film takes up, releases, or reacts with the probe gas.
We present measurements of m(t), P(t), and R(t) as self-assembled monolayers of C4 and C9 linear alkylthiols are formed at a gold surface. When thin polymeric films absorb water vapor or organic solvents, they both release heat and become more pliable. We present measurements of the dependence of the sorption isotherms and sorption enthalpies of water and ethanol vapor on the thickness of an aliphatic polyurethane polymer. Motional resistance data show that the polymer softens as it adsorbs the volatile component. Phase changes upon hydration are observed in a two-component film of myoglobin/phosphate buffer as a function of water vapor activity. Thin films of pharmaceutical film-coating materials are exposed to step changes in relative humidity, and mass uptake, heat release, and viscoelastic property changes are measured for films of different thickness.
Finally, the design and c
nstruction of a second-generation QCM/HCC will be presented, along with preliminary results on the interaction of liquids with thin films.
1. P.O. Box 1616, W. Chatham, MA 02669
2. Chemistry Department, 32nd and Chestnut St, Philadelphia, PA 19104]
[Speaker: Dr. Allan L. Smith, Masscal Corporation(1) and Drexel University(2)]

Study of Interface Physics through Combination of Surface Plasmon Resonance and the Quartz Crystal Microbalance

[Wednesday, March 5, 2003, 3:30pm—4:20pm]

[Speaker: Prof. Curt Frank, Stanford University]

Advancements in Infrared Micro Sampling Technology

[Wednesday, March 5, 2003, 4:20pm—5:10pm]

[Speaker: Ms. Bonnie Leimer, Thermo Nicolet]
A number of technological advancements have been made in infrared micro sampling in recent years. These include advancements in Fourier Transform Infrared (FT-IR) microspectroscopy as well as in focal plane array (FPA) imaging.

Design enhancements in the FT-IR microscope include the addition of dichroic filters, which allow for viewing and collecting of the sample simultaneously. Infinity corrected optics are currently incorporated into the microscope, providing a collimated beam through the microscope. This collimation increases the number of contrast techniques available for defining a sampling area. These techniques include brightfield, darkfield, polarized light, differential interference contrast, and fluorescence illumination.

Imaging is gaining widespread acceptance as FPA detectors continue to improve for FT-IR applications. The imaging system allows you to rapidly visualize heterogeneity as well as spatial distribution of distinct chemical species over the full field of view.


Mark A. Phipps received his BSc and PhD from The University of Kent, UK in chemistry and pharmaceutical chemistry respectively. He has held posts in achademia and industry, in the UK and US, investigating the role of thermal analysis and specifically isothermal microcalorimetry to pharmaceutical problems. Mark is a chartered chemist with the Royal Society of Chemistry and is a member of the RSC Thermal Methods Group Committee. Mark currently holds two positions within Thermometric as General Manager of the UK distribution company and as an International Product Manager for the Swedish parent company. [E-mail:]

Anthony E.Beezer is Professor of Biophysical Chemistry at Medway Sciences, University of Greenwich, UK. He graduated from the university of Keele ,UK where he also obtained his PhD and DSc degrees. He has been Professor of Biophysical Chemistry and Head of Department in the Universities of London and Kent. Awards include: 1994 Swiss Society for Thermal Analysis and Calorimetry “Applied Thermodynamics Award”; 1997 (US) Calorimetry Conference, J.J.Christensen Award for “Innovation in Calorimetry”; 1999 the Lavoisier Medal of the International Society for Biological Calorimetry. Published >200 papers and 2 books in the area of biological calorimetry, pharmaceutical calorimetry and, particularly, the determination of both kinetic and thermodynamic parameters characterising reaction systems from direct microcalorimetric data. [Email:]

Michael Pikal is currently Professor of Pharmaceutics at the University of Connecticut. Prior to September, 1996 he was a Senior Research Scientist with the Lilly Research Laboratories and an Adjunct Professor of Pharmaceutics at the University of Michigan and at the University of Minnesota. He received his Ph.D. in physical chemistry (1966) from Iowa State University and was a Postdoctoral Research Fellow with the Lawrence Livermore Laboratory(1966-1967 His current research activities include the solid state chemistry of pharmaceuticals, particularly the stability of amorphous materials, characterization of solids by calorimetry, and the science and technology of freeze drying with a focus on optimization of formulation and process for labile proteins. Dr. Pikal is a member of the ACS, AAPS, and the PDA. He received the Eli Lilly & Co."Presidents Award" in 1996. Dr. Pikal is a Fellow of the AAPS, and was the 2001 recipient of the AAPS Research Achievement Award in Pharmaceutical Technology. []]

Mike Reading has over 25 years experience of applying thermal methods to a wide variety of systems. 12 years have been spent in industry working for ICI the rest in academic institutions both in France and the UK. He is now head of the Advanced Thermal Methods Unit at the IPTME in Loughborough University UK. Winner of the Royal Society of Chemistry young scientist award and the NATAS-Mettler Prize, he is best known as the inventor of Modulated Temperature DSC and Micro-thermal analysis. []

Allan Smith is Professor of Chemistry at Drexel University (1975-present) and President of Masscal Corporation (2001-present). He is an experimental physical chemist, with 70 publications in peer-reviewed journals and 4 issued patents. He has served as Chair of the 56th Calorimetry Conference and as an Editorial Board member of the CRC Handbook of Chemistry and Physics. He has been a NATO Senior Postdoctoral Fellow and an Alfred P. Sloan Foundation Fellow. Since December 1997 he has made many invited presentations at national and international meetings on the QCM/HCC, and serves as a reviewer for twelve journals. He has obtained recent research funding from Sandia National Laboratory, Merck Corporation, and the National Science Foundation. Dr. Smith’s present research interests are quartz microbalance calorimetry and its application to chemical, physical, and biological phenomena in thin films. Further details his academic career may be found at, and of his company at [Email:]

Curt Frank received his Ph.D. from the University of Illinois in 1972. Fellow, American Physical Society. C. M. A. Stine Award, American Institute of Chemical Engineers. Principal Investigator, National Science Foundation Materials Research Science and Engineering Center on Polymer Interfaces and Macromolecular Assemblies (CPIMA).

Bonnie Leimer received her Bachelor of Arts and Sciences in chemistry from the University of Wisconsin – Madison. She joined Thermo Nicolet in May of 1993 as part of the Madison spectroscopy research center where she was involved in the development of infrared and Raman systems and accessories. In June of 1997 she began work as the applications chemist for the western region of the United States where she analyzes samples using various spectroscopic techniques including infrared and IR microscopy, Raman and Raman microscopy, TGA-IR, GC-IR and Photoacoustic spectroscopy. (E-mail:

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