The use of Inverse Gas Chromatography in formulation development and manufacturing of dry powder inhalation products

Dr. Frank Thielmann

Pharmaceutical Operations, Novartis Pharma, Stein, Switzerland 

The development and manufacturing of dry inhalation products is a challenging task due to small drug content, tight product specifications and therefore strong impact of process changes on product performance. The choice of techniques available for the analysis and differentiation of small physicochemical differences is very limited and requires advanced characterization methods.  Inverse gas chromatography (IGC), a highly sensitive and versatile tool first developed over 40 years ago to study surface and bulk properties of particulate and fibrous materials, has recently been demonstrated to offer vast potential in the pharmaceutical industry.

IGC is particularly sensitive if measurements are carried out in the low concentration or infinite dilution regime since small differences between similar materials or batches of the same material that have been processed under slightly different conditions can be measured by varying probe concentration, temperature, flow rate, or background relative humidity.  At high concentration (finite concentration) the heterogeneity of the material surface can be studied to obtain e.g. surface energy distributions that can help in the understanding of particulate interactions as between lactose carrier and drug substance particles.

This talk will summarize a number of examples from the literature as well as own work in which IGC has been utilized to address important issues in pharmaceutical development and manufacturing such as batch-to-batch variability, impact of excipient variability on product performance, blend segregation, triboelectrification and others.

IGC as a key tool for the characterization of porous materials: implications in the development of adsorbents and heterogeneous catalysts

Salvador Ordóñez

Department of Chemical and Environmental Technology, University of Oviedo (Faculty of Chemistry)

Inverse gas chromatography (IGC) is a versatile, instrumentally simple, and relatively fast technique for characterizing the physicochemical properties of materials. Although first applications of IGC for characterizing solids were focused on non-porous or macroporous materials (such as polymers, pharmaceuticals, minerals, etc.), in the last decades this technique has been applied to mesoporous and microporous materials, including recently developed materials, such as metal-organic frameworks (MOFs) and carbon nanomaterials (CNTs, CNFs, etc.). For all these materials (of key technological interest nowadays), IGC allows a thorough chemical characterization of the surfaces by determining thermodynamic parameters of the adsorption (enthalpy, entropy, free energy, surface energies, dispersive and specific contributions, etc.) of different gaseous probes. These chemical properties determine the application of these materials for different purposes (adsorbents, heterogeneous catalysts, etc.).

The presentation explores the application of IGC to different kinds of porous materials, such as mesoporous supports (aluminas, mesoporous silicas, etc) and heterogeneous catalysts, activated carbons, non-microporous carbons (carbon nanotubes, nanofibers, graphene, etc.), ordered microporous materials (zeolites) and metal-organic frameworks (MOFs). Different kind of information for being obtained (acid-base character, reactivity of surface functional groups, dispersive and specific interaction with the probe molecules) will be explored.

Finally, IGC will be compared with other techniques providing similar information, such as immersion calorimetry, micro-calorimetry, thermo-desorption methods, etc.

 Application of IGC for estimation of the magnitude of adhesion in complex polymer systems

Beata Strzemiecka, Adam Voelkel

Poznan University of Technology, Faculty of Chemical Technology, Institute of Chemical Technology and Engineering, Poznan, Poland

Interactions between the components of complex polymer systems are crucial for their utilitarian applications. The usefulness of IGC for studying adhesion between the components of the abrasive articles is demonstrated.

Abrasive tools consist of abrasive grains bonded by a binder which is usually a phenol-formaldehyde resin (novolak type). In addition, the abrasive tool includes various types of inorganic fillers, such as pyrite, cryolite, red iron oxide, and the resole resin which is used as a wetting agent. In such a complex system the final properties of the abrasive tool depend on many factors:

– surface and physical properties of the abrasive grain and fillers,

– homogeneity of the semi-product,

– the physicochemical properties of the resins used as the binder, their degree of hardening,

– interactions between components, i.e. abrasive grain-binder, filler-binder.

The adhesion between abrasive grains and a binding agent (binder) is an extremely important factor influencing the rate of wear of the abrasive tool. Adhesion between the components in the final product should be sufficiently strong to keep the abrasive grains until they will become blunt, then such blunt grains should be ejected from the polymer matrix and sharp grains should be exposed. Currently, there is no effective, inexpensive and simple method of evaluation of adhesion which could be applied in industry of abrasive tools.

IGC method was successfully used to evaluate the adhesion of the following systems: abrasive grains-resin, filler-resin [1, 2]. It is also possible to assess the effect of fillers on adhesion of the binder to the abrasive grain. The presence of filler significantly affects the strength of the interactions between the abrasive and binder. The example of the dependence of the adhesion between the abrasive grain and the resite resin (hardened resole) on the presence of different fillers will be also presented. Moreover, the application of IGC procedure utilizing thermodynamic theory of adhesion and cohesion [2, 3] for evaluation of the dispersion of micro- and nanofillers in the polymer matrix will be shown. The IGC results were correlated with results obtained by dynamic thermo-mechanical analysis (DMTA).

A short review of other applications of IGC technique for studying polymer composites will be presented (estimation of hardening degree of resins [4], ageing of phenolic resins [5]).


1. B. Strzemiecka, A. Voelkel, 2012, Int. J. Adhes. Adhes., 38, 84–88.
2. B. Strzemiecka, A. Voelkel, D. Chmielewska, T. Sterzyński, 2014, Int. J. Adhes. Adhes., 51, 81-86.
3. B. Strzemiecka, A. Voelkel, J. Donate-Robles, J. M. Martín-Martínez, 2013, J. Chromatogr. A, 1314, 249-254.
4. B. Strzemiecka, A. Voelkel, M. Hinz, M. Rogozik, 2014, J. Chromatogr. A, 1368, 199-203.
5. B. Strzemiecka, A. Voelkel, J. Zięba-Palus, T. Lachowicz, 2014, J. Chromatogr. A, 1359, 255-261.

Hansen Solubility Parameters via IGC – problems and possibilities

Prof. Steven Abbott, Ipswich, UK

To understand how solvents, polymers and particles interact, terms like hydrophilic/hydrophobic or polar/non-polar are too crude to be helpful. The 3 Hansen Solubility Parameters, Dispersive, Polar and Hydrogen Bonding provide a much more useful framework for interactions. If all three parameters are similar then, say, a solvent and polymer will be “like” each other and if one or more of them are very different then they will be “unlike”. This simple idea has found application in paints, pharmaceuticals, nanoscience, photovoltaics, cosmetics and more. “All” we need, then, are the 3 parameters. They can be readily estimated for small molecules and measured for polymers and particles. It is hard to get values for intermediate molecules such as cosmetic excipients. This is where IGC comes in. But how are HSP and IGC related? Well, how does IGC measure anything? Using free “apps” co-developed with AdScientis these ideas are brought alive. How good are the apps? That’s a question for the symposium. If they could be better then tell us how and they will be made better!

HSP of liquids; a practical determination via High Throughput sample preparation and manual evaluation

Dr. Sander van Loon

VLCI Amsterdam, Netherlands

Practical HSP determination for liquids is known to be accomplished via IGC but was, until now, not feasible via the conventional HSP methods. Conventionally, for solids HSP determination, various solvents with known HSP are used to find the solubility sphere of the solid. When applying that for liquids, a very broad miscibility is in most cases observed, causing uncertainty in HSP spheres. The new practical method inverts the conventional procedure, by using known solubility spheres to determine the HSP of the liquid. To speed up and be more precise, High Throughput is used for sample preparation. Samples are then evaluated manually. This new practical liquid HSP determination will be explained in this presentation.

Characterization of Porous Solids by Inverse Gas Chromatography: Precise, Easy & Significant

Michael Rückriem

Porotec, Hofheim am Taunus, Germany

The characterization of the surface of porous materials is of great importance for understanding their performance in almost all fields of application. This comprises the characterization of the texture properties on the one hand and on the other hand the characterization of the surface chemistry. The characterization of texture properties is well established on the basis of the standard techniques of low temperature nitrogen sorption and mercury intrusion porosimetry for macroporous materials (pore width >50 nm). Spectroscopic methods and elemental analyses provide information about the composition of the surface.

Inverse gas chromatography (IGC) is a fast and versatile technique to determine thermodynamic properties of solids. Thermodynamic properties (e.g. dispersive and specific surface energy, heat of adsorption and acid-base properties) are obtained on the basis of several chromatograms of different non-polar and polar gaseous probe molecules. These thermodynamic properties are significant for a better understanding and further development of porous materials.

This study highlights the characterization of micro- and mesoporous silica. The IGC technique was applied successfully for the characterization of porous silica. Furthermore, the effect of surface modification of porous silica was investigated. Correlations were observed between different surface groups or concentration of surface groups and physic-chemical properties determined by IGC. The dispersice surface energy, specific interactions, heat of sorption and acid-base properties were determined and discussed in the presentation.