Quantitative Characterization of Pharmaceutical Powder Surface Interactions Using Inverse Gas Chromatography-Derived Surface Energy Profiles

Abstract

Quantitative characterization of surface and interfacial properties is important for understanding the behavior of pharmaceutical powders, but conventional approaches to powder wettability and surface free energy can be influenced by measurement procedures and sample-specific factors. Inverse gas chromatography (IGC) provides a sensitive approach for characterizing powder surface energetics as a function of fractional surface coverage; however, the reproducibility and interpretation of IGC-derived surface energy profiles require careful evaluation.

In this study, the reproducibility of IGC-derived surface energy profiles was examined using pharmaceutical excipients, and the resulting energetic characteristics were compared with wettability measurements obtained using sessile drop and Washburn methods. Surface-energy profiles were further used to calculate thermodynamic work-of-adhesion profiles for powder– water interactions and for drug–excipient systems. Distinct differences in surface-energy profiles were observed among pharmaceutical excipients, including materials with identical nominal chemical compositions but different grades.

Drug–excipient work-of-adhesion profiles further demonstrated coverage-dependent differences in calculated interfacial interactions among pharmaceutical materials. The results demonstrate that IGC-derived surface-energy profiles canprovide reproducible characterization of pharmaceutical powder surfaces and can be extended to quantitative evaluation of solid–liquid and solid–solid interfacial interactions. These findings support the use of surface-energy profiles as a quantitative framework for characterization of pharmaceutical powders and for comparison of potential interfacial interactions among formulation components.

Introduction

Surface and interfacial properties of pharmaceutical powders play important roles in a wide range of formulation and manufacturing processes. Interactions between particles and between powders and surrounding phases can influence powder wetting, adhesion, cohesion, mixing, dispersion, and other properties relevant to pharmaceutical development. In particular, the interaction of a powder surface with water is closely related to its wetting behavior and can be an important consideration when evaluating pharmaceutical excipients and active
pharmaceutical ingredients.

Powder wettability is commonly evaluated using contact-angle-based approaches.1 Sessile drop measurements provide a direct approach for determining the contact angle of a liquid on a solid surface, whereas the Washburn method can be applied to powders without preparation of a macroscopically flat surface.2,3 These approaches are useful for characterizing wetting behavior; however, measurements on powders can be affected by factors such as surface roughness, porosity, particle packing, liquid penetration, and sample preparation. Consequently, obtaining quantitatively comparable surface properties from pharmaceutical powders can be challenging. Surface free energy provides a thermodynamic description of the energetic state of a solid surface and has been used to characterize interactions between solid surfaces and contacting phases. Several theoretical approaches have been proposed to describe the surface free energy of solids in terms of dispersive and polar or acid–base contributions. These approaches provide a basis for relating experimentally determined surface properties to intermolecular interactions at interfaces.4–9

Inverse gas chromatography (IGC) is an alternative approach for characterizing the surface energetic properties of powders.10–13 In IGC, probe molecules with different interaction characteristics are passed over a packed powder sample, and their retention behavior is used to estimate surface energetic parameters. Unlike measurements that provide a single macroscopic contact angle, IGC can also be used to determine surface energy as a function of surface coverage. This feature provides information about the energetic heterogeneity of a powder surface, because probe molecules preferentially interact with energetically favorable surface sites at low surface coverage.13–16

Despite these advantages, the practical interpretation of IGC-derived surface energy remains challenging. The measured values can be influenced by experimental and analytical factors, including sample preparation, chromatographic peak analysis, probe retention, and changes in the surface state of the powder.13,17 In addition, the absence of universally accepted reference materials for pharmaceutical powder surfaces can make it difficult to assess the reliability and comparability of measured values.

IGC has also been applied to pharmaceutical powders to investigate differences in raw material properties, the effects of lubrication, and the surface characteristics of lactose and other pharmaceutical materials.18–20 The use of alkane probe molecules at low surface coverage provides a basis for characterizing the dispersive contribution to surface energy and the energetic characteristics of powder surfaces.21

A further advantage of a surface energetic approach is that surface free energy can be used to estimate thermodynamic interaction quantities between different phases. In particular, the workof adhesion describes the reversible work associated with bringing two phases into contact and therefore provides an energetic measure of interfacial interaction.22–24 For pharmaceutical powders, this concept can be extended beyond solid–water interactions to interactions between different excipients and between active pharmaceutical ingredients and excipients. Such information may provide a complementary perspective to conventional measurements of
powder wettability, adhesion, and cohesion.

However, a systematic framework linking the reproducibility of IGC-derived surface energy profiles with powder wettability and thermodynamic interfacial interactions has not been sufficiently established for pharmaceutical powders. In particular, it remains important to clarify whether surface energy profiles obtained by IGC can provide reproducible material-specific characteristics and whether these characteristics can be translated into quantitative descriptors of interactions with liquids and other pharmaceutical solids.

Therefore, the objective of this study was to evaluate IGC-derived surface energy profiles as quantitative descriptors of pharmaceutical powder surface and interfacial properties. First, the reproducibility and environmental sensitivity of surface energy profiles were examined over a range of surface coverages. Second, IGC-derived surface energetic parameters were compared with wettability measurements obtained by sessile drop and Washburn methods. Third, the work of adhesion between pharmaceutical powder surfaces and water was calculated as a thermodynamic descriptor for comparison among materials. Finally, the approach was extended to solid–solid interactions, including excipient–excipient and drug–excipient systems, to examine the potential utility of IGC-derived surface energetics for characterizing pharmaceutical formulation components.

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Materials

Microcrystalline cellulose (MCC) products CEOLUS PH-102 and CEOLUS KG-1000 (Asahi Kasei Corporation, Japan) were used as model excipients for evaluation of surface energetic properties and wettability. Mannitol materials included Parteck M100 and Parteck M200 (Merck KGaA, Germany) and Mannit P (Roquette Frères, France). Lactose materials included SuperTab 21AN and SuperTab 11SD (DFE Pharma, Germany), Dilactose S (MEGGLE GmbH & Co. KG, Germany), and Pharmatose 100M (DFE Pharma, Germany). Polyvinylpyrrolidone (PVP, Kollidon K17 PF, BASF SE, Ludwigshafen, Germany) was included as a representative polymeric excipient. Acetaminophen (Sigma-Aldrich, St. Louis, MO, USA) was used as a model active pharmaceutical ingredient for evaluation of drug–excipient interactions.

Ken Yoshioka, Kohei Tahara. Quantitative Characterization of Pharmaceutical Powder Surface Interactions Using Inverse Gas Chromatography-Derived Surface Energy Profiles. ChemRxiv. 09 October 2026.
DOI: https://doi.org/10.26434/chemrxiv.15010186/v1