Characterization of Drug Particle Surface Energetics and Young’s Modulus by Atomic Force Microscopy and Inverse Gas Chromatography

Abstract

Particulate interactions are dominated by aspects such as surface topography, exposed chemical moieties, environmental conditions, and thermodynamic properties such as surface free energy (gamma). The absolute value and relative magnitude of surface energies of a drug and excipients within a formulation can significantly influence manufacture, processing, and use. This study utilizes and compares the potentially complementary analytical techniques of atomic force microscopy (AFM) and inverse gas chromatography (IGC) in the quantitative determination of the surface energy of drug (budesonide) particles (micronized and unmilled) relevant to inhaled delivery. In addition, the study investigates with AFM another important parameter in determining material interactions, the local mechanical properties of the drug. AFM was used to acquire force of adhesion (Fadh) and related work of adhesion (WA) and surface energy values between individual mironized drug particles and also model substrates (graphite and mica). In addition, AFM probes were used to interrogate the surface energy of unmilled drug particles. Measurement with AFM probes also yielded localized measurements of Young's modulus for the unmilled drug. IGC was also used to probe the surface characteristics of the bulk drug material. The average values for surface energies acquired from budesonide micronized particle interactions with graphite, mica, and drug particles of the same substance were found to range from 35 to 175, 5 to 40, and 10 to 32 mJ m(-2), respectively. The unmilled material displayed a range of values of 39-88 mJ m(-2) with an average of 60 mJ m(-2). The IGC result for the surface energy of the micronized material was 68.47 +/- 1.60 mJ m(-2). The variability in surface energy from AFM, a feature particularly apparent for the micronized material was attributed to two factors, intrinsic material variations within a single particle and assumptions present within the contact mechanics model used. Here we provide a detailed description of these factors to go some way to rationalize the results. The Young's modulus of the unmilled drug was determined to be approximately 10 GPa. The range of determined surface energies between the AFM measurement on graphite, mica, and the drug is proposed to reflect the different chemistries displayed by the drug at the single particle level. The maximum values of these ranges can be related to the sites most likely to be involved in adhesion. AFM and IGC yield surface energy estimates in approximate agreement, but clearly are interrogating surfaces in different fashions. This raises questions as to the nature of the measurement being made by these approaches and to the most appropriate time to use these methods in terms of a direct relation to formulation design, manufacture, and drug delivery. Finally, we demonstrate a novel method for assessing the Young's modulus of a drug from a single particle.