Purpose This study compares the surface characteristics and surface energetics of two potential bulking excipients, anhydrous sub-micron α-lactose and sub-micron sucrose, for use with low-dose, suspension formulations in pressurised metered dose inhalers (pMDIs). Both sub-micron bulking excipients are processed from parent materials (α-lactose monohydrate/α-lactose monohydrate and silk grade sucrose, respectively) so the surface characteristics of each material were determined and compared. Additionally, the surface energetics and adhesive interactions between each sub-micron bulking excipient and some chosen active pharmaceutical ingredients (APIs) used in pMDI formulations were also determined. From this data, it was possible to predict the potential degree of interaction between the APIs and each sub-micron bulking excipient, thus determining suitable API–excipient combinations for pMDI formulation optimisation. Salmon calcitonin was also investigated as a potential API due to the current interest in, and the potential low-dose requirements for, the pulmonary delivery of proteins. Methods The size and morphology of each sub-micron excipient (and parent materials) were determined using scanning electron microscopy (SEM) and the crystalline nature of each sub-micron excipient and parent material was assessed using X-ray diffraction (XRD). The surface chemistry of each sub-micron excipient was analysed using X-ray photoelectron spectroscopy (XPS). The surface energies of each sub-micron excipient, along with their respective parent materials and any intermediates, were determined using two techniques. The surface energies of these materials were determined via (a) single particle adhesive interactions using atomic force microscopy (AFM) and (b) ‘bulk’ material surface interactions using contact angle measurements (CA). From the CA data, it was possible to calculate the theoretical work of adhesion values for each API–excipient interaction using the surface component analysis (SCA). The Young's modulus for each sub-micron excipient and parent material was also determined using AFM. Finally, the adhesive interactions were determined between each sub-micron bulking excipient and five APIs (formoterol fumarate, salmeterol xinafoate, salbutamol sulphate, mometasone furoate and salmon calcitonin). Results Both sub-micron sucrose and anhydrous sub-micron α-lactose exhibited a lower surface free energy than their respective parent materials/intermediates. In addition, both AFM and CA surface energy measurements also showed that sub-micron sucrose has a higher surface energy than anhydrous sub-micron α-lactose. Theoretical work of adhesion values between anhydrous sub-micron α-lactose and each API are considerably lower than those observed between micronised α-lactose monohydrate and each API. Corresponding theoretical work of adhesion values between sub-micron sucrose and each API were almost identical to those observed between silk grade sucrose and each API. Young's modulus determination revealed that sub-micron sucrose has a greater crystal hardness/elasticity ratio than anhydrous sub-micron α-lactose. With the exception of salmon calcitonin, sub-micron sucrose showed larger adhesive interactions to the selected APIs than anhydrous sub-micron α-lactose. Conclusions Anhydrous sub-micron α-lactose has been found to have lower adhesive interactions with a range of chosen, low-dose APIs compared to sub-micron sucrose. This could be related to the lower surface energy for anhydrous sub-micron α-lactose. Knowledge of the surface free energy and mechanical properties of potential sub-micron bulking excipients and API materials could provide useful information regarding the selection of suitable API-submicron bulking excipient combinations during the development and optimisation stages of suspension pMDI formulations.