1. Comparing the Surface Energetics and Mechanical Properties of two Potential Sub-micron Sugar Bulking Excipients for use in Low-dose, Suspension Formulations in Metered Dose Inhalers Jeff James, a * Clive J Roberts, a Martyn C Davies, a Richard Toon, b Phil Jinks. b a School of Pharmacy, Laboratory of Biophysics and Surface Analysis, The University of Nottingham, UK b ; 3M Drug Delivery Systems, Loughborough, UK School of Pharmacy, The University of Nottingham Introduction and Background Highly potent, low-dose active pharmaceutical ingredients (APIs) may require the incorporation of a bulking excipient within a suspension formulation in order to reduce the variability of the delivered dose between actuations from a pressurised metered dose inhaler (pMDI). This study compares the characteristics and processing of two potential bulking excipients, anhydrous sub-micron α-lactose and sub-micron sucrose. The dispersive surface free energy and Young’s Modulus were determined for each sub-micron material, their respective parent materials and any intermediates. The adhesive interactions of the potential sub-micron bulking excipients were then assessed against a selection of APIs. Salmon calcitonin was also investigated due to the current interest in, and the potential low dose requirements for, the pulmonary delivery of proteins. Acknowledgements The author gratefully acknowledges Prof. Xinyong Chen for valuable advice and assistance regarding the use of AFM. Matt Bunker and Barry Crean (LBSA), for their help and support, and finally 3M Drug Delivery Systems and The University of Nottingham for their financial support of this research. For further information Please contact the author * Email: paxjj@nottingham.ac.uk More information on this and related projects can be obtained at URL: www.nottingham.ac.uk/lbsa P. Jinks. Preparation and utility of sub – micron lactose: a novel excipient for HFA MDI suspensions formulations. Drug Del. Lungs XIV: 199-202 (2003). References Method Fig. 1. The principle of AFM Conclusions Fig. 3. Left: Surface energy values for anhydrous sub- micron α-lactose and its parent materials. A significant increase in surface energy is seen upon micronisation, an effect which is reversed following high pressure homogenisation Right: Surface energy values for sub-micron sucrose and its parent material. Sub micron sucrose has a lower surface energy than silk grade sucrose. Anhydrous sub–micron α-lactose has been found to have lower adhesive interactions with a range of chosen APIs compared to sub-micron sucrose. This could be related to the lower surface energy of anhydrous sub-micron α-lactose as determined by AFM. However, the significance of these results needs to be assessed during the development phase of a real pMDI suspension formulation. The higher levels of adhesion of sub-micron sucrose with APIs, compared to anhydrous sub-micron α-lactose, may not be detrimental to the overall shelf-life of a suspension formulation. Young’s Modulus, as determined by AFM, can also offer an insight into the processing of such materials as softer crystal structures can potentially be processed more easily to give smaller particle sizes. Both a knowledge of the surface free energy and the mechanical properties of potential bulking excipients could provide useful information during the processing and development stages of such materials 100 µm Force of Adhesion (nN) Results Surface Energy Determination Young’s Modulus Determination The surface energies of each sub-micron excipient, along with their respective parent materials and any intermediates, were determined using two Atomic Force Microscopy (AFM) methods. The results were calculated for each material based upon the Johnson-Kendal-Roberts theory. Similar AFM based force measurements were determined to quantify nanoscale elastic deformation and hence, Young’s Modulus. The adhesive interactions of each sub-micron bulking excipient were determined with formoterol fumarate, salmeterol xinafoate, mometasone furoate and salmon calcitonin using colloid probe AFM (salbutamol sulphate was also assessed as this is a pulmonary API that is commonly used in the literature). API – Excipient Particle Interaction Fig. 5. The adhesion of each sub – micron excipient to five different APIs potentially employed in pMDI formulations. With the exception of salmon calcitonin, sub-micron sucrose showed larger adhesive interactions to the selected APIs than anhydrous sub–micron α-lactose. Fig. 4. Left: Young’s modulus values for anhydrous sub-micron α-lactose and its parent materials. A decrease in hardness is observed following both micronisation and homogenisation Right: Young’s modulus values for sub-micron sucrose and its parent material. Processed sub micron sucrose is a softer material than silk grade sucrose. Surface free energy (mJm -2 ) Young’s Modulus E (GPa) Surface free energy (mJm -2 ) Young’s Modulus E (GPa) Fig. 2. Top: SEM image of anhydrous sub – micron α-lactose. Bottom: SEM image of sub – micron sucrose.