Jan Vos

Production of highly selective binding sites in synthetic polymers via bio-molecular imprinting

For inhalable dosage forms, drug actives and/or excipients usually undergo high energy mechanical processing to reduce particle size (e.g. micronisation). Such materials often experience considerable damage to the crystal lattice, resulting in the generation of amorphous regions. The bulk properties of these materials in terms of stability, flowability and others are significantly impacted during the process. This is very likely to be linked to the occurrence of these regions. Recently, Phase-Imaging (an advanced feature of atomic force microscopy (AFM)) has been employed to detect changes in the physico-mechanical properties of crystalline materials that have undergone high-energy processing (Begat et al 2003; Price & Young 2005). Phase-Imaging involves the oscillation of a micro-fabricated AFM imaging probe over a sample. By measuring the phase lag it becomes possible to concurrently measure variations in the physico-mechanical properties of a surface (e.g. viscoelastic response). In this study, selected particles of an active were imaged by AFM before and after mechanical activation. In addition to phase lag data, force-volume measurements of the same areas were conducted. Particles on the AFM stub were mechanically activated using a mechanical press to apply stress to the sample on the AFM stub. The surface morphology of drug particles was investigated using an AFM (Multimode AFM with a Nanoscope 3a controller and extender electronics module (all DI, Cambridge, UK). Topographical data was collected in Tapping mode, at a scan rate of 1.0 Hz using a high aspect ratio AFM probe oscillating 350 kHZ. Height, amplitude and phase data were collected simultaneously. Force volume data were obtained in contact mode, measuring the force between crystalline and activated areas of the drug particle and the AFM tip. AFM topographical studies of crystalline drug particles showed relatively smooth surfaces, with a root mean square roughness (RRMS) of 0.742 nm. Phase imaging of the crystalline drug particles indicated little variation in the physico-mechanical property across the sample surface. However, exposure of the same surface to stress, induced a large effect on the surface characteristics of the crystalline drug particle surface. An increase in surface roughness was observed (RRMS to 18.869 nm), coupled with large variations in the physicomechanical properties, with the presence of discrete regions across the surface of the sample, as confirmed via phase imaging analysis (phase shift > 50 °). Force-volume analysis of the crystalline drug particles pre and post mechanical activation is shown in Table 1. The data suggest that on mechanical activation the surface of the drug particles become significantly (P < 0.05) more adhesive than its native crystalline form. This may attribute to the mechanically activated areas contributing to increase the overall adhesive properties of the drug surface, which, in turn, might explain the significant increase in agglomeration of micronised drug particles.The purpose of this study was to overcome some of the key difficulties known to be associated with preparing molecularly imprinted polymers using proteins.