The nanoscale characterization and interparticulate interactions of pharmaceutical materials
The aim of this project is to compare pharmaceutical particles made using a Nektar supercritical fluid technology technique called solution enhanced dispersion by supercritical fluids (SEDSTM) to those made using more traditional techniques. This involves a comparison of not only the surface properties of both types of particles, but also the interparticulate interactions. The majority of the work has involved the use of the atomic force microscope (AFM) as both a tool for imaging and for the acquisition of localized force measurements. The first experimental chapter of this work describes a method developed in order to image the contacting asperities of a particle. The AFM has the potential to provide useful information regarding single particle interactions to complement data generated from bulk techniques. In this chapter, the AFM artefact of tip imaging was used to produce 3D images of the asperities of particles of micronised and SEDSTM salbutamol sulphate, an anti-asthma drug, contacting a model surface of highly orientated pyrolytic graphite (HOPG). These data were recorded in a model propellant environment, used in order to simulate the environment that would be found in pressurised metered dose inhalers, such as those used by asthmatics. From the images generated the contacting area was estimated to be 1.1x10-3 mm2 for the micronised material, and 1.4x10-3 for the SEDSTM material. The work of adhesion for both of the materials was also calculated, and the values of 19.0 mJm-2 and 4.0 mJm-2 were obtained for the micronised and SEDSTM samples respectively. This supported available data that indicated the SEDS material had a lower surface energy than the micronised drug, and that it is possible to make comparisons between different modified AFM probes. The second chapter develops this work so that it can be applied to an air environment, which is applicable to more pharmaceutical systems. Here, force measurements were again performed using AFM, with the same drug samples studied in the first chapter, except a controlled relative humidity (RH) environment was used, so that the variation in adhesion with increasing RH could be studied. Two types of measurement were undertaken. The first involved the use of blank AFM tips on compressed disks of drug material, and the second involved the use of drug particles mounted onto AFM tips on both HOPG and compressed disks of drug. With the blank AFM tip and particle modified AFM tip on HOPG work it was observed that the SEDSTM materials showed a peak in adhesion force at 22% RH while the micronised salbutamol showed a peak at 44% RH. From this, a three-scenario model of linking morphology of contact to adhesion was developed to explain the observed peaks in adhesion. In addition, the surface energies of each of the two samples were calculated using the force measurements acquired against HOPG and compressed disks of material and compared. The micronised material was found to have a higher surface energy than the SEDSTM material (10.8 mJm-2 cf 5 mJm-2) when data acquired against HOPG was used. However, when data acquired using the compressed disks of drug were used, the SEDSTM had a higher surface energy than the micronised (29.9 mJm-2 cf 22.6 mJm-2). This higher value was attributed to different surface roughness effects found with the compressed disks. The third chapter uses the techniques and models developed in the previous chapters to examine the effect of polymorphism on surface energy, structure and particulate interactions. Three polymorphs of the drug sulphathiazole (forms I, II and IV) were formed using the SEDSTM technique, one of which (form I) was formed using two different solvents: methanol and acetone. Force measurements were performed using the AFM at controlled humidity using particles of each of the polymorphs mounted onto AFM tips against substrates of HOPG and the polymorph under analysis. This data was then related to the model developed in the previous chapter, and calculations were undertaken to assess the different surface energies of each of the four samples. For some of the samples it was observed that peaks were again occurring in the data, at 22% RH for polymorphs I-methanol and III, and 44% for polymorph IV. No peak was seen for polymorph I-acetone. These peaks were then related to the surface energy calculated for each of the polymorphs, as polymorphs I-methanol and III were found to have lower surface energy (0.99 mJm-2 and 1.17 mJm-2 respectively) than polymorphs IV and I-acetone (20.33 mJm-2 and 309 mJm-2). The fourth chapter examines the application of AFM to an industrial problem. When using the SEDSTM process to manufacture insulin, it was observed that the SEDSTM material had poorer flow properties than that of the unprocessed material. Using the AFM as both an imaging and force measurement tool, this chapter explores the application of imaging and the adhesion models and surface energy calculations previously developed to understand this problem. The AFM images showed the presence of highly aggregated particles of SEDSTM insulin, compared to the unprocessed insulin that appeared to be more crystalline. When force measurements were performed against both HOPG and particles of the material under analysis, non of the unprocessed, and only one of the SEDSTM particle tips prepared displayed the peak behaviour seen with previous measurements, and instead displayed a continual increase in adhesion force with humidity. In addition, when the surface energy was calculated, the SEDSTM material was found to be higher than the unprocessed insulin (77.5 mJm-2 cf 2.4 mJm-2). The increase in adhesion force was related to the particles agglomerating together, due to the presence of a higher surface energy and high amorphous content of the particles. The final experimental chapter uses techniques that compliment AFM analysis to examine another industrial problem. The SEDSTM process can be used to co-formulate drugs with other materials such as polymers. In this chapter, the drug pregabalin has been co-formulated with lipid in order to produce a coating around the drug to mask taste. The use of AFM as an imaging tool, and the additional techniques of X-ray photoelectron spectrometry (XPS) and time-of-flight secondary ion mass spectroscopy (ToF-SIMS) have been used to generate an understanding of surface structure and chemistry of this heterogeneous system. The AFM images showed no areas of surface heterogeneous behaviour, although the largest scan size was only 5 mm x 5 mm. However both the XPS and ToF-SIMS spectra, which samples far larger areas (up to 75 mm x 75 mm) showed the presence of lipid and drug molecules. It was concluded that the lipid was not forming a uniform layer around the drug molecule, but was instead forming large patches that were beyond the resolution of the AFM. This work aims therefore to provide a fundamental study of the application of AFM to real pharmaceutical systems. In particular models are developed which allow not only ranking of particle interactions but the quantification of factors such as surface energy and work of adhesion. Finally the significance of the morphology of the inter-particulate contact has been explored at the nanoscale.