W. Richard Bowen and Nidal Hilal 4

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178 6. NANOSCALE ANALySIS Of PHARMACEUTICALS by SCANNINg PRObE MICROSCOPy These and other studies can broadly be divided into two types: those that rank relative particulate interactions and those that attempt to make a quantitative comparison of force per unit area of contact. Ranking studies address, e.g., how drug-drug cohesion compares to drug-excipient particle and drug-device adhesion. Since particulate interactions are dominated by aspects such as surface morphology, surface roughness, exposed chemical moieties and thermodynamic properties, all of which can vary from particle to particle and indeed within a single particle, such ranking comparisons are normally made using the same particle to challenge all the possible combinations of interactions. In this case, ranking should be consistent for each drug particle probe, but the absolute values of adhesion force determined cannot be used to make comparisons from particle to particle or between materials [18]. To quantify such measurements, particle variability and a lack of direct knowledge of the contacting regions must be overcome to allow the determination of factors such as surface energy and work of adhesion. The use of AFM to determine such properties on model flat surfaces, such as silicon, was established relatively early [25]. However, its application to pharmaceuticals due to difficulties of rough and variable particle morphology came later [19, 21, 22]. In these works, the principal variable that is allowed for is contact area. Contact areas have, to date, been estimated either via a direct imaging approach [22] or indirectly through imaging indents made by the particle probe in a plastic polymer film [19]. The subsequent use of adhesion models such as Johnson–Kendall–Roberts and Derjaguin–Muller–Toporov can then allow the surface energy of the particle (over the region of contact) to be determined. In this way, e.g., micronised (milled) salbutamol sulphate and a version prepared via a novel supercritical fluid method have been compared [22]. An alternative to this approach of trying to model the variable contact region between particles is to compare ratios of cohesive and adhesive forces between different particles rather than actual separation forces. This has allowed an assessment for relatively flat crystals of the affinity of salbutamol sulphate to lactose and budesonide to lactose, showing that salbutamol sulphate has a stronger affinity for lactose [26]. This information was then related successfully to the likely blend uniformity these materials would form. In addition to monitoring force normal to a surface, AFM is also capable of assessing frictional forces between a probe and a surface. This is achieved by recording the twist of the cantilever in addition to its vertical bend as it scans a surface in continuous contact with that surface (Figure 6.3a). This approach has recently been used to obtain singleparticle friction measurements on DPI formulations [27] and blister packaging material (used in DPIs) [28] and provides an opportunity to consider sliding as well as separation forces. Figure 6.3 shows examples
6.2 THE AfM AS A fORCE MEASUREMENT TOOL IN PHARMACEUTICALS 179 (a) (b) Scan direction (c) Position 1 Lateral force signal Position 2 Particle A Particle B Particle C PTFE Glass Zanamivir Zanamivir Magnesium � Magnesium stearate stearate PTFE of the results of recording the sliding friction of single lactose particles on various drugs, excipients and materials used in inhaler devices. This showed a ranking of glass�zanamivir � zanamivir–magnesium stearate blend�magnesium stearate�PTFE (see Figure 6.3c). The addition of magnesium stearate (a commonly employed lubricant) to the drug zanamivir was seen to dominate the behaviour of this system and significantly reduced the friction [27]. 6.2.2 Mechanical Properties from Single-particle Measurements Consideration of the schematic force distance curve in Figure 6.2(b) reveals that not only can adhesion data be determined, but if the region of contact is considered where the probe is pressed into a surface and is then withdrawn, then it is clear that this contains information on the mechanical properties of the sample. Indeed, data gathered from a nanoscale contact in this manner is similar to traditional indentation Drug MgSt Glass Drug � MagSt FIgure 6.3 (a) Schematic of AFM particle friction set-up. Position 1: low-friction surface causes very small lateral force on cantilever. Position 2: high-friction surface causes large lateral force and cantilever twists. Inset: SEM image of lactose particle attached to cantilever. (b) 5 �m � 5 �m topographic AFM images of surfaces under study. From the top, clockwise: PTFE; glass; the drug zanamivir with magnesium stearate; magnesium stearate and zanamivir. (c) Processed data showing friction on all surfaces for three lactose particles.
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Butterworth-Heinemann is an imprint
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x Preface in their work. Hence, it
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xii Preface them from hostile condi
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xiv About thE Editors Professor Nid
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xvi List of Contributors Dr Daniel
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2 1. BAsIC PRINCIPLEs OF ATOMIC FOR
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32 2. MEASUREMENT OF PARTICLE ANd S
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82 3. QUANTIFICATION OF PARTICLE-BU
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100 3. QUANTIFICATION OF PARTICLE-B
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C H A P T E R 4 Investigating Membr
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4.2 THE RANgE OF POssIbILITIEs FOR
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4.2 THE RANgE OF POssIbILITIEs FOR
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4.3 CORREsPONdENCE bETwEEN sURFACE
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4.3 CORREsPONdENCE bETwEEN sURFACE
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4.4 IMAgINg IN LIqUId ANd THE dETER
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4.4 IMAgINg IN LIqUId ANd THE dETER
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4.5 EFFECTs OF sURFACE ROUgHNEss ON
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4.6 ‘vIsUALIsATION’ OF THE REjE
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4.7 THE UsE OF AFM IN MEMbRANE dEvE
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Page 146 and 147: REFERENCEs 137 [4] W.R. Bowen, N. H
Page 148 and 149: C H A P T E R 5 AFM and Development
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Page 156 and 157: 5.3 MODIFICATION OF MEMBRANEs 147 t
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Page 180 and 181: REFERENCEs 171 [29] W.R. Bowen, T.A
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228 8. ATOMIC FORCE MICROSCOPy ANd
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246 9. APPLICATION OF ATOMIC FORCE
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276 10. FuTuRE PRosPECTs most AFM s
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278 10. FuTuRE PRosPECTs targeted d
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A Actin stress fiber, 197 Adhesion,
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Natural organic matter, 140 Negativ
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W. Richard Bowen and Nidal Hilal 4

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