(340f) Application of Interfacial Rheological Techniques in Pharmaceutical Product Development
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Fluid-fluid interfacial layers are common in living systems. One such example from my research is the lung surfactant (LS) monolayer that forms at the alveolar air/water interface and its relation to Acute Respiratory Distress Syndrome (ARDS). We have found that the domain size in lung surfactant monolayers is approximately 10-100 microns on a flat Langmuir trough interface, which is comparable to the average size of human alveoli. Therefore, it is important to study LS rheology and morphology on curved interfaces with dimensions of 40-60 microns radius. Part of my research has been to develop new instrumentation that can examine purely dilatational deformations (changing area at constant shape) at associated breathing frequency.
Although it is not known how ARDS develops, recent experience with COVID-19 shows that the immune response appears to trigger ARDS. Inflammation promotes the release of phospholipase A2 (PLA2) which catalyzes the lysis of virus and bacterial membranes by breaking down phospholipids into lysolipids and fatty acids. This inflammatory response leads to an order of magnitude increase in the concentration of lysolipids in the alveolar fluids. We found that the increasing concentration of lysolipids in the alveolar fluids is linked to lung instabilities that are one of the primary symptoms of ARDS. Specifically, lysolipid competes with lung surfactant components such as dipalmitoylphosphatidylcholine (DPPC) and causes lung surfactants to desorb from the interface, thereby increasing the minimum surface tension while simultaneously decreasing the dilatational modulus. The combined effects of higher surface tension and lower dilatational modulus trigger the Laplace Instability in which smaller alveoli have a higher capillary pressure than connected larger alveoli, leading to flooding and collapse of the smaller alveoli and distention of the larger alveoli, which results in breathing difficulty.
The techniques and instruments I have developed for dilatational rheology both in the linear viscoelastic (LVE) and non-linear (NLVE) regions can also be used to study the interfacial properties of pharmaceutical proteins such as monoclonal antibodies (mAb). mAb can aggregate and denature during manufacture, shipping, storage, and delivery due to adsorption to air-water and oil-water (syringes) interfaces. To resist aggregation and increase protein stability, surfactants are used to minimize the available air/solvent area. Dilatational rheometry can give us insights into the unintentional colloidal destabilization on the relevant length scales and conditions experienced in manufacturing, shipping, and delivery. Combining simultaneous confocal imaging techniques to observe structural changes by using fluorescently labeled proteins and surfactants during dilutional measurements can provide information on mAb stability that is impossible by any other techniques and can be an indispensable tool to characterize proteins at the interface.
Interfacial process such as shear (constant area with changing shape) is an important tool to study the pharmaceutical colloids and their stability. One relevant example can be Pickering emulsion â a particle laden interface, environmentally friendly, less irritable, and surfactant free colloids useful for resisting protein denaturation. Simultaneous visualization techniques have been developed and coupled with a double wall ring (DWR) system to understand the structural relationship with viscoelastic parameters in the Langmuir trough. A transition from shear thinning is observed due to aggregated cluster breakup to yielding at a slip plane within the interface. Interestingly, we found that aggregated interfaces transition to yielding well before they reached a jammed state. It is possible to control the magnitude of repulsive and attractive interactions and hence the microstructure of interfacial particles at an air/water interface by adjusting subphase composition. It is possible to modify interfacial viscoelasticity from elastic to viscous behavior through these changes to interfacial microstructure.
Three distinct microstructures are observed. Low repulsion and high attraction systems exhibit soft glassy rheology with a disordered but dense microstructure. Creating high repulsion results in a dense hexagonal crystal. Finally, in systems with reduced repulsion and attraction, a hexatic phase can be observed. Each of these microstructures exhibits unique interfacial viscoelastic behavior. These results indicate that control over the properties of these interfaces, and hence Pickering emulsions, is possible through manipulation of interparticle forces.
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