The high throughput capabilities and low sample volume requirements of microfluidic technology make it an attractive prospect for the pharmaceutical industry. This thesis concerns the development of microfluidic devices to investigate two important challenges to the pharmaceutical industry: to interface microchannel systems with electrospray ionisation mass spectrometry, an extensively used technique in drug discovery and development, and to investigate drug precipitation and its prevention through formulation. A microfluidic electrospray ionisation mass spectrometry interface was developed which could be placed within the source enclosure of a Waters ZQ mass spectrometer with little requirement for modification. The microfluidic interface showed a signal improvement of 38% over a capillary voltage of 4 - 4.75 kV when compared to the commercial probe which was operated at a desolvation gas flow rate of 120 L hr-1. Under typical desolvation temperatures of 350 ºC, the commercial probe outperformed the microfluidic interface which was operated at a desolvation temperature of 60 ºC, however, only an 18% improvement in signal intensity was observed for a 290 ºC increase in temperature, and there is scope to increase the operating desolvation temperature of the microfluidic interface.A novel droplet-based microfluidic light scattering detection system was developed to monitor drug precipitation of weakly basic poorly water soluble drugs. These drugs frequently exhibit poor bioavailability and variability due to precipitation in the GI tract. A pH-shift method was used to simulate gastric emptying conditions and generate a supersaturated state. Ketoconazole was used as the model drug in this study and was found to precipitate rapidly upon supersaturation. The extent of precipitation was shown to have a linear dependence on the degree of supersaturation for physiologically relevant supersaturations. This thesis also reports the first example of microfluidic screening of precipitation inhibitors. The inhibitory effect of two water soluble polymers, polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) on ketoconazole precipitation was evaluated. HPMC was found to be a more potent precipitation inhibitor than PVP, with just 0.05 mM HPMC resulting in approximately a 75% decrease in ketoconazole precipitation, outperforming that of 1.7 mM PVP, which only decreased precipitation by approximately 60%. These findings corroborate results obtained from macroscale experiments employing dynamic light scattering detection. The onset time of precipitation for a range of ketoconazole supersaturations was measured using the scattered light intensity observed from the initial 22 seconds of ketoconazole precipitation. Onset times of between 0.24 - 2.45 seconds were determined for ketoconazole supersaturations of between 30 - 65.
|Date of Award||31 Dec 2013|
- The University of Manchester
|Supervisor||Nicholas Goddard (Supervisor)|
- Drug Precipitation