Polymorphism of Polymeric Drug Excipients at High Pressure

The aims of the current study were to investigate the effect of pressure on polyethyelene glycol (PEG4000) to create an effective drug delivery system for poorly water soluble drugs, with a view to increasing their bioavailability. The effect of pressure exerted by a diamond anvil cell on PEG4000 and the model drug respectively, and the polymer and drug together were examined using Raman and infrared spectroscopy. PEG4000 was shown to melt at 5GPa using a diamond anvil cell, as exemplified by flowing. Hydrocortisone does not melt under pressure or physically change and thus could be effectively encapsulated in the PEG at high pressure. Differential scanning calorimetry was carried out on the samples. PEG4000 was observed to melt over an average range of 58.67 to 63ºC and hydrocortisone was observed to melt over an average range of 223.49 to 228.15ºC. The latter was observed to change from a white powder into a marigold yellow liquid. Thermogravimetric analysis revealed degradation occurred at temperatures distinct from the melting range, thus when PEG melts at high pressure it is not degrading. Drug release testing was carried out on the diamond anvil cell samples in simulated intestinal and gastric fluids over 8 hours in a pulsatile fashion, mimicking traditional cortisol replacement therapy but with one administration rather than multiple administrations daily. Scale up using a large volume press was investigated. Drug release occurred over 10 days in a similar pulsatile fashion to the small volume study. Unfortunately due to the highly unstable nature of hydrocortisone in aqueous solutions future work may require the use of stabilisers such as fructose or disodium edentate. Overall PEG does increase the solubility of poorly soluble drugs but further work could be carried out in terms of formulation