Characterisation and optimisation of amorphous suspensions

by Sachin Appasaheb Surwase

Institution: University of Otago
Year: 0
Keywords: New Indomethacin polymorphs; Solid Dispersions; Drug-Polymer interactions; Aqueous amorphous suspensions; Supersaturation
Record ID: 1310487
Full text PDF: http://hdl.handle.net/10523/4834


Suspensions with amorphous drug in aqueous media are emerging as one of the promising formulation options to increase the in vivo exposure of the drug in preclinical toxicology studies involving poorly water soluble drugs. These formulations should be physically stable during the course of the study, which is typically several weeks. However, the aqueous environment and the inherent unstable nature of the amorphous form make crystallisation almost inevitable. The crystallisation can occur either during storage of the amorphous form in aqueous suspensions or during dissolution in the gastrointestinal tract. Hence, the characterisation of crystallisation behaviour and development of strategies to prevent crystallisation in amorphous suspensions at those two stages were the aims of this thesis. Poorly soluble indomethacin (IND) was selected as model drug for the studies. Firstly, the crystallisation behaviour of amorphous IND in aqueous suspension during storage was investigated at different pH values and temperatures (without excipients). The crystallisation onset time (detected by FTIR spectroscopy) decreased with decreasing temperature, but not pH. However, this decrease was not significant enough for temperature to be used as a method for crystallisation inhibition. This indicated that excipients, such as polymers, must be used to improve the physical stability. Interestingly, diverse polymorphic forms were observed, with three new forms being identified; these were named ε, ζ and η form. A This led to the additional conclusion that amorphous suspensions are worth considering when performing polymorphic screening studies. In a subsequent study, the potential of different polymers (poly(vinyl pyrrolidone) (PVP), hydroxypropyl methyl cellulose (HPMC) and Soluplus® (SP)) and polymer addition methods (solid dispersion (SD) with IND or predissolved polymer solution) to inhibit IND crystallisation and maintain supersaturation of amorphous IND, during storage in the aqueous suspensions was investigated. The SDs were better at inhibiting IND crystallisation than the predissolved polymer solution. SDs were also better at maintaining the supersaturations generated upon dissolution of amorphous IND. Use of SP showed more IND crystallisation inhibition and supersaturation potential than the other polymers. However, this depended on the method of addition. The IND in SD with the SP did not crystallise or generate any supersaturation, whereas IND in the corresponding predissolved solution crystallised into the new η form but also led to a more than 20-fold higher IND solution concentration than was observed for the crystalline IND. The ranking of the SDs with respect to crystallisation inhibition potential was SP SD >>> PVP SD > HPMC SD. This shows that the crystallisation inhibition depends strongly on the type of polymer used. Therefore, mechanisms behind the polymer actions were investigated in relation to the antiplasticisation ability of the polymers and nature and strength of the drug–polymer interactions. The stability…