An investigation into the use of ion-exchange resins as a formulation approach for modified-release oral liquid preparations

Abstract

This thesis focuses on the use of ion-exchange resins (IERs) to modify the release profile of an active pharmaceutical ingredient (API) that would help address an unmet clinical need in the population if formulated as an oral liquid. Contrasting levels of success were achieved using two different APIs (Metronidazole and Tizanidine HCl) from which therapeutic benefit could be potentially derived if the incorporation of a “strongly” acidic IER was successful in enabling a slowing of the API release kinetics, as well as affording a degree of liquid stability for drug-resin complexes (DRCs) held in suspension in a liquid vehicle. By identifying TZD HCl as a suitable option for use with IERs, the exploration of alternative resin types aside from the powdered form (Amberlite™ IRP69) became a topic of interest. The gel/bead-type resins (Amberlite™ IR120) were also effective complexation agents, as evidenced by the drug loading. Loading studies were also undertaken used “weakly” acidic resins. The findings of these trials were consistent with the expectation that the loading process involving a “weak” resin, such as Amberlite™ IRP64, and an ionisable API requires more care (than those employing a “strong” resin such as Amberlite™ IRP69), owing to the more selective dissociation tendency of the resin relative to the “strong” resin. Despite all DRCs exhibiting rapid release behaviour in acidic medium and some resistance to drug leaching in an aqueous medium, the complexes formed using the Amberlite™ IRP64 grade displayed a suppressed rate of drug release in pH 6.8 buffer medium, which is typical of DRCs formed using “weak resins”. The release profiles of the IRP88 based-system were in stark contrast and depicted rapid release in all dissolution media tested, exemplifying the unsuitability of this resin type. A further set of experiments utilising an alternative approach (spray-drying) relative to the more traditional batch method of complexation were successful, indicated by the drug loading figures attained and the drug release behaviour observed. However, solid-state analyses highlighted several downsides associated with the process such as the presence of sodium chloride and uncomplexed TZD HCl in the spray-dried product. A consistent feature of DRCs formed using the “strong” resin in either of its physical forms (powder - Amberlite™ IRP69 or bead - Amberlite™ IR120) was the rapid release of drug in ionic media which necessitated the application of a rate-controlling polymer on the DRC to achieve a sustained-release profile. After ruling out the possibility of using a granulation process as part of the formulation approach to achieve the desired release profile, a sustained-release formulation of TZD HCl was successfully formulated using Wurster coating of bead-type DRCs. Stability studies showed that the solid-state characteristics were shown to remain unchanged and the chemical stability was maintained over the 3 month study. The liquid stability studies which examined the drug leaching tendency and the impact of suspending the coated DRC material in an aqueous medium indicated that the formulations require further development work. The work conducted and presented in this thesis highlighted that the selection of suitable APIs for use with IERs is dependent on a variety of factors that relate to both components. Based on the results from the studies in the thesis, a sustained-release formulation of TZD HCl produced using the Wurster process demonstrated an appreciable difference in release behaviour relative to the uncoated systems. Stability conditions, at which the “dry” microparticles were physically and chemically stable were identified, but the stability of the liquid suspension formulation indicated that further optimisation of the system is required to develop a stable sustained-release oral liquid with a reproducible release profile.