Formulation strategies and engineering processes for orally disintegrating tablets:the importance of robustness and disintegration

Abstract

Orally disintegrating tablets (ODTs) are a dosage form ideal for paediatric or geriatric patients as they disintegrate/disperse within the oral cavity. Direct compression manufacture of ODTs is increasing in popularity due to its cost effectiveness and use of traditional tableting equipment, however excipients are required to fulfil certain requirements to form robust, fast disintegrating tablets. Mannitol is a vital excipient for ODT manufacture due to its high palatability, however its fragmentation behaviour under compression leads to mechanically weak and friable tablets. The work in this thesis aimed to investigate the fragmentation behaviour of milled mannitol, followed by development of preblends to obtain ideal ODT properties without the use of any superdisintegrant. Development of a novel method for ODT disintegration testing was also conducted due to the lack of current techniques that are representative of oral conditions.Mannitol fracture occurred primarily at the (011) crystal plane, which was the most hydrophilic, therefore increasing the wettability of milled mannitol. Resulting ODTs had a faster disintegration time than the unmilled equivalent, with enhancement in compressibility due to increased plastic deformation. Milled mannitol presented a suitable alternative for ODT production compared to current commercial grades, with high mechanical strength and improved disintegration time. Novel optimised ODT preblends were developed with milled mannitol incorporated alongside micro crystalline cellulose (MCC) and silica to aid powder flow.Dry particle coating was also employed to develop an MCC/silica hybrid to enhance MCC properties. Silicified MCC had previously been shown to enhance MCC compression, whilst improving MCC powder flow and reducing lubricant sensitivity. Dry coated MCC was optimised with 1%w/w silica, with ODT disintegration being significantly lower than the spray dried alternative or uncoated MCC, whilst allowing a 40% drug load of a non-compressible API to be formed into a robust fast disintegrating ODT.A novel ODT disintegration method was developed to mimic In Vivo oral conditions. A vastly improved correlation to In Vivo results was observed with the newly developed method, in comparison to the recommended USP tester, with a linear correlation obtained with the new test method compared to the curved dataset gathered with the USP test.Novel preblends were developed utilising dry particle coating, with resultant ODTs showing improved ODT behaviour, with disintegration time being low even without the use of superdisintegrant. To supplement ODT disintegration, novel ODT disintegration time test method was developed and results indicated it was a superior alternative compared to the currently recommend USP test.