Orally disintegrating tablets: formulation development, novel engineering solutions and fixed dose combinations

Student thesis: Doctoral ThesisDoctor of Philosophy

View graph of relations Save citation

Authors

Thomas Dennison

Abstract

Orally disintegrating tablets (ODTs) are an attractive solid dosage form for patients who suffer from dysphagia, a difficulty in swallowing, which is particularly prevalent in paediatric and geriatric populations. ODTs and fixed dose combination (FDC) formulations are popular as they improve patient compliance and combination of the two has not previously been explored.

The requirement for ODTs to disintegrate rapidly whilst also being mechanically robust means that high drug loading is a significant challenge. An ODT formulation for the betalactam antibiotic flucloxacillin was developed at doses of 250 and 125 mg. ODTs were mechanically robust, however this limited disintegration to within 3 mins, with mannitol fragmentation being a major limitation.

Polymeric film coating was devised as a potential technique to enhance ODT mechanical properties. Due to high attrition during fluidisation a novel stationary coating technique was developed as a proof of concept. ODTs coated in this way, coupled with a postcoating curing step, demonstrated an increase in hardness of almost double and essentially zero friability. This novel coating technique could prove hugely beneficial in the formulation of high dose or poorly compactable drugs.

The application of ODTs for FDCs was tested with four model drugs: amlodipine (5 mg), atorvastatin (10 mg), isoniazid (50 mg) and rifampicin (75 mg). ODT formulations for single and FDCs showed rapid disintegration and good mechanical properties. Comparison of single and FDC dissolution profiles was performed using FDA recommended f1 and f2 testing. Bioavailability from ODTs was assessed using in vitro Caco-2 permeability and dissolution data and in silico physiologically based pharmacokinetic modelling. Bioequivalence was demonstrated between single and FDC for each drug in both fed and fasted states, whilst atorvastatin showed a positive food effect (enhanced peak plasma concentration and area under the curve), due to reduced metabolism by CYP3A4.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
Award date14 Mar 2017

    Keywords

  • orally disintegrating tablets, formulation development, novel engineering solutions, fixed dose combinations, ODTs, FDCs

If you have discovered material in the Aston Research Explorer, which is unlawful e.g. breaches copyright, (either theirs or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please read our Takedown Policy and contact the service immediately.

Download statistics

No data available

Employable Graduates; Exploitable Research

Copy the text from this field...