Academic literature on the topic 'Orally Disintegrating Tablets (ODTs)'

Orally disintegrating tablets (ODTs) which are also referred to as orodispersible and fast disintegrating tablets, are solid oral dosage forms which upon placing on the tongue, disperse/disintegrate rapidly before being swallowed as a suspension or solution. ODTs are therefore easier and more convenient to administer than conventional tablets and are particularly beneficial for paediatric and geriatric patients, who generally have difficulty swallowing their medication. The work presented in this thesis involved the formulation and process development of ODTs, prepared using freeze-drying. Gelatin is one of the principal excipients used in the formulation of freeze-dried ODTs. One of the studies presented in this thesis investigated the potential modification of the properties of this excipient, in order to improve the performance of the tablets. As gelatin is derived from animal sources, a number of ethical issues surround its use as an excipient in pharmaceutical preparations. This was one of the motivations, Methocel™ and Kollicoat® IR were evaluated as binders as alternative materials to gelatin. Polyox™ was also evaluated as a binder together with its potential uses as a viscosity increasing and mucoadhesive agent to increase the retention of tablets in the mouth to encourage pre-gastric absorption of active pharmaceutical ingredients (APIs). The in vitro oral retention of freeze-dried ODT formulations was one property which was assessed in a design of experiments – factorial design study, which was carried out to further understand the role that formulation excipients have on the properties of the tablets. Finally, the novel approach of incorporating polymeric nanoparticles in freeze-dried ODTs was investigated, to study if the release profile of APIs could be modified, which could improve their therapeutic effect. The results from these studies demonstrated that the properties of gelatin-based formulations can be modified by adjusting pH and ionic strength. Adjustment of formulation pH has shown to significantly reduce tablet disintegration time. Evaluating Methocel™, in particular low viscosity grades, and Kollicoat® IR as binders has shown that these polymers can form tablets of satisfactory hardness and disintegration time. Investigating Polyox™ as an excipient in freeze-dried ODT formulations revealed that low viscosity grades appear suitable as binders whilst higher viscosity grades could potentially be utilised as viscosity increasing and mucoadhesive agents. The design of experiments – factorial design study revealed the influence of individual excipients in a formulation mix on resultant tablet properties and in vitro oral retention of APIs. Novel methods have been developed, which allows the incorporation of polymeric nanoparticles in situ in freeze-dried ODT formulations, which allows the modification of the release profile of APIs.

Orally disintegrating Tablets (ODTs), also known as fast-disintegrating, fast-melt or fast-dissolving tablets, are a relatively novel dosage technology that involves the rapid disintegration or dissolution of the dosage form into a solution or suspension in the mouth without the need for water. The solution containing the active ingredients is swallowed, and the active ingredients are then absorbed through the gastrointestinal epithelium to reach the target and produce the desired effect. Formulation of ODTs was originally developed to address swallowing difficulties of conventional solid oral dosage forms (tablets and capsules) experienced by wide range of patient population, especially children and elderly. The current work investigates the formulation and development of ODTs prepared by freeze drying. Initial studies focused on formulation parameters that influence the manufacturing process and performance of lyophilised tablets based on excipients used in commercial products (gelatin and saccharides). The second phase of the work was followed up by comprehensive studies to address the essential need to create saccharide free ODTs using naturally accruing amino acids individually or in combinations. Furthermore, a factorial design study was carried out to investigate the feasibility of delivering multiparticulate systems of challenging drugs using a novel formulation that exploited the electrostatic associative interaction between gelatin and carrageenan. Finally, studies aimed to replace gelatin with ethically and morally accepted components to the end users were performed and the selected binder was used in factorial design studies to investigate and optimise ODT formulations that incorporated drugs with varies physicochemical properties. Our results show that formulation of elegant lyophilised ODTs with instant disintegration and adequate mechanical strength requires carful optimisation of gelatin concentration and bloom strength in addition to saccharide type and concentration. Successful formulation of saccharides free lyophilised ODTs requires amino acids that crystallise in the frozen state or display relatively high Tg', interact and integrate completely with the binder and, also, display short wetting time with the disintegrating medium. The use of an optimised mixture of gelatin, carrageenan and alanine was able to create viscous solutions to suspend multiparticulate systems and at the same time provide tablets with short disintegration times and adequate mechanical properties. On the other hand, gum arabic showed an outstanding potential for use as a binder in the formulation of lyophilised ODTs. Compared to gelatin formulations, the use of gum arabic simplified the formulation stages, shortened the freeze drying cycles and produced tablets with superior performance in terms of the disintegration time and mechanical strength. Furthermore, formulation of lyophilised ODTs based on gum arabic showed capability to deliver diverse range of drugs with advantages over commercial products.

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.

ODTs have emerged as a novel oral dosage form with a potential to deliver a wide range of drug candidates to paediatric and geriatric patients. Compression of excipients offers a costeffective and translatable methodology for the manufacture of ODTs. Though, technical challenges prevail such as difficulty to achieve suitable tablet mechanical strength while ensuring rapid disintegration in the mouth, poor compressibility of preferred ODT diluent Dmannitol, and limited use for modified drug-release. The work investigates excipients’ functionality in ODTs and proposes new methodologies for enhancing material characteristics via process and particle engineering. It also aims to expand ODT applications for modified drug-release. Preformulation and formulation studies employed a plethora of techniques/tests including AFM, SEM, DSC, XRD, TGA, HSM, FTIR, hardness, disintegration time, friability, stress/strain and Heckel analysis. Tableting of D-mannitol and cellulosic excipients utilised various compression forces, material concentrations and grades. Engineered D-mannitol particles were made by spray drying mannitol with pore former NH4HCO3. Coated microparticles of model API omeprazole were prepared using water-based film forming polymers. The results of nanoscopic investigations elucidated the compression profiles of ODT excipients. Strong densification of MCC (Py is 625 MPa) occurs due to conglomeration of physicomechanical factors whereas D-mannitol fragments under pressure leading to poor compacts. Addition of cellulosic excipients (L-HPC and HPMC) and granular mannitol to powder mannitol was required to mechanically strengthen the dosage form (hardness >60 N, friability <1%) and to maintain rapid disintegration (<30 sec). Similarly, functionality was integrated into D-mannitol by fabrication of porous, yet, resilient particles which resulted in upto 150% increase in the hardness of compacts. The formulated particles provided resistance to fracture under pressure due to inherent elasticity while promoted tablet disintegration (50-77% reduction in disintegration time) due to porous nature. Additionally, coated microparticles provided an ODT-appropriate modified-release coating strategy by preventing drug (omeprazole) release.

Following the European regulation for paediatric formulations, the demand for the production of paediatric dosage forms has escalated. Managing the clinical needs of children is challenging, especially as this must often be accomplished using adult medicine formulations. For this reason, further paediatric dosage forms need to be developed to address their clinical needs. There are various formulations which can be administered via the oral route including tablets, capsules, liquids and chewable tablets. It is essential to mention orally disintegrating tablets (ODTs) which have been a popular area of research for scientists in the last decade. The overarching aim of this thesis was to develop novel oral dosage forms for children and young adults aged 6 to 18 years. The principal theme of this thesis is sub divided into two main areas of research: the first area evaluated dosage form preferences in children and young adults and assessed the key pragmatic dosage form characteristics that would enable formulation of patient centred ODTs; the second area focused on a wide range of laboratory-based investigations for development of low dose blends and pre-blends of ODT formulations using various blending techniques. The results of clinical investigations revealed that ODTs are a preferred dosage form among children because they combine the advantages of both solid and liquid dosage forms, without incorporating their disadvantages such as difficulty in swallowing and lack of stability respectively. Healthcare professionals indicated that taste and disintegration time were the most important factors to provide both suitable dose units and acceptable medicines for paediatric patients. Results from powder blending indicated that the dry particle coater provided a robust platform for obtaining content uniformities at 1% and 0.5%w/w API using non-sieved carriers. Micro crystalline cellulose as a carrier showed superior flow properties and better drug content uniformity for both geometric and ordered blending techniques. Furthermore, the co-processed excipients containing 86.5% w/w of milled-mannitol, 12% w/w pregelatinised starch and 1.5% w/w silica using Aston Particle Technology (APT’s) new coating technique can be utilised as a potential multifunctional directly compressible ODT pre-blend. An investigation into the role of moisture content on micro/macro properties of ODTs illustrated that moisture considerably affects the consolidation characteristics of blended powders; and the extent of consolidation and the bonding of particles depend, not exclusively on moisture content, but also on the powder processing conditions. In conclusion this work supports the World Health Organisation (WHO)’s claim for a paradigm shift from liquid towards ODT dosage forms for drug administration to young children older than 6 years. Data from this study will equip formulators to prioritise development of key physical/performance attributes within the delivery system.

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.