Dissertations / Theses on the topic 'Orally Disintegrating Tablets (ODTs)'

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.

碩士<br>高雄醫學大學<br>藥學研究所碩士班<br>95<br>Chlorzoxazone is a muscle relaxant of central nervous system. It is used in the treatment of lumbago, shoulder ache, nerve ache, reduction the symptom of muscle ache, muscle convulsion and muscle tetanus after sports. Orally rapidly disintegrating tablets are solid dosage forms that disintegrate in the oral cavity leaving an easy-to-swallow residue. A statistical factorial experimental design was used to optimize the formulation of orally rapidly disintegrating chlorzoxazone tablets. A 23 experimental design was employed to evaluate the disintegration of the orally rapidly disintegrating tablets; subsequent data was compared using analysis of variance (ANOVA). The characterization of the orally rapidly disintegrating tablets were studied, such as disintegration time, hardness, friability, uniformity content of the tablets, and in-vitro release test of the orally rapidly disintegrating chlorzoxazone tablets. Host-guest interactions were studied in the solid state by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The experimental design study illustrated that the concentration of disintegrants and compression force had significant effect on the disintegration time. The results of DSC and FTIR spectra indicated that chlorzoxazone-HP?毧D was prepared successfully and no interaction between chlorzoxazone and excipients. An optimum formulation showed a shortest disintegrating time of 8.3 s.

碩士<br>高雄醫學大學<br>藥學研究所碩士班<br>93<br>Orally rapidly disintegrating tablets are solid dosage forms that disintegrate in the oral cavity leaving an easy-to-swallow residue. When such tablets are placed in the oral cavity, saliva quickly penetrates into the pore to cause rapidly tablet disintegration. A direct compression method was used to prepare the tablet containing gliclazide as an oral hypoglycemic drug. Gliclazide is an oral hypoglycemic drug, belonging to second-generation sulphonylureas, which is used in type 2 diabetes. It has been suggested that due to its short-term acting, gliclazide may be suitable for use in diabetic patients with renal impairment and also in elderly patients whose reduced renal function may increase the risk of hypoglycemia following some sulphonylureas. The major drawback in the therapeutic application and efficacy of gliclazide as oral dosage forms is its very low aqueous solubility because of its hydrophobic nature. We used the neutralization technique to prepare a solid mixture of gliclazide with beta-cyclodextrin in a molar ratio of 1:1. Host-guest interactions were studied in the solid state by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). A statistical factorial experimental design was used on optimization study for tablet formulation of orally rapidly disintegrating gliclazide tablets, subsequent data was compared using analysis of variance (ANOVA). In-vitro release test of the gliclazide tablets was performed according to the USP 24 paddle apparatus. The results of DSC and FTIR spectra indicated that gliclazide is either dispersed in, or mixed with beta-cyclodextrin by neutralization technique. The dissolution rate of gliclazide from the inclusion solid mixture was faster than the pure gliclazide. An optimum formulation showed a shortest disintegrating time of 28 s.

碩士<br>高雄醫學大學<br>藥學研究所碩士在職專班<br>94<br>Ramipril is a strong and longterm angiotensin converting enzyme inhibitor. It is used in the treatment of hypertension, heart failure, myocardial infarction, reduction the dangerous of stroke and death. Orally rapidly disintegrating tablets are solid dosage forms that disintegrate in the oral cavity leaving an easy-to-swallow residue. A statistical factorial experimental design was used to optimize the formulation of orally rapidly disintegrating ramipril tablets. A 32 experimental design was employed to evaluate the disintegration of the orally rapidly disintegrating tablets; subsequent data was compared using analysis of variance (ANOVA). The characterization of the orally rapidly disintegrating tablets were studied, such as disintegration time, hardness, friability, uniformity content of the tablets, and in-vitro release test of the orally rapidly disintegrating ramipril tablets. Host-guest interactions were studied in the solid state by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The experimental design study illustrated that the concentration of disintegrants had significant effect on the disintegration time. The results of DSC and FTIR spectra indicated that some interaction between ramipril and excipients. An optimum formulation showed a shortest disintegrating time of 21.5 s.

The thesis work entails a bench-to-bedside translational research approach to the development of pediatric fixed dose combination of zidovudine/lamivudine/nevirapine (60/30/50mg) orally disintegrating tablets. A simple and cost-effective, direct compression method was used. Preformulation studies that included analytical and bio-analytical assay development, excipient selection and characterization of drug-excipient interaction for initial formulation were conducted. Response surface methodology was utilized to optimize the formulation in terms of disintegration time and crushing strength. Stable ODT tablet was developed with desired friability (&lt; 1%), reasonable crushing strength, disintegration time (&lt; 30sec) and other quality attributes such as potency and dissolution. An open label randomized two-way cross-over bioequivalence of the product (with approved IRBs), conducted in 24 healthy adult volunteers, indicated the product to be bioequivalent with the innovators. 90% C.I of the point estimates of PK parameters evaluated were in the range of 80-125% as specified by FDA.<br>Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences;<br>Pharmaceutics<br>MS;<br>Thesis;

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2017<br>Drug Delivery Systems (DDS) are a strategic tool that has become increasingly sophisticated over the years. Their main contributions involve expanding the life cycle of pharmaceutical products, by improving the administration process according to the patient’s needs. Since the drug delivery through oral route still represents the most common and preferred way of drug administration, our work of study relies on the development of orodispersible tablets (ODTs). This dosage form provides a quick onset of action and therefore was chosen as an alternative for paediatric, geriatric and mentally ill patients were the swallowing ability may be compromised. In the present study orodispersible tablets with a new shape were produced by direct compression using furosemide as the model drug. The production with this novel punch design led to scored tablets with a cloverleaf shape, thus allowing dose flexibility. The tablets were evaluated by thickness and diameter, uniformity of weight and of content, uniformity of the tablet’s subunits, resistance to crushing, weight loss, wetting time, water absorption ratio and disintegration time. Through Design of Experiments (DoE) was done a 22x31 full-factorial test that showed the influence of three independent variables (upper punch compression force, tablet weight and speed of rotation of tabletting machine) on the tablet’s properties. The obtained ODTs were according to the limits for both weight and content uniformity and revealed tablet units with very low coefficients of variation and satisfactory mean percentages of furosemide. The results for resistance to crushing revealed very high values corroborated by low friability of tablets. They also showed uniformity of the subdivided tablets with very low mass deviations and minimum percentage of mass lost during breaking process. The biopharmaceutical tests revealed a different outcome of what was expected from this dosage form. All the disintegration and wetting times failed to comply with the required standards along with the water absorption ratio, thus showing space for improvement.<br>Os sistemas de administração de fármacos têm, ao logo do tempo, logrado obter um acentuado grau de desenvolvimento com o objetivo de ultrapassar as limitações terapêuticas existentes. Como principal objetivo é visada a expansão do ciclo de vida dos produtos farmacêuticos, bem como melhorar o processo de administração dos mesmos de acordo com as necessidades da população alvo. Uma vez que a via oral representa o modo de administração mais comum e utilizado, o presente trabalho tem como objeto de estudo o desenvolvimento de comprimidos orodispersíveis (ODTs). Esta forma farmacêutica proporciona um início de ação rápido e apresenta como aspeto diferenciador o seu possível uso em pacientes pediátricos, geriátricos e mentais, onde a capacidade de deglutição pode estar comprometida. No presente estudo, os comprimidos orodispersíveis com furosemida como fármaco-modelo foram produzidos por compressão direta e apresentavam uma forma inovadora. Na produção recorreu-se ao uso de punções em forma de trevo de quatro folhas, originando comprimidos divisíveis em quatro, permitindo assim possíveis ajustes de dose. Os comprimidos foram posteriormente avaliados em termos de espessura e diâmetro, uniformidade de teor e massa, uniformidade da divisão em quatro partes do comprimido, resistência ao esmagamento, friabilidade, tempo de molhamento, quantidade de água absorvida e tempo desintegração. Através do desenho experimental, fatorial (22x31), foi possível avaliar a influência de três variáveis independentes (força de compressão do punção superior, massa do comprimido e velocidade de rotação da máquina de comprimidos) nas propriedades dos comprimidos produzidos. Os comprimidos obtidos encontravam-se de acordo com os limites estabelecidos de uniformidade de teor e massa e, após divisão, apresentaram subunidades com coeficientes de variação muito baixos e com percentagens de furosemida satisfatórias. Os resultados de resistência ao esmagamento revelaram valores muito elevados corroborados pela baixa friabilidade de comprimidos. Constatou-se ainda a uniformidade de massa nas subdivisões dos comprimidos, com desvios muito baixos e percentagens mínimas de perda de massa durante o processo de quebra. Os testes biofarmacêuticos revelaram um resultado diferente do esperado para esta forma farmacêutica. Os tempos de desintegração e molhamento não cumpriram com os padrões exigidos, bem como o índice de absorção de água que se revelou baixo, o que induz ainda existir espaço para melhoria.

L’objectif de ce projet était de développer une formulation liquisolide (LS) de clozapine ayant des propriétés de dissolution améliorées et évaluer sa stabilité et ainsi que sa robustesse à la modification d’excipients. Le propylène glycol (PG), la cellulose microcrystalline (MCC) et le glycolate d’amidon sodique (SSG) ont été utilisés respectivement en tant que véhicule liquide non volatile, agent de masse et agent désintégrant pour la préparation de comprimés LS. Le dioxyde de silicium colloïdal (CSD), le silicate de calcium (CS) et l'aluminométasilicate de magnésium (MAMS) ont été choisis comme agents d’enrobage sec. La caractérisation complète des mélanges et des comprimés a été effectuée. Le taux de libération des comprimés LS était statistiquement supérieur à celui des comprimés réguliers. La surface spécifique des matériaux d’enrobage avait un effet sur les propriétés d’écoulement des mélanges et la taille des particules des matériaux d’enrobage a eu un effet sur la vitesse de dissolution. Le ratio support/enrobage du mélange de poudres (valeur de R) était un paramètre important pour les systèmes LS et devait être plus grand que 20 afin d’obtenir une meilleure libération du médicament. La formulation choisie a démontré une stabilité pour une période d’au moins 12 mois. La technique LS s’est avéré une approche efficace pour le développement de comprimés de clozapine ayant des propriétés de dissolution améliorées. Les comprimés oro-dispersibles (ODT) sont une formulation innovante qui permettent de surmonter les problèmes de déglutition et de fournir un début d'action plus rapide. Dans l’optique d’améliorer les propriétés de dissolution, un essai a été effectué pour étudier la technique LS dans la formulation des ODT de clozapine. Le PG, la MCC, le CSD et la crospovidone (CP) ont été utilisés respectivement en tant que véhicule liquide non volatile, agent de masse, agent d’enrobage sec et agent superdésintégrant pour la préparation de comprimés oro-dispersibles liquisolides (OD-LST). Le mannitol a été choisi comme agent de masse et agent édulcorant. La saccharine de sodium a été utilisée comme agent édulcorant. La caractérisation complète des comprimés a été effectuée. Le taux de libération des OD-LSTs était statisquement supérieur comparativement aux comprimés ODTs. La formulation choisie a démontré une stabilité pour une période d’au moins 6 mois. Il a été conclu que des ODT de clozapine peuvent être préparés avec succès en utilisant la technologie LS dans le but d’améliorer la désintégration et le taux de dissolution de la clozapine dans la cavité orale.<br>The objective of this research was to develop a liquisolid (LS) formulation of clozapine with improved dissolution properties and evaluate its robustness to excipient modifications as well as its stability. Propylene glycol (PG), microcrystalline cellulose (MCC) and sodium starch glycolate (SSG) were employed as non-volatile liquid vehicle, carrier material and disintegrant respectively for preparing LS compacts. Colloidal silicon dioxide (CSD), calcium silicate (CS) and magnesium aluminometasilicate (MAMS) were selected as coating materials. Complete characterisation of the blends and tablets was performed. The drug release rates of LS compacts were distinctly higher as compared to regular tablets. The specific surface areas of coating materials had an effect on the flow properties of the blends and the particle sizes of coating materials affected the dissolution rate. The carrier : coating ratio of the powder system (R value) was an important parameter for LS systems and had to be larger than 20 to obtain enhanced drug release. The selected formulation demonstrated stability for a period of at least 12 months. The LS technique was an effective approach to prepare clozapine tablets with enhanced dissolution properties. Orally disintegrating tablets (ODT) constitute an innovative dosage form that overcomes the problems of swallowing and provides a quick onset of action. In view of enhancing dissolution properties an attempt has been made to study LS technique in formulation of ODT of clozapine. PG, MCC, CSD and crospovidone (CP) were employed as non-volatile liquid vehicle, carrier material, coating material and superdisintegrant respectively for preparing orally disintegrating liquisolid tablets (OD-LST). Mannitol was selected as a carrier material and sweetening agent. Sodium saccharin (SS) was employed as a sweetening agent. Complete characterisation of the tablets was performed. The drug release rates of OD-LSTs were distinctly higher as compared to regular ODTs. The selected formulation demonstrated stability for a period of at least 6 months. It was concluded that the ODT of clozapine can be successfully prepared using LS technology in order to improve disintegration and dissolution rate of clozapine in oral cavity.