Date of Award

2010

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Zebunnissa Ramtoola

Funder/Sponsor

Enterprise Ireland (EI)

Keywords

Chemistry, Pharmaceutical, Dosage Forms, Tablets

Abstract

Oral dosage forms are the safest and most convenient dosage forms and of these tablets are the most popular with patients because of their portability, ease and convenience of dose intake and with manufacturers because of their simple and low cost manufacturing process. Fast disintegrating dissolving tablets (FDDTs), a more recent innovation, have gained a great deal of attention particularly for use in various patient groups such as the paediatric, geriatric, travelling patients and patients having dysphagia. The name "fastdissolving" indicates that the tablets dissolve fast in the mouth without the aid of water, allowing ease of dose intake by the patients (Banker and Rhodes, 2002).

To meet the goal of fast disintegration in the mouth generally in less than 1 minute, early techniques developed for the production of FDDTs were based on freeze drying or lyophilization (Seager, 1998), molding at low pressure (Makino et al., 1998), sublimation (Koizumi et al., 1997) and tableting followed by humidity and temperature treatment (Mizumoto et al., 1996). A number of these techniques have been commercialized by Cardinal health (Zydis®), Janssen Pharmaceutica (Quicksolv®), Pharmalyoc (Lyod®), Yamanouchi (Wowtab®). Limitations of these technologies and of the resulting products include complex processing, high cost, tablets with low mechanical strength requiring specialised packaging and low dose content of these tablets.

Subsequently, conventional tableting technologies have been examined and adapted to produce FDDTs. These are based on either granulation or direct compression, and to produce tablets with fast disintegration properties, effervescent excipients and osmotic agents are used and/or tablets are compressed at a low compression force, which results in tablets of low hardness and hence high disintegration properties. Examples of such technologies include Orasolv®, Durasolv® by Cima labs, Advatab® by Eurand.

In the present thesis, a relatively simple direct compression technique was developed in order to prepare FDDTs with high mechanical strength while keeping the attributes of fast disintegration.

To allow for the fast disintegration qualities of the tablets, sugar alcohol based and cellulose based direct compression bases (DCBs) which are either highly water-soluble or water dispersible in combination with one or more disintegrants with differing disintegration mechanism on the mechanical strength and disintegration time of tablets was studied. The addition of hydrophobic and hydrophilic lubricants on the mechanical strength and disintegration characteristics of the tablets was also examined.

The influence of various tableting process variables on the characteristics of the tablets was also studied. Compression force is known to affect the hardness and tensile strength of the tablets as well as the tablet disintegration time (Tye et al., 2004). The influence of increasing compression force from 10 to 20kN on the mechanical strength and DT of the tablets at various tablet diameters, shapes and weights was investigated.

The hardness and tensile strength of tablets formulated using the cellulose based filler, Prosolv®, was found to be higher than tablets formulated using the sugar based fillers including sorbitol and Mannitol 200 (M200; mannitol). This was related to the better binding properties of microcrystalline cellulose (MCC) component of the Prosolv filler®. Only Mannitol 200, Prosolv@ and sorbitol tablets resulted in tablets which were not friable showing a percent weight loss of less than 1 % during the friability test.

The DT of the FDDTs formulated increased in the order of fillers used; mannogem > Mannitol 300 > Prosolv® > Mannitol 200 > Ludipress® > Sorbitol. The lowest DT of 5.67 seconds was observed for Mannogem FDDTs while the highest DT of > 2 minutes was observed for sorbitol.

Tablets containing either Prosolv® or Mannitol 200 (M200) as filler showed a fast DT of below 20 seconds and harder than Ludipress® or any other mannitols therefore were chosen for further study to evaluate the influence of the type of disintegrant on tablet characteristics.

The disintegration time of the tablets was found to be a function of the type of disintegrant used. For tablets containing M200, osmotic agents were found to result in faster disintegration of the tablets, while for tablets formulated with Prosolv®, the superdisintegrants resulted in faster disintegration.

For the M200 based tablets, the disintegration time was found to increase in the order of sodium citrate < calcium silicate < Luquasorb® < Kollidon CLSF < citric acid < SSG. M200 tablets containing SSG produced tablets with the highest disintegration time of 36.67 seconds. On the contrary, for tablets containing Prosolv®, the reverse order of the superdisintegrants was true and can be arranged in the increasing order of DT as SSG < Kollidon CLSF < Luquasorb®. Luquasorb® gave the highest DT of 47.67 seconds for Prosolv® tablets.

The addition of flavours and sweeteners to enhance the palatability of FDDTs at a concentration of 0.5 - 4%w/w or the use of a hydrophilic lubricant did not affect the characteristics of the tablet.

Formulations based on Mannitol 200 or Prosolv® in combination with the superdisintegrants; sodium starch glycollate (SSG), Luquasorb® or Kollidon CLSF (K-CLSF) were found to generate tablets with high tensile strength and low DT in the range of 2 - 49 seconds, hence were selected and applied to the two model drugs. The low DT of 2 seconds was observed for the formulation composition containing Mannitol 200. This was the lowest DT observed or reported for compressed tablets.

The effect of increase in the compression force on the characteristics of the tablets was found to be dependent on the diameter, shape and weight of the tablets. In general, an increase in compression force had a higher effect on the hardness and DT of smaller diameter tablets compared to the larger diameter tablets. Both, the hardness and DT of tablets were directly proportional to the applied compressional force and inversely proportional to tablet diameter for flat faced bevelled (FBE) tablets. For biconvex (BC) tablets, the tablet hardness was proportional to compression force and inversely proportional to the tablet diameter, however, the DT of the BC tablets was found to be independent of the compressional force and tablet diameter.

At similar compressional force, the FBE tablets possessed lower hardness, tensile strength and disintegration time compared to the BC tablets. The disintegration time for the FBE tablets was found to be below 49 seconds, while for the BC tablets the DT was > 1 minute. This was related to the lower hardness and higher porosity of the FBE tablets.

The two model drugs formulated as FDDTs were diclofenac sodium and simvastatin. Both drugs are commercially available as conventional tablets meant to be swallowed with a drink of water. Diclofenac sodium (DFS) is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of pain. FDDT formulations of the DFS would offer a convenient dosage form for the fast relief of pain. In addition, to avoid a multiple dosage regimen, attempts were made to formulate DFS as an FDDT containing modified release microparticles of DFS. Spray drying (SD) was used for the microencapsulation of the DFS using the sustained release ethylcellulose (EC) polymer.

The influence of different spray drying process parameters such as spray flow rate (SFR), feed flow rate (FFR) and air aspirator rate (AAR) on the characteristics of the microparticles showed that a change in the SFR was the most influential factor affecting the particle size, morphology and drug release characteristics from the microparticles, while FFR influenced the rheology of microparticles. The drug release comprised of an initial burst release of more than 39% in most cases, providing loading dose and subsequent sustained release over 7 hours. DFS release from the ethylcellulose microparticles was characterised by Fickian diffusion.

Diclofenac sodium (DFS) and the microparticles of DFS were used to formulate immediate release and modified release FDDTs, respectively. The use of DFS API showed issues of sticking during tableting which was related to its hydrophobic nature and small particle size of 8.501m of DFS. In contrast, microparticles of DFS were easily incorporated and formulated as FDDTs. The resultant FDDTs possessed high tensile strength and high porosity, resulting in fast disintegration of the FDDTs. A preclinical palatability study in the canine model showed that the dogs voluntarily accepted the FDDTs, suggesting good palatability of the FDDTs and efficient taste masking of the diclofenac sodium microparticles.

The second model drug investigated was simvastatin, a cholesterol lowering drug particularly used by patients in the 40+ years who most probably are on a range of other medications and are non-compliant with their therapy and hence could benefit from an FDDT formulation. Simvastatin API was formulated using selected mannitol based and Prosolv® based placebo FDDT formulations. FDDTs of low disintegration time of less than 36 seconds and high mechanical strength with hardness in the range of 28.83 to 109.95N were formed. The Prosolv® based FDDTs were found to have higher hardness in the range of 72.28 to 109.95N compared to mannitol based tablets which showed hardness of 28.83 to 54.19N.

However, an increase in tableting speed from 7rpm to 49rpm resulted in tablets with variable weight, hardness and DT. This was related to the hydrophobicity and small particle size of simvastatin resulting in segregation and irregular flow at higher tableting speed.

Two approaches were therefore investigated to improve manufacture of simvastatin FDDTs at higher tableting speed of 49rpm.

1) To improve rheology and compressibility, simvastatin was first formulated in a matrix of hydrophilic disintegrants by spray drying an aqueous dispersion of the drug and selected disintegrant. The resultant solid dispersions were evaluated for their rheological properties. The formation of such solid dispersions may improve wetting of the drug, resulting in an enhanced dispersibility on contact with aqueous medium and hence dissolution of the drug.

(2) A flow enhancer, colloidal silica (Aerosil®) was added to the formulation as per the conventional industrial technique of improving the rheology of the tablet blend.

Solid dispersions (SDP) formulated using Kollidon CLSF (K-CLSF), sodium starch glycollate (SSG) or calcium silicate (CaS) showed enhanced rheology compared to simvastatin API. This was a result of the greater particle size and uniform particle size distribution. The simvastatin in the SDP was found to be in its crystalline form.

The scalability potential of the simvastatin formulations was examined using mannitol based formulations containing simvastatin-K-CLSF SDP. FDDTs of uniform weight, high hardness and tensile strength of 35.48N and 0.0693N/mm2 respectively were formed. The DT of the tablets were low in the range of 15.17 to 19.17 seconds. The hardness and tablet tensile strength was lower than the hardness observed at 7rpm which was explained by the decrease in dwell time as the tableting speed increases.

Similarly, mannitol based tablets containing simvastatin API and Aerosil® as a glidant were successfully prepared at both, 7rpm and 49rpm. At 49rpm, the tablets produced were uniform in weight, with hardness of 53.07N and showed low DT of 16.33 seconds. An increase in the compression speed from 7 to 49rpm caused a small decrease in tablet hardness from 54.48 to 53.07N was noted.

Simvastatin FDDTs formulated using a combination of Prosolv® and mannitol with Aerosil® added as a glidant were associated with greater hardness and tensile strength than corresponding mannitol based FDDTs. FDDTs with uniform weight were produced at high tablet turret speed of 49rpm, suggesting good rheology of the formulation blends used. The hardness and tensile strength of the tablets was found to decrease in the order mannitol and Prosolv® 1:1> mannitol 200 and Prosolv® at 3:1> mannitol 200. Addition of Prosolv® to the tablet blend resulted in a decrease in the DT from 16.33 seconds for mannitol 200 based tablets, to 7.17 and 10 seconds for tablets containing a mannitol and Prosolv® in the ratio 3:1 and 1:1, respectively.

The dissolution characteristics of the simvastatin FDDTs formulated at the high speed of 49rpm were compared with the innovator Zocor® tablets. The dissolution of simvastatin from FDDTs prepared using solid dispersion (SDP) of simvastatin was found to be faster in comparison to the FDDTs containing simvastatin API and Aerosil® as a glidant. FDDTs containing SDP of simvastatin were shown to release almost 100% of the simvastatin after 5 minutes. In comparison, 87.05% of the simvastatin released from the FDDTs containing simvastatin API and formulated with Aerosil®. While, 20% of simvastatin was released from Zocor® tablets after 5 minutes. The faster dissolution of simvastatin from the FDDTs may result in faster onset of pharmacological action and has the potential to reduce variability in simvastatin absorption resulting in a simvastatin product with improved and less variable pharmacokinetic profile.

Stability testing carried out on the simvastatin FDDTs produced at 49rpm showed the FDDTs to be stable over a period of 6 months when stored under uncontrolled lab conditions. Negligible changes in mechanical strength, DT, drug content and dissolution characteristics over the 6 months was observed.

Future development of this work would involve investigation of the simvastatin FDDTs in a human pharmacokinetic study to explore its potential for delivering simvastatin with reduced variability. Future work should also investigate the effect of increasing drug content and drug physicochemical properties on (1) the processing of FDDT formulations developed in this thesis and (2) the characteristics of resulting FDDTs to understand the application potential of these FDDT formulations to a wider range of therapeutic areas and higher dose actives.

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A Thesis sumbmitted to the Royal College of Surgeons In Ireland for the degree of Doctor of Philosophy.

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