Effect of intragranular porosity on compression behaviour of and drug release from reservoir pellets

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Abstract

In this study, reservoir pellets were prepared and their compression behaviour as well as the importance of their porosity for compression-induced changes in drug release was investigated. Pellets of three different porosities, consisting of microcrystalline cellulose and salicylic acid, were prepared by extrusion–spheronisation and spray-coated with ethyl cellulose (ethanol solution). Lubricated reservoir pellets were compressed and retrieved by deaggregation of the tablets. The retrieved pellets were analysed regarding porosity, thickness, surface area, shape and drug release. It was found that the coating did not significantly affect their compression behaviour. Compaction of pellets of high original porosity considerably affected densification and degree of deformation, whereas the effect on drug release was minor. For low porosity pellets the influence of compaction on drug release was appreciable, but only slight regarding densification and degree of deformation. In conclusion, the porosity of pellets is a potential factor that the formulator can use to optimize drug release and one that can affect the robustness of a formulation during manufacture. Moreover, the coating may be able to adapt to the densification and deformation of the pellets.

Introduction

A common way to design oral modified release systems is to coat spherical granules (pellets) with a polymer that regulates their drug release rate. Such reservoir pellets can be incorporated into hard gelatine capsules or compacted into multiple unit tablets. The tablets are normally intended to disintegrate into discrete pellets in the gastrointestinal tract and the drug should subsequently be released from the individual pellets. A challenge with such a multiple unit tablet is to maintain the controlled drug release after compaction, as the application of compaction pressure can lead to structural changes in the film coating and consequent altered drug release. To protect the reservoir pellets, excipients with cushioning properties are usually incorporated in multiple unit tablets.

The compression-induced changes in the structure of the film coating may be caused by the tabletting process and can depend on formulation factors, such as the type and amount of coating, the incorporation of excipient particles in the tablet formulation, and the properties and structure of the pellet core. Investigations into the importance of the coating and the use of excipient particles are reported upon extensively in the literature (Bodmeier, 1997, Tunón, 2003). The properties and structure of the substrate pellet have been studied to a somewhat lesser extent (Aulton et al., 1994, Maganti and Çelik, 1994, Schwartz et al., 1994, Wang et al., 1995, Beckert et al., 1996, Haslam et al., 1998, Iloañusi and Schwartz, 1998, Salako et al., 1998). In a number of studies soft materials have been incorporated into pellets in order to alter their compactability, generally with the intention of protecting reservoir pellets that they are mixed with prior to compaction (Mount and Schwartz, 1996, Lundqvist et al., 1997, Lundqvist et al., 1998, Pinto et al., 1997a, Iloañusi and Schwartz, 1998, Salako et al., 1998, Nicklasson and Alderborn, 1999, Vergote et al., 2002). The structure of both the pellet core and the coating are inter-related and it is suggested that, as a general rule, film coating and pellet core should have similar properties (Aulton et al., 1994, Felton et al., 1997). There are, however, contradictory recommendations as to whether the pellets should be hard and non-deformable, making them better able to withstand coating rupture (Beckert et al., 1996) or plastically deformable, so as to accommodate a possible change in shape when compacted (Schwartz et al., 1994).

One possible way to modulate the deformation of pellets during compression is to vary the intragranular porosity (Millili and Schwartz, 1990, Johansson et al., 1995, Nicklasson and Alderborn, 2000, Tunón and Alderborn, 2001, Habib et al., 2002). To our knowledge, the influence of the porosity of reservoir pellets on compression behaviour and compression-induced changes in drug release has hitherto not been studied. The aim of the present study was therefore to investigate the influence of intragranular porosity on the densification and deformation behaviour and the subsequent effect on drug release from compacted reservoir pellets.

Section snippets

Materials

The materials used included salicylic acid (puriss, Merck, Germany, apparent particle density 1.426±0.0001 g/cm3), microcrystalline cellulose (Avicel PH101, FMC, Ireland, apparent particle density 1.571±0.0010 g/cm3), deionized water, ethanol (95% Finsprit, Kemetyl, Sweden), ethyl cellulose 10 cps (Hercules, USA, apparent particle density 1.141±0.0011 g/cm3). Magnesium stearate (Ph. Eur.) was purchased from Kebo, Sweden. The powders were used as received, except for salicylic acid which was

Characteristics of uncoated pellets

The preparation procedure used gave pellets of similar size, shape and external specific surface area but with a wide range of intragranular porosity (Table 1). The small difference between poured and vibrated density indicated a good flowability for all pellets by virtue of their size and shape characteristics. The drug release from the uncoated drug pellets was rapid, half of the salicylic acid (t50%) being released in about 30 min from the less porous pellets and even faster from the more

Compression behaviour of reservoir pellets

In previous studies (Johansson et al., 1995, Johansson and Alderborn, 1996, Tunón and Alderborn, 2001) it was found that uncoated pellets formed from microcrystalline cellulose deform and become denser during compression. It was also shown that increasing the original pellet porosity will increase the degree of deformation and densification which the pellets undergo during compression. We have also shown (Tunón and Alderborn, 2001) that extragranular factors, such as the properties of pellets

Conclusions

In this study, reservoir pellets were prepared and their compression behaviour—as well as the importance of their porosity for compression-induced changes in drug release—was investigated. We found that the coating did not significantly interfere with the compression behaviour of the pellets. Moreover, the coating used in this study seemed to adapt to the densification and deformation of the pellets and remained tightly adhering to the pellet cores, even after compaction. The effect of

Acknowledgements

This study is part of a research programme in Pharmaceutical Materials Science at Uppsala University. Financial support was provided by Pharmacia AB, AstraZeneca AB, NUTEK (Swedish National Board for Industrial and Technical Development) and the Wallenberg Foundation in Sweden. Gunilla Andersson is gratefully acknowledged for skilful experimental assistance.

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