Cross-linked cellulose as a tablet excipient: A binding/disintegrating agent
Introduction
In the preparation of a tablet from a drug as a dosage form, pharmaceutical ingredients are required: fillers are added to increase bulk to the formulation, and lubricants, to reduce friction during the tableting process. Some pharmaceutical ingredients require a binder for tableting. This provides the cohesiveness necessary for bonding together ingredient granules under compression. The quantity used must be carefully regulated, since the tablet must disintegrate after administration to liberate the drug. Disintegrants are usually added for the purpose of causing the compressed tablet to break apart when placed in an aqueous medium. Some excipients, such as Avicel PH101® and Avicel PH102®, demonstrate both properties, being disintegrants and binders (Lieberman et al., 1989). For a successful formulation, equilibrium between binder and disintegrant concentrations must be reached for the ingredient granules to be easily compressed, to form a tablet and finally disintegrate after reaching an aqueous medium.
The solubility of the filler in a formulation affects both the rate and mechanism of tablet disintegration. Water-soluble fillers tend to dissolve rather than disintegrate, while insoluble fillers produce rapid disintegration. It has been shown that superdisintegrants have a greater effect on disintegration time in an insoluble system than in a soluble or partially soluble system (Bathia et al., 1978, Cartilier et al., 1987, Sheen and Kim, 1989, Johnson et al., 1991).
Cellulose is a polymer of d-glucose in which the individual units are linked by β-glucosidic bonds from the anomeric carbon of one unit to the C-4 hydroxyl of the next unit. It is a linear polysaccharide, the isolated form containing an average of 3000 units per chain, corresponding to an average molecular weight of about 500 000. It is a natural polysaccharide, where hydroxyl groups of each glucose have different reactivities: the C-6 OH group (OH1) is the most reactive (primary carbon), the C-2 OH group is less reactive (OH2) and the C-3 OH group (OH3) is the weakest for the ‘bent’ conformation with reasonable distance which allows the formation of a hydrogen bond between C-3 OH and the neighboring oxygen molecule (Fig. 1) (Champetier, 1933, Walton and Blackwell, 1973, Streitweiser and Heathcok, 1985).
Cross-linked cellulose (CLC) (Fig. 2) was prepared by cellulose treatment with epichlorohydrin in a strongly basic medium at 60–65°C (Encyclopedia of Polymer Science and Engineering, 1985).In this way, two neighboring cellulose chains are attached to form a network which binding and disintegrating properties are a function of the cross-linking degree (CLD). The studied polymer will be hereinafter referred as CLC-C25, where CLC means cross-linked cellulose, C is the type of cellulose used (microcrystalline) and 25 represents the degree of cross-linking expressed as the ratio: g of epichlorohydrin/100 g of cellulose. CLC-C25 was proven to have better disintegrating properties of those of superdisintegrants known for their high efficiency (Ac-Di-Sol™ and Explotab®), and good binding properties in comparaison to Avicel PH101 and Avicel PH102.
This paper presents facts and experimental results on the use of CLC-C25 as a binding/disintegrating agent.
Section snippets
Materials
Avicel PH101® and Avicel PH102® (FMC Corperation, Avicel sales, Philadelphia, PA), Spray-dried lactose® (Mallinckrodt Chemicals, Toronto), Lactose 100 mesh® (Mallinckrodt), dicalcium phosphate known as Emcompress® (Mendell, New York), cross-linked carboxymethylcellulose, Ac-Di-Sol™, (FMC, Food and Pharmaceutical Products division, Philidelphia, PA), sodium starch glycolate, Explotab® (FMC) magnesium stearate (Sigma, St. Louis, MO), epichlorohydrin (Sigma) and acetaminophen (Mallinckrodt).
CLC synthesis
20 ml
Surface morphology
According to scanning electron photomicrographs, Avicel PH101® consisted of relatively large and iregular particles, among which were numerous smaller more regularly shaped particles (Fig. 3). The structure of CLC-C25 particles consisted mainly of large and roughly more elongated particles, among which were fewer small particles (Fig. 4).
Particle size analysis
Table 2 gives the parameters related to the size and shape of cellulose particles before (Avicel PH101®) and after (CLC-C25) the cross-linking reaction.
Conclusion
CLC-C25, a new tablet excipient, is essentially water insoluble, but is highly absorbent and provides excellent disintegration and binding properties when used in tablets at levels 10–20%. The mechanism of disintegration appears to be governed first by the capillarity, then by the mechanical phenomenon, the breaking up of interparticulate bonds.
CLC-C25 will make formulation simpler by introducing one double-function excipient instead of two with less probability of incompatibility of the
Acknowledgements
The authors thank Laboratoires cm2, École polytechnique (Montréal, Canada), for the use of their scanning electron microscope.
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