Assessment of the tableting properties of chitosan through wet granulation and direct compression formulations / Marique Elizabeth Aucamp

Abstract

Chiiosan is a natural polysaccharide that is obtained by the partial deacetylation of chitin, the second most abundant natural polymer. Chiiosan is currently extensively utilised in various pharmaceutical and non-pharmaceutical preparations. It has found wide applicability in conventional pharmaceutical devices as a potential formulation excipient. As a pharmaceutical excipient, its main contribution seems to be as an absorption enhancer of large molecule drugs from the gastro-intestinal tract (through "tight junctions") and as a fat absorber in dietary products. Although it is present in various tablet preparations, l i l e if any is known about the tabletabiliiy of this versatile polymer. Characterisation of chiiosan raw material revealed poor flowabili, a large partide size distribution and poor compressibility. These properties provided the challenges circumvented in this study. The direct compression of chiiosan indicated that the flowabilii and compressibility of the polymer were insufficient to produce acceptable tablets comprising of pure chiiosan raw material. Therefore, chitosan was combined with ~vicepP H200 and ~rosolpSM CCm 90 respectively. The properties of tablets comprising of chitosan and these directly compressible fillers were compared in terms of filler concentration and mixing time. It was found that ~vicepPH 200 proved to be most effective at a concentration of 30% (whnr). Furthermore, a mixing time of 10 minutes produced optimal results for all the chiiosan Ifi ller combinations. The inclusion of single dry binders was investigated to assess the suitability of dry binders as enhancers of the binding properties of chiiosan raw material. Kollidon" VA-64 (co-polyvidone) and Methocep KlOOM (hydroxypropylmethylcellulose) were combined respectively with chiiosan raw material in concentrations of 4, 5, 7, 10, 15 or 20% wb. It was evident that chiiosan exhibited a significantly higher sensitivity for Kdlidon' VA-64 than for Methocep K100M. A log-linear relatiin between the Kollidon" VA-64 concentration and crushing strength was identified. This could be considered a significant attribute of the chiiosan I Kdliion' VA-64 combination, since this correlation could be utilised to predict the crushing strength of tablets comprising of chitosan and Kollion' VA-64 at any given concentration of the binder. In comparison with the combinations containing the directly compressible fillers the formulation comprising of 20% w/w Kollidong VA-64 produced superior crushing strength and friability. Conversely, the chiiosan I ~ethocef' KlOOM mixtures revealed erratic and relatively unacceptable results in terms of crushing strength and friability. However, the presence of Methocep KlOOM in the formulations seemed advantageous to tablet disintegration. Therefore, the combination of both binders in different concentration ratios were investigated to determine whether a combination of the dry binders would result in potentiation of the binding effect during compression and furthermore if the presence of Methocap KlOOM would enhance the disintegration of the tablets. Concentration ratios of 1:l; 3:l and 1:3 (~ollidon~ VA-64 : ~ e t h ~ ~K1e00PM ) were utilised during these experiments. The formulations comprising of single dry binders produced superior results compared to the formulations containing the dry binder combinations. Furthermore, it was evident that the binder combinations did not result in the potentiation of the binding effect nor did it prove advantageous in terms of tablet disintegration. Since the characterisation of chiiosan raw material proved that this polymer exhibited poor flowability, the subsequent wet granulation of chiiosan was investigated utilising low and high speed granulation. ~ollidon" VA-64 (mpolyvidone) and ~ e t h ~ ~ e p KlOOM (hydroxypropylmethylcellulose) were the two binders utilised in concentrations of 3% and 5% w/w respectively during granulation. Wet granulation of the polymer did improve the flowabillity, however, the inherent characteristics of chiiosan still affected the tabletability of the material. Therefore, the indusion of extragranular binder was necessitated to improve the binding of chiiosan granules during compression. Kollidon" VA-64 and Methocep KlOOM were utilised as external binders in concentrations of 3,5,7 and 10% w/w. Generally, the granulation processes overall improved the tabletability of the polymer since it was possible to compress larger quantities of chitosan with the aid of selected binders. ~ollidoVnA~- 64 posed to be better suited as a granulation binder for chitosan, compared to Methocep K100M. Dissolution studies provided a method to determine the effect(s) of chiiosan as well as the induded binders on drug release. Furosemide was induded in seleded formulations as a tracer drug. The gel-forming ability of chiiosan in acidic pH evidently decreased the release rate of the incorporated drug. Dissolution profiles of all the formulations containing chiiosan granules and extragranular binder indicated sustained release of furosemide (24 hour period). Since ~ethocepK lOOM also possesses the ability to form a gel layer on contact with water or biological fluid, the produdion of matrix tablets was a possibility. However, it was clear that a total concentration of 15% wlw ~eth-P KIOOM was insufficient to achieve matrix-like dissolution profiles. The combination of chiosan and ~ethoce$K IOOM proved to be advantageous in the formulation of sustained release dosage forms. Short-term stability testing of chiosan raw material proved that the exposure of chitosan to elevated temperatures had a detrimental effect on the tabletability of the polymer. Furthermore, it was evident that lower moisture content (sorbed water) detrimentally affected the compressibility of chiiosan raw material. Long-term stability testing indicated that ambient conditions could have pronounced effects on the physical properties of the raw material, chiosan tablets as well as the granules. Furthermore, the tablets comprising of ~ethocep KIOOM revealed the most significant deterioration in terms of crushing strength and friability. In contradidion, the tablets containing Avicep PH200 revealed the most acceptable results, confirming that direct compression produced the optimal system in terms of product stability. However, the combination of chitosan with binders allows the exclusion of Avicep PH200. However, the formulations containing binders (granulate) revealed poor stability. It could be concluded that the storage of chiosan raw material, tablets or granules should be ensured at temperatures lower that 25 "C and relative humidity not exceeding 60%. The optimisation of chiiosan raw material for utilisation in tablet formulations as well as its applicability as pharmaceutical excipient was pertinently illustrated.