Chitosan as a multipurpose excipient in directly compressed minitablets
De Kock, Johanna Magdalena
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The development of direct compression as the choice method of tablet manufacture can be promoted from two major advantages posed by the process. The method is a phenomenal time saving process due to its relative simplicity (blending of components followed by tableting directly afterwards). The consequence of these phenomena is acceleration of the production rate of tablets, ultimately resulting in vast economical benefits (Otto, 2002:X). The growing interest for multiple-unit dosage forms, especially mini-tablets (2-3 mm in diameter), and their increasing share of the pharmaceutical product market are claimed by their proponents to stem from advantages they offer over single-unit dosage forms, such as more uniform transit, less variability and a smaller risk of dose dumping. Other advantages like their large surface area and uniformity adds to their wide field of applications. The use of mini-tablets would therefore constitute a potential economic saving through the use of less excipients, few and inexpensive production steps, and if to be coated, reduced amounts of coating material required. Chitosan is a natural polysaccharide that is obtained by the partial deacetylation of chitin, the second most abundant natural polymer. Since chitosan combines unique physicochemical characteristics, in vivo biodegradability, biocompatibility, non-toxicity, and antimicrobial action, it has been widely investigated over the last few years for potential applications in the medical and pharmaceutical fields. As a pharmaceutical excipient, its main contribution seems to be as an absorption enhancer of large molecular drugs from the gastrointestinal tract (through "tight junctions") and as a fat absorber in dietary products. Although it is present in various tablet preparations, little if any is known about the tablet-ability or inclusion of this versatile polymer into mini-tablets. Characterisation of chitosan powder revealed a large particle size and a narrow particle size distribution which had a detrimental effect on the flow-ability of the powder, however, did not preclude the employment of chitosan. Due to its density results it could be predicted that chitosan would produce significantly compacted tablets of minimum weight, thus questioning its compactibility propensity. During preformulation studies it was found that the production of pure chitosan tablets were impossible without the inclusion of other excipients, however, it was possible to produce mini-tablets which did not necessitate the presence of a lubricant. The chitosan mini-tablets did however, not disintegrate and were of poor mechanical strength. It was these properties that provided the challenges that were circumvented in this study. The addition of the sparingly water-soluble, hydrophobic drug, furosemide, perplexed the formulations of chitosan mini-tablets, however, provided a mode of evaluation of the effects of formulation variables on tracer substance dissolution behaviour. The physical stability of chitosan mini-tablets indicated sensitivity towards varying ambient conditions regardless the inclusion of Kollidon (R)VA64 as chitosan easily dehydrate. It was furthermore evident that the presence of moisture (sorbed water) had a considerable influence on the tabletability and disintegration of chitosan powder. Furthermore, the stability of chitosan powder deteriorated to a greater extent than the chitosan mini-tablets which were subjected to the same conditions. It is therefore recommended that chitosan mini-tablets should be stored at a temperature not exceeding 25°C at a relatively low humidity (60%). It was also evident that the presence of Kollidon (R)VA64 as well as the method of inclusion of this binder influenced the stability of chitosan tablets. Thus, direct compression of chitosan granules which comprised of 5% w/w Kollidon (R)VA64 produced the optimal system in terms of product stability. Additionally, evaluation of chitosan tablets should be performed at consistent intervals as these tablets showed a time-dependent behavioural pattern regarding their physical properties. Systematic evaluations of various commercially available excipients were investigated to determine their effects on the physical tablet properties as well as on tracer (furosemide) dissolution. The tablet weight and dimensions of the different formulations did not vary discernibly, regardless the method used for production of the filler-system. Thus, exceptional good flowability was illustrated despite the extensive percentage chitosan, and the inclusion of furosemide into the formulations. The inclusion of furosemide did, however, portray a slightly detrimental effect on the crushing strength of the mini-tablets compressed at the same compression setting. Furthermore, the crushing strengths of all the mini-tablet formulations were very low (> 80 N) and the addition of other excipients did play a significant role in the crushing strengths of the different formulations. It might be suggested that the inclusion of a binder could not be seen as the only contributor to tablet strength. Friability results for all of the formulations were in congruence with the results obtained for tablet strength. Friability and tablet hardness do not, however, play an important role in mini-tablets as these tablets are encapsulated and are thus, not subjected to intensive handling. The efficiency of the mini-tablet formulations in this study were, however, determined and set apart through the disintegration, and more importantly, the dissolution properties of the different formulations. Most of the formulations resulted in tablets that disintegrated well within the set limit of 15 minutes. The production of a 5% w/w Kollidon (R)VA64 filler-system through granulation proved detrimental to the disintegration process for all the different formulations. Interestingly, formulations containing a buffer disintegrated faster than formulations where a disintegrant was incorporated. It was furthermore demonstrated that formulations containing ascorbic acid disintegrated slower than formulations containing sodium bicarbonate, whereas formulations containing Kollidon(R) CL disintegrated significantly slower than formulations containing Ac-Di-Sol(R). These results indicated that Ac-Di-Sol(R) is the preferred choice of disintegrant when used in these concentrations and in combinations with various buffers. Furthermore, the level of disintegrant or buffer determined the efficiency of disintegration to a large extent. The higher level imparted a more significant enhancement of disintegration effectiveness than did the type of excipient incorporated. When considering formulations where sodium bicarbonate and a disintegrant were combined, formulations which contained 2% w/w sodium bicarbonate disintegrated the fastest. It would seem that. the inclusion of sodium bicarbonate imparted a more significant enhancement of disintegration effectiveness than did any other variable and that this buffer should be included in formulations containing Ac-Di-Sol(R) so as to enhance the disintegration process. Comparison of the dissolution parameters of all of the formulations clearly indicated the dependency of the area under the dissolution curve (AUC) on the initial dissolution rate (DRi). The decreased DRi-values of both furosemide and chitosan, however, were contradictory to the prodigious disintegration of all the chitosan formulations which validated that tablet disintegration is no absolute guarantee for drug dissolution. It was further evident that formulation variables played a much more pronounced role during dissolution testing than with the physical properties. The incorporation of 5% w/w Kollidon(R)VA64 into the different formulations through physically mixing provided tablets with enhanced dissolution properties for both furosemide and chitosan, whereas Methocel(R) KIOOM inhibited the onset of dissolution. The high AUCn values of all of the formulations containing a buffer, regardless the concentration used, suggested dissolution conditions comparable and even superior to that of a furosemide suspension. This could be attributed to thorough dispersion of the primary drug particles throughout the medium before settling at the bottom of the dissolution vessel. Incorporation of 0.5% w/w ascorbic acid led to an increased dispensation of furosemide due to increased chitosan solubility. However, the ascorbic acid created an unfavourable micro environment for the furosemide to be able to dissolve promptly. A more significant increase in dissolution of furosemide was produced through the incorporation of sodium bicarbonate into the minitablet formulations. The observed increase in the DRi of furosemide from these tablets was attributed to a pH-increase in the micro environment and an increase in solvent penetration into the tablets due to the creation of capillaries. However, an increase in sodium bicarbonate concentration had a negative influence on the micro environment of the chitosan which only dissolves in an acidic environment, thus inhibiting prompt dissolution. It could clearly be seen that the incorporation of a disintegrant resulted in the most significant change in the dissolution profiles and the efficiency of these super-disintegrants were indeed concentration-dependent. Furthermore, it could be concluded that formulations containing Ac-Di-Sol(R)depicted faster dissolution rates and more pronounced extent of dissolution than formulations containing Kollidon(R)CL. The formulations containing 0.625% w/w Ac-Di- Sol(R) illustrated a significant positive linear dependence of (AUC)n on (DRi)n, whilst Kollidon(R)CL formulations illustrated a slightly less apparent dependence. However, an increase in concentration of Ac-Di-Sol(R)resulted in an inadequate correlation coefficient, thus, indicating that the (AUC)n were less dependant on the (DRi)n with increasing concentrations of this disintegrant. There was no discernable vindication for the inclusion of a combination of a disintegrant and ascorbic acid into the formulations. It was rather the inclusion of a disintegrant which played a more pronounced role in the dissolution parameters. It was however clear that the inclusion of 2.0% w/w sodium bicarbonate into formulations containing Ac-Di-Sol(R)rendered tablets with exceptional dissolution properties. Ac-Di-Sol(R)and sodium bicarbonate had a synergistic effect on the dissolution of both furosemide and chitosan in an acidic medium. The formulation (CF/36) which contained a physically mixed filler-system (consisting of chitosan and 5% w/w Kollidon(R)VA64) with 1.25% w/w Ac-Di-Sol(R)and 2% w/w sodium bicarbonate derived the most suitable dissolution properties (84.18% furosemide dissolved). It is thus evident that the undesirable properties of chitosan could be modified to comply with the set standards of directly compressed minitablets. The incorporation of the CF/36 formulation into capsules proved successful as the capsules Disintegrated within +- 60 seconds releasing and dispersing their contents into the dissolution medium. It was only due to the lag time that the disintegration of the capsules and the Avicel(R) PH-IOI matrix provided that the end furosemide concentration dissolved, had not yet been reached. However, these dissolution profiles still followed the same curve as the profile of the CF/36 minitablets. Capsules containing CF/36 tablets and Avicel(R)PH-IOI did not separate as promptly as capsules which did not contain a protective filler and contrary to previous findings these capsules depicted slightly less favourable dissolution profiles than capsules containing only the minitablets. This was probably due to the formation of a rather viscous microcrystalline cellulose matrix around the minitablets which first had to disintegrate preceding disintegration of the minitablets. Chitosan does not rank highly regarding its employment as first choice filler. Undesirable properties that limit its utilisation include its hydration propensity influencing stability, problematic tablet strength characteristics and the availability of fillers that circumvent some of the undesirable properties of chitosan. This study, however, proved that chitosan could serve as a relatively cheap alternative to other direct compression fillers especially in the formulation of mini tablets, if the formulations were carefully optimised. Furthermore, its mucoadhesive and absorption enhancing properties could also benefit and improve bioavailability of various poorly absorbed compounds or active ingredients. Based on these results, the development of an optimised chitosan multifunctional excipient seems an attainable and relevant objective which is comparable and even superior to commercial products.
- Health Sciences