Evaluation of the matrix-forming ability of chitosan through direct compression using a freely water-soluble drug

Abstract

To utilise the direct compression method in this study was a very challenging task due to the physical powder properties of chitosan. The compressibility of chitosan was evaluated in the initial phase and the results revealed that chitosan could not be compressed as a single component mixture. The following step was to improve the compressibility of the powder and this was done by the inclusion of Emcompress® , filler with high compressibility properties. Various ratios of the two powders were evaluated and the results revealed that only a small quantity of Emcompress® was necessary to facilitate direct compression. However, increasing quantities of chitosan in this powder mixture caused a decrease in tablet crushing strength. The following step in the formulation process was to determine whether chitosan could form a matrix tablet. At this stage, a placebo tablet was formulated. In order to enhance tablet properties as well as the binding capability of chitosan, an additional hydrophilic polymer binder, Methocel®, was included in the formulation and evaluated at varying concentrations of 20, 25 and 30%. These formulations caused an increase in crushing strength and no disintegration, a property that is favourable for matrix tablets. Chitosan was the primary excipient at this stage and the tablet properties revealed the potential matrix-forming ability of chitosan. The rank order for the binders were found to be Methocel® K15M>K4M>K100M with regards to the improvement of the tablet properties of the initial powder mixture. Propranolol hydrochloride, a freely water-soluble drug, was chosen for this study. This drug is characterised as having very weak flow properties and due to the high concentration included in the final phase of the formulation, the powder mixture was adversely affected. Various measures were taken to improve the flow of the powder mixture and thus also the tablet properties, such as, the incorporation of a lubricant and glidant, changing the binder concentration and binder type and changing the chitosan:Emcompress® ratio. The additional binder that was introduced was Kollidon® SR. The measures taken proved successful because tablets with excellent properties were produced. In order to determine if a matrix system was in fact achieved, a dissolution study was conducted. During the disintegration test, a gel layer was formed and swelling took place. This presentation is indicative of a matrix system. However, the fact that a freely water-soluble drug was used, the extent of drug release may not be as desired. Two tests were conducted, one in which a single medium was used and one in which two mediums were used. The results revealed sustained release during all of the tests conducted. The dissolution testing extended to 24 hours. The two-medium dissolution in which and initial 2 hours in a HC1 buffer of pH 1.2 followed by a 22-hour test in a phosphate buffer of pH 6.8 revealed 24-hour drug release with the drug still in tact after 24 hours. Literature indicates that chitosan cannot facilitate sustained-release at a high pH. The rank order for the different formulations with regards to drug release was K15M>K4M>K100M>Kollidon®SR. Chitosan still consumed the highest concentration in the formulation (38.36% w/w) and thus acted as a filler, binder and matrix carrier and the objective was thus achieved. During this study an additional experiment was conducted to evaluate the stability of the final formulation containing the active ingredient. For all Methocel® formulations a slight increase in tablet weight and a decrease in tablet hardness were observed over the 3 months at both storage conditions. The magnitude of these changes was more significant during the first month of storage compared to the following 2 months. The changes could be attributed to moisture absorption by tablet compounds, especially chitosan and the binders. Stabilization after 1 month could probably be attributed to the fact that the compounds responsible for moisture absorption reached their equilibrium moisture content within the first month and further absorption was negligible. The results of this study revealed: Chitosan can be used in a directly compressed formulation with the aid of small quantities of additional excipients; Chitosan can be used in a directly compressed formulation where a large quantity of a very weakly flowing active ingredient is used; Chitosan can be incorporated in the largest quantity of a directly compressed formulation; and Chitosan can be utilized in a directly compressed matrix tablet and produce sustained release of up to 24 hours.