Assessment of the characteristics of chitosan processed by spherical agglomeration / Abel Hermanus van der Watt

Abstract

Chitosan, derived from the most abundant natural polymer available next to cellulose, lacks the micrometric properties a pharmaceutical excipient intended for direct compression has to comprise. Excellent flowability, compactibility and dust freeness are primary micrometric properties required from direct compression excipients to ensure the success of the method. The successful exploitation of direct compression as a tablet manufacturing process could result in phenomenal time saving and economical benefits. Size enlargement is a technique utilized to alter the micrometric properties of powders on a physical level. Several methods are available to enlarge particle size, but no techniques experimented offered the same advantages in terms of efficiency, simplicity, time and cost effectiveness than the spherical agglomeration technique. An intensive preliminary experimental study revealed the predominant factors contributing to the successful spherical agglomeration of chitosan. A factorial design identified the optimum factors and factor levels. An agitation speed of 400 rpm provided agglomerates of desirable size and shape. Higher speeds disrupted the process. A suspension agglomeration time of 15 minutes produced perfectly spherical agglomerates, but had no influence on tablet properties. A bridging liquid volume of 3 ml per 3 g powder was sufficient to wet the suspended particles. Higher volumes per powder weight produced large undesirable agglomerates which failed during compression. A bridging liquid concentration of 5% v/v facilitated adequate wetting. The optimum binder was identified as ~ o l l i d o nK~25 and a binder concentration of 30% w/w seemed adequate to coat the entire powder mass, as SEM micrographs indicated. The optimal parameters and levels of the spherical agglomeration of chitosan were recognized and further investigated. A study on the effect of each variable level was conducted in an attempt to explore the influence of a factor level on spherical chitosan agglomerate recovery and formation. Results indicated that no trends were present and that it could be suggested that agglomerate recovery was the result of the interaction of certain factors and specific factor levels. Spherically agglomerated chitosan possessed phenomenally enhanced flow, compressibility and dust free properties. An angle of repose test indicated an improvement in fluidity from 23.2' to 2.5'. No lamination during compression was encountered. Spherically agglomerated chitosan was compressed successfully and used in tablet formulations without any tableting excipients other than ~ o l l i d o nK~2 5, an excipient that proved essential in the agglomeration step. No glidants were necessary, as the powder flowed freely into the tablet die. In addition, the formulations required no lubrication in view of the fact that the tablets underwent no friction during compression. The tablets were hard (>lo0 Newton), and had minimum friability and complied with the weight variation standards of the British Pharmacopoeia. Propranolol hydrochloride is an extremely poor flowing powder and could only be compressed with chitosan after being spherically agglomerated with chitosan. The drug remained stable during and after spherical agglomeration. The process proved safe, given the results obtained from the X-ray powder diffraction and infrared absorption spectroscopy. Dissolution parameters in 0.1 M HCI and Sorensen buffer pH 4.5 were tested. The InderalB LA 80 mg was the norm (1.000). Formulation 1 presented an average (DR,), of 1.42 and a (AUC), + (DR,), (combined) of 3.52. Formulation 2 displayed an average (AUC), of 2.05. Formulation 3 had the overall best dissolution performance compared to InderalB LA 80 mg, with an f2-value in both mediums of 34.46. Formulation 1 had an f2-value in 0.1 M HCI of 51.45, an (AUC), of 1.30 and a (DR,), of 1.46. The initial dissolution rate decreased with an increase in crushing strength and concentration propranolol and chitosan per tablet formulation. The incorporation of spherically agglomerates of chitosan into tablets resulted in sustained release of the drug. It can be concluded that the release of propranolol from spherically agglomerated chitosan tablets is in accordance with the matrix model where diffusion is the rate limiting factor, with an almost desirable linear dependency for zero order drug release. A linear correlation is present between the percentage of drug released and the square root of time (R2 = 0.9434). Additionally, a linear relationship was found between the logarithm of the amount of drug released and the logarithm of time (R2 = 0.9172). With a slope of 0.6594, it can be concluded that drug release took place passing through a porous system and as a result of a combination of diffusion through a polymer and diffusion through pores in the system. The suitability of chitosan as a multipurpose excipient was illustratpd. An effective method was developed, chitosan obtained enhanced micrometric properties as a result of the method, and spherically agglomerated chitosan sustained release tablets were obtained.