Novel formulation strategies with a mechanistic approach to improving the dissolution of a poorly water-soluble drug

Abstract

The intrinsic cohesive nature of micronized poorly water-soluble drug particles often promotes the formation of drug agglomerates with reduced surface areas for dissolution. The objective of this thesis was to investigate novel and innovative formulation strategies to improve the de-agglomeration behaviour and in vitro dissolution rate of a micronized model poorly water-soluble drug, indomethacin. In the first approach, various micronized poorly water-soluble excipients (including aluminium hydroxide, barium sulphate, calcium phosphate and calcium sulphate) were incorporated into lactose-based indomethacin interactive mixtures. In the second approach, the indomethacin powders were mechanically dry coated (by mechanofusion) with force control agents (such as magnesium and sodium stearate). Mathematical modelling approaches were explored using multi-exponential and mechanism-based models in order to gain an insight into the de-agglomeration and dissolution mechanisms. Dissolution of the various mixtures and coated powders of indomethacin was conducted with an automated dissolution apparatus (Erweka DT6, Germany) using the USP paddle method in buffered media at pH 5.0 under sink conditions. Dissolution data were modelled with multi-exponential equations via the standard-two-stage (STS) estimation method and mechanism-based models were developed by population estimation methods in S-ADAPT. Particle size distributions of the raw materials, interactive mixtures and coated powders were measured by laser diffraction using the Mastersizer S (Malvern Instruments Ltd., UK). The dispersion of indomethacin mixtures was measured by laser diffraction in dissolution media under non-sink conditions. The addition of cohesive aluminium hydroxide and calcium phosphate (10% each) to binary lactose-based interactive mixtures of 10% indomethacin was found to counter-intuitively and significantly increase the dissolution rate of indomethacin. The improvements in dissolution for these ternary mixtures were unrelated to pH effects but associated with the ability of the poorly water-soluble excipients to facilitate the de-agglomeration of indomethacin agglomerates. Multi-exponential modelling revealed increases in the estimated initial concentration (Cd) and dissolution rate constant (kd) of dispersed indomethacin particles upon addition of the cohesive additives to the binary mixtures. Dissolution of indomethacin was found to increase as a function of the concentration of aluminium hydroxide (5-20%) added to the binary mixtures. Where three particle size fractions of aluminium hydroxide (with significantly different D90 sizes) were used, increasing the proportion of larger particles of the aluminium hydroxide increased the dissolution rate of indomethacin. Modelling revealed increases in the kd for the ternary 5-20% aluminium hydroxide mixtures compared with the binary mixture, indicating larger exposed surface areas of dispersed indomethacin particles to the dissolution medium; Cd increased with both the concentration and particle size of the added aluminium hydroxide to the mixtures. Monitoring the extent of particle dispersion over time in dissolution media under non-sink conditions demonstrated an increasing trend in dispersion during the first 12 minutes for the ternary mixtures containing 5-15% aluminium hydroxide; however, no change in the degree of dispersion was observed for the mixture incorporating micronized aluminium hydroxide particles. The underlying mechanisms of dissolution were elucidated and quantified by development of a mechanism-based compartmental model. A series of 5 transit compartments included into the model successfully described the slow initial dissolution rate of the indomethacin mixtures. More importantly, this indicated that agglomerates had inter-converted to dispersed particles; the mean dissolution time of the dispersed particles decreased with the addition of aluminium hydroxide to the binary mixtures. For the ternary mixtures incorporating at least 10% aluminium hydroxide, the faster dissolution was attributed to lower mean de-agglomeration times and reduced initial concentrations of agglomerates compared with the binary mixture. This supported the hypothesized phenomenon of the role of aluminium hydroxide in enhancing the de-agglomeration of cohesive indomethacin powders. Dry coating micronized powders of indomethacin with magnesium stearate (0.25, 1, 5%) and sodium stearate (5%) by mechanofusion resulted in significantly reduced intrinsic cohesion. Initial increases in the dissolution of indomethacin were found to be dependent on the concentration of magnesium stearate that was mechanofused onto the drug powders; X-ray photoelectron spectroscopy analysis confirmed a thicker surface coating was achieved with increasing concentrations of the hydrophobic material. The dissolution enhancing effect of the indomethacin powders mechanofused with 5% sodium stearate was attributed to its surfactant properties that increased the dispersion of indomethacin agglomerates. Initial drug release (during the first 10 minutes of the dissolution study) from the coated powders was able to be described by a matrix-diffusion system in accordance with the Higuchi model. Application of these novel and innovative formulation strategies which demonstrated enhanced dissolution of indomethacin would greatly benefit in the development of poorly water-soluble drug formulations with potentially improved oral bioavailability.