Feasibility study of high-loaded dosage form of 5-ASA by extrusion spheronisation

Purpose. 5-aminosalicylic acid (5-ASA) has demonstrated its potential to treat IBD (Inflammatory Bowel Disease). However, formulations available on the market are generally associated with a number of limitations, including poor patient acceptability due to the high daily dose required (2.4-4.6 g/day). A high-strength solid formulation containing more than 1 g 5-ASA would be attractive for once/twice daily administration, improving compliance. High density pellets for the formulation of multiple unit dosage forms are therefore sought. A systematic study of extrusion-spheronisation was performed to determine the formulation window for this material. Methods. Microcrystalline cellulose (MCC) was used as the primary extrusion aid. Colloidal grades of MCC containing carboxymethylcellulose were also investigated. The minimal water content required to give a plastic mass was established using centrifugation testing, supported by extrusion. This also indicated the upper limit of water addition. Ram extrusion of solid-liquid paste formulations through multi-holed square-ended dies was used to assess the extrudability of different formulations. Extrudates were spheronised using a benchtop spheronisation device (Caleva) and the quality of extrudates monitored via visual and automated shape analyses. Promising formulations were tested at a small (50 g) scale on an axial screen extruder based on a domestic mincer, and final testing performed on a pilot scale screen extruder (Nica). Results. A systematic study of 5-ASA/MCC formulations was performed. Chronic liquid phase migration was observed with several batches of commercial 5-ASA. This was demonstrated to be dependent on both the drug load and the extrusion aid type, and was identified as arising from the particle shape. This was confirmed by extruding calcium sulphate/MCC pastes, where the sulphate polymorph was selected to match the 5-ASA shape. A micronisation step was adjusted accordingly and the modified 5-ASA used in the final formulations. The impacts of pH on MCC behaviour, and inhibition of rubbery transition, were also investigated. Conclusion. The feasibility of an extrusion-spheronisation route to manufacture pellets with high 5-ASA loading (90 wt%) was demonstrated. The drug particle morphologhy was identified as the critical process parameter. A colloidal MCC grade, Avicel RC 591, was identified as a promising material for extrusion alongside 5-ASA.