Using metformin HCl as the model drug and hydroxypropylcellulose (HPC) as the polymeric excipient, a melt granulation (MG) process that employs a twin-screw extruder has been developed to enhance compactibility of poorly compactible high-dose drug substances. A high (90%) drug-load tablet formulation, containing 1025 mg of active pharmaceutical ingredients and 109 mg of excipients, was produced. Drug-polymer-powder mixtures were melt granulated at a temperature above glass transition of HPC (130°C) but below melting point of metformin HCl (224°C). MG was compared with modified wet granulation (WG) and solvent granulation (SG) processes. Under identical compression force, the hardness of tablets produced was MG>SG>WG and the friability was MG<SG<WG. The hardness of WG tablets was highly sensitive to moisture content both during compression and subsequent storage, and, although not to the same extent, the hardness of SG tablets was also affected by loss-on-drying levels. MG provided a robust manufacturing process with highest compactibility and lowest friability that were not sensitive to changes in atmospheric moisture level. The process can decrease tablet sizes of high-dose drugs and combination products by decreasing the need for relatively large amounts of excipients generally used to overcome physicochemical limitations of drug substances. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1553-1565, 2011.
Keywords: extrusion; formulation; granulation; solid dosage form; tableting; water in solids.
Copyright © 2010 Wiley-Liss, Inc.