Lubricant based determination of design space for continuously manufactured high dose paracetamol tablets.

The objective of this study was to devise robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication-based parameters influencing the continuous direct compression tableting of high dose paracetamol tablets. Experimental design was used to generate a structured study plan which involved 19 runs. The formulation variables studied were the type of lubricant (magnesium stearate or stearic acid) and its concentration (0.5, 1.0 and 1.5%). Process variables were total production feed rate (5, 10.5 and 16kg/h), mixer speed rpm (500, 850 and 1200rpm), and mixer inlet port for lubricant (A or B). The continuous direct compression tableting line consisted of loss-in-weight feeders, a continuous mixer and a tablet press. The Quality Target Product Profile (QTPP) was defined for the final product, as the flowability of powder blends (2.5s), tablet strength (147N), dissolution in 2.5min (90%) and ejection force (425N). A design space was identified which fulfilled all the requirements of QTPP. The type and concentration of lubricant exerted the greatest influence on the design space. For example, stearic acid increased the tablet strength. Interestingly, the studied process parameters had only a very minor effect on the quality of the final product and the design space. It is concluded that the continuous direct compression tableting process itself is insensitive and can cope with changes in lubrication, whereas formulation parameters exert a major influence on the end product quality.