Prediction of compressibility of pharmaceutical excipients in solid oral dosage forms

Abstract

Tablets are one of the most preferred dosage forms for patients, but pre-formulation studies for tablets are often time consuming and expensive. The SeDeM Expert Diagram System attempts to address this problem by decreasing the amount of experiments required to develop an acceptable direct compression tablet formulation. This is done by processing and interpreting data obtained from known techniques already widely in use in the pharmaceutical industry to characterise active pharmaceutical ingredients (API’s) and excipients. In this study, the prediction ability of the SeDeM Expert Diagram System with a special focus on testing the limits of the system was investigated. Three different API’s with different direct compression properties (i.e. paracetamol, furosemide and pyridoxine) as well as seven excipients representing different classes and types of widely used direct compression excipients (i.e. Tablettose® 80, FlowLac® 100, Avicel® PH200, Emcompress®, Cellactose® 80, MicroceLac® 100 and StarLac®) were selected and characterised by applying the SeDeM Expert Diagram System. Predicted formulations were tableted and evaluated according to the set criteria. If a tablet formulation failed to meet the criteria, the ratio of excipient to API was increased in 5 % w/w increments until a successful formulation was obtained, whereas the reverse was applied if a formulation was successful to determine failure point. The SeDeM Expert Diagram System proved to be proficient at predicting acceptable tablet formulations, with a few exceptions. This was specifically the case where paracetamol and furosemide were concerned as well as some excipients. While SeDeM predicted that paracetamol would only be able to deliver acceptable tablets with three excipients (i.e. FlowLac® 100, Avicel® PH200 and StarLac®), all the selected excipients were in fact able to create acceptable direct compression tablets. When all the paracetamol formulations were considered, tablet failure most often occurred due to capping. However, the reason for failure of the novel direct-compression excipients (i.e. Cellactose® 80, MicroceLac® 100 and StarLac®) was due to problems other than capping. In the case of furosemide, the limits of five parameters were not met, including particle size limits, powder flow as well as the cohesion index. The SeDeM System was unable to successfully predict any furosemide direct-compression tablet formulations because the powder mixtures exhibited poor powder flow properties. This can be explained by the fact that furosemide has very small particles, which coated the excipient particle surfaces and thereby formed interactive powder mixtures, which was confirmed with the use of SEM microscopy. SeDeM was able to correctly predict five of the seven selected excipients for successful directcompression tablet formulations for pyridoxine within an acceptable margin of error. Only two excipients (Emcompress® and Cellactose® 80) performed better than expected by the SeDeM System. From the results of this study it is evident that certain physicochemical properties of API’s such as elasticity and cohesive behaviour are not compensated for or compensated for sufficiently by the SeDeM System. Furthermore, some novel direct-compression excipients (e.g. co-processed excipients) proved to exceed the SeDeM Expert Diagram Systems’ expectations and predictions to correct for API failure to produce direct compressible tablets