Powder flow analysis: A simple method to indicate the ideal amount of lactose fines in DPI formulations
Many efforts have been made in the past to understand the function of lactose fines which are given as a ternary component to carrier-based dry powder inhaler formulations. It is undisputed that fines can significantly improve the performance of such formulations, but choosing the right amount of fines is a crucial point, because too high concentrations can have negative effects on the dispersion performance. The aim of this study was to indicate the optimal concentration of fines with a simple test method. For this purpose, mixtures with salbutamol sulfate and two different lactose carriers were prepared with a high shear mixer, measured with a FT4 powder rheometer and tested for fine particle delivery with two different inhaler devices. A correlation between the fluidization energy, measured with the aeration test set up, and the fine particle fractions (FPF) could be proven. This also applied for the aeration ratio, as well as the permeability of the powder samples. In addition, drug-free mixtures hardly differed in their rheological properties from mixtures containing the active pharmaceutical ingredient (API), which indicates that the method could be suitable for cost-saving screening trials. Furthermore, important aspects that explain the function of fines, such as the saturation of active sites, the formation of agglomerates and an increase in fluidization energy, could be shown in this study.
The study showed that the FPF increased with increasing amounts of fines, reached a maximum and dropped again or formed a plateau. With the help of the powder rheometer, it was possible to get an indication of the optimum proportion of fines for two very different lactose carriers tested with different devices. In this context a combination of aeration test and permeability test has proved to be useful. If the fluidization energy is in excess of 20 mJ and the permeability higher than 9 · 109 cm2, more fines can be added to the mixture. However, if the permeability is less than 9 · 109 cm2, it means that the maximum of the fluidization energy has been exceeded and less fines should be used. An additional consideration of the aeration ratio facilitates the inter- pretation of the results. Furthermore, important aspects that explain the function of fines, such as the saturation of active sites, the formation of agglomerates and an increase in fluidization energy, could be shown in this study. Also, the formation of a second phase of fine particles which explains the decrease in FPF with high concentrations of fines, was demonstrated. Powder rheology might be a suitable tool for DPI for- mulation screening, because the drug-free formulations did not differ in their properties in this study. This could reduce costs, considering no API is needed for the screening trials.