Defining Critical Material Attributes of Micronised Lactose in Dry Powder Inhaler Formulations

Harsimran Singh Bansal, Gerald Hebbink, Jagdeep Shur, Robert Price

Several studies have shown that the amount of fine lactose particles in dry powder inhaler (DPI) formulations is a key performance indicator of DPI drug product performance[1-4]. The use of micronised lactose is however limited because of thermodynamic and chemical instability issues as a result of process-induced structural disorder upon micronisation. This disorder is present at the materials’ surface in the form of thermodynamically unstable amorphous regions which undergo relaxation post micronisation.

Investigations in relaxation of micronised lactose via conditioning at 20°C/70%RH at various time points are presented in this study. Physico-chemical changes were observed using cohesive-adhesive balance, isothermal perfusion calorimetry and particle size distribution measurements. The d10, d50, d90 and volume mean distribution (VMD) measurements increased with conditioning time. Perfusion calorimetry suggested a decrease in surface disorder through enthalpy of recrystallisation measurements decreasing with conditioning time. Force microscopy shows decreasing interfacial tensions between specific particles upon conditioning and agglomeration behavioural tendencies both in and out of formulation.

Furthermore, in-vitro aerodynamic performance studies of specific formulations were studied using a next generation impactor. The conditioning of lactose fines affected the aerodynamic particle size distribution and mass mean aerodynamic diameter (MMAD) of the drug. Relationships between lactose conditioning time and specific aerodynamic diameters of a nominal drug were seen. Specifically, the relationship between VMD and MMAD shows how drug adheres to lactose to directly influence formulation performance. This relationship clearly shows that fines play a key role in shaping formulation structure thus enhancing performance of orally inhaled drug products

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