In vitro dry powder inhaler formulation performance considerations.

It has long been desired to match airflow conditions during formulation evaluation to those of relevance to lung deposition. In this context several strategies have been adopted involving sampling at different: flow rate (without consideration of flow conditions, e.g. shear, Reynolds number, work function); pressure drop (with and without consideration of flow conditions) and; flow rate and pressure drop. Performance testing has focused on the influence of these sampling conditions on delivered dose uniformity and aerodynamic particle size distribution. However, in order to be physiologically relevant it is also important to know when the drug was delivered with respect to initiation of airflow as variation in this parameter would influence lung deposition. A light obscuration method of detecting the dose delivered from a dry powder inhaler while sampling for aerodynamic particle size distributions (APSD) by inertial impaction has been developed. Four formulations of albuterol sulfate and budesonide in sieved and milled lactose, respectively, were dispersed and their rate of delivery monitored. The differences observed have the potential to impact the site of delivery in the lungs. The rate of delivery of drug is clearly an important companion measurement to delivered dose and APSD if the intent is to predict the similarity of in vivo performance of dry powder inhaler products.

Determination of low levels of amorphous content in inhalation grade lactose by moisture sorption isotherms.

Alpha-lactose monohydrate is widely used as an excipient in dry powder inhalers, and plays a very important role in the efficiency of the drug delivery. Due to the processing, low levels of amorphous lactose could be present in the blends. Varying amounts could have a strong effect on the efficiency of drug delivery of the powder blends. Therefore, the accurate measurement of low levels of amorphous lactose content is very important. A new method was developed to measure the amorphous content, based on dynamic vapour sorption (DVS). In contrast to the traditional re-crystallization approach of amorphous lactose, the new method is based on moisture sorption isotherms. Moisture sorption isotherms of blends of crystalline alpha-lactose and freeze-dried or spray-dried amorphous lactose were measured. By fitting the data with a Brunauer, Emmett, and Teller (BET) isotherm, a linear correlation was found between measured and actual amorphous content for the whole range of 0.1-100%. Differences between freeze-dried and spray-dried lactose, due to different molecular arrangements, could be removed by a preconditioning the samples at 35% RH prior to the isotherm measurement. It was shown that accurate determination of very low concentrations of amorphous lactose content is possible using moisture sorption isotherm analyses.