Abstract

Purpose: Various methods of analyzing foam stability have been reported in the literature (foam wetting test, height test, and rheological measurements) providing semi-quantitative information which can be useful in characterizing and selecting a formulation. However, many of them present high variability due to the subjective determination of the initial and ending points of this dynamic phenomenon. Therefore, a reliable and more detailed screening technique is required to study the impact of formulation or devices on the foam stability. We developed a reproducible, relatively inexpensive and non-user dependent alternative method capable of analyzing the complete collapsing foam process under temperature controlled conditions, similar to in vivo use. Methods: Two nasal foam formulations were compared using the shadow motion analysis (SMA) method to assess the foam stability at room temperature as well as at 34oC (temperature of the nasal cavity). To test the capability of the method to differentiate between formulations, two different types of surfactant were used to assist the generation of the foam (polysorbate 80 or poloxamer 407 ). The propellant (HFA134a) was kept constant. The SMA setup includes a stage that provides support to hold and actuate the canisters from a fixed height onto a polystyrene disc. After the emitted foam hits the stage, the sample is illuminated by a light source projecting a shadow onto a flat surface that holds a sheet of white paper. The paper has markers used as reference points to correct and scale the images during the image analysis. Then, the projected shadow of the foam is recorded by a camera located behind the paper sheet. This camera is positioned inside a box to avoid direct exposure to any other source of light that may decrease the quality of the image. To simulate the nasal cavity environment, the stage which received the foam was heated in advance by using heating tape located underneath the stand. The temperature of the heating tape was adjusted using a pulsed width modulation controller connected to a 12v DC transformer. The final temperature was continuously monitored using a thermocouple connected to the sample holder. Image processing was performed using ImageJ to decompose the videos to image stacks. The processed images include the frames where the projected shadow reach their maximum area until the end of the area change. Firstly, the image stacks from each foam actuation were converted into binary format to facilitate the boundary recognition of the shadow. Further treatment of the images was kept consistent across all experiments. The area analysis was then performed using ImageJ to determine the change in area of the foam shadow over time. The resulting areas were subtracted from the baseline area, before foam actuation, to remove the area generated by the foam stand. The resulting areas were plotted against time and fit to an exponential curve (Matlab R2015b), and the half-life of the foam was calculated based on the first order rate constant. Statistic significances differences were assessed using a student’s t-test. Results: Image analysis of the foam area of the polysorbate 80 based foam at room temperature resulted in a half-life of 10.65 ± 0.78 seconds (mean +- standard deviation) (n=5).This was found to be significantly different from that found for the poloxamer 407 based foam (7.19 seconds +- 1.3, p = 0.0018). The half-lives for the polysorbate 80 and poloxamer 407 foams at 34oC were found to be 8.73 +-0.59 s and 7.95 +- 1.26 s respectively. Interestingly, we were unable to detect a significant difference between the two different formulations at the increased temperature. While the collapse of the polysorbate 80 foam significantly decreased with an increase in temperature, the collapse of the poloxamer 407 foam marginally increased. Conclusions: Image analysis techniques allow for a relatively rapid and inexpensive method to measure foam collapse dynamic phenomenon. Additionally, SMA method opens up possibilities of making pharmaceutical foam collapse studies better reflect in vivo conditions. In the instance of testing polysorbate 80 and poloxamer based foams at room temperature and at elevated temperature, they were significantly different at room temperature, but were not found to be different at the elevated temperature. Therefore, temperature was determined to be an important factor not considered in other techniques, which produced significant effects on the collapse half-life. SMA method has proven to be reproducible and capable of differentiating formulations, analyzing the dynamic process instead of the stationary initial-end approachinitial to endpoint approaches used in the past. Thus, SMA is a promising method that may provide more realistic and comparable results to predict the final in vivo performance of nasal foam formulations.