(W1130-10-56) Mechanistic Evaluation of Microstructure and Performance Attributes of Medicated Topical Shampoos

Purpose: Medicated topical foams and shampoos are described as thermodynamically and mechanically unstable dispersions of gas in liquid containing surfactants and are characterized by a vast interface, which tends to shrink through foam drainage at the air-liquid interface due to the breakdown of bubbles.¹ Surfactants are a dispersant component allowing for better accommodation of an active pharmaceutical ingredient (API) in both ionic and non-ionic friendly components of skin and hair. The local and systemic availability of the API from foam or shampoo products may vary depending on how the foam is generated, microstructure attained after actuation, stability and decay kinetics, residual formulation attributes after breakdown, physicochemical characteristics of drug substance and complexity of inactive ingredients contributing to the arrangement of matter.² It is essential to understand the performance attributes of topical foam and shampoo formulations and identify appropriate sensitive and discriminating characterization techniques that can be used to understand their microstructure. Additionally, there is an unmet research need to understand the relationship between microstructure and performance of foams following application to skin. Accordingly, this study aimed at evaluating and identifying appropriate characterization techniques and tools for assessing the critical performance attributes of complex foam formulations using ketoconazole shampoos as model products.

Methods: Nizoral (ketoconazole) topical shampoo, 1% was used as the model shampoo for the study. Foam height and foam structure of the shampoo were simultaneously analyzed using dynamic analysis of foam structure (Krüss Dynamic Foam Analyzer, DFA100) over 15 minutes at 22°C. Foam height was measured using the differences in measured light intensity values when LED light is allowed to pass through the foam and liquid solution. Foam structure was measured using the total reflection of light from the LED illumination unit through prism glass column to a high-resolution camera. In each experiment, a variety of foam height and foam structure parameters were evaluated using foam height and structure measurements. Maximum foam height/volume, initial bubble count per mm² and initial average bubble radius were determined to describe the foamability, while drainage half-life time and bubble count half-life time were determined to describe the foam stability. These parameters were evaluated over 3 dilutions (1:25 v/v, 1:50 v/v, 1:100 v/v), sparging rates (0.20 L/min, 0.35 L/min, 0.50 L/min) and sparging times (30 seconds, 60 seconds, and 90 seconds).  Each experiment was triplicated, and data are presented as average ± SD (standard deviation).

Results: Diluting the shampoo with water at 1:25 v/v, 1:50 v/v, or 1:100 v/v did not significantly affect the maximum height of 130 mm attained by foams. On the contrary, diluting the shampoo at 1:100 v/v resulted in faster rate of foam decay as observed by a 70% decrease in foam height as well as changes in foam structure. Therefore, a dilution of the shampoo at 1:50 v/v was used in further investigations. Increasing the sparging rate for foaming from 0.2 L/min to 0.5 L/min resulted in a two-fold increase in maximum foam height/volume and initial average bubble radius and a two-fold decrease in initial bubble count per mm². Sparging rate and time affected the stability of the foams produced as observed by changes in the foam decay parameters. For example, increasing the sparging rate from 0.2 L/min to 0.5 L/min and sparging time from 15 seconds to 60 seconds produced a gradual increase in drainage half-life time by two-folds, and a gradual increase in half-life time of bubble count by two-folds. These changes in foam structure demonstrated that parameters such as sparging rate and time enhances foamability and foam stability of the shampoo solution upon dilution. Therefore, these foaming and foam decay test conditions should be optimized to develop characterization-based methods for topical foam products.

Conclusion: Foamability and foam stability are critical performance attributes of foam formulations. These attributes could be evaluated by assessment of microstructure parameters using standardized and optimized dynamic characterization methods in terms of dilution percent, sparging rate and time. The foam height- and structure-driven characteristics may be useful in comparison of different foam formulations.

References: 1. Guidance for Industry: Safety of Nanomaterials in Cosmetic Products, Docket Number: FDA-2011-D-0489, June 2014, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-safety-nanomaterials-cosmetic-products#IIIB1a
2. Xerova, D., Khristov, K.H.R., Penev, I., 1976. Some techniques for the investigation of foam stability. In: Akers, R.J. (Ed.), Foams, Proceedings of a Symposium organized by the Society of Chemical Industry, Colloid and Surface Chemistry Group, and held at Brunel University, Academic Press, London, pp. 109–127.

Acknowledgements: This project is supported by the CORES pathway of the Office of the Chief Scientist and in part by an appointment (Ishanka Liyanage) to the Research Participation Program at the FDA Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. The views expressed in this poster abstract do not reflect the official policies of the U.S. FDA or the U.S. Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the U.S. Government.

Figure 1: (A) Representative foam height over time plots at three sparging rates (SR) of 0.2 L/min, 0.35 L/min and 0.50 L/min and (B) effect of sparging time on bubble count half-life (average of three) using 1:50 v/v dilution of model ketoconazole topical shampoo, 1%.