Self-organizing Map Analysis for Understanding Comprehensive Relationships between Formulation Variables, State of Water, and the Physical Stability of Pharmaceutical Emulsions

Abstract

The physical stability of pharmaceutical emulsions is an important quality attribute to be considered. To obtain a better understanding of this issue, this study investigated the contribution of the state of water to the physical stability of pharmaceutical emulsions. The key technology to evaluate the state of water was magnetic resonance imaging (MRI). For sample preparation, model emulsions with different formulation variables (surfactant content, water content, and hydrophilic-lipophilic balance) were prepared. The T 1 relaxation time, diffusion coefficient, and viscosity were measured as physical properties. The physical stability of the samples was evaluated using apparent diffusion coefficient maps acquired by MRI. Data analysis of the observed data was performed using the nonlinear response surface method and Kohonen's self-organizing map (SOM). It was determined that, depending on the formulation variables, the state of water was substantially changed and it played a significant role in the physical stability. SOM analysis successfully classified the conditions of formulation variables into four distinct clusters in terms of the similarity of the physical properties of the resultant emulsions, and then clarified the characteristics of the stable emulsions. This study provided us with a comprehensive understanding of the formulation variables, physical properties, and stability concerning the preparation of the model emulsion.Key words pharmaceutical emulsion; magnetic resonance imaging; physical stability; T 1 relaxation time; diffusion coefficient Oil-in-water type emulsions are widely used for various semisolid topical dosage forms. Pharmaceutical emulsions are less greasy than ointments, they are easier to apply and can be easily washed off from the skin surface; thus, they are highly acceptable to patients. 1) For the development of pharmaceutical emulsions, physical stability is a very important quality attribute to be considered. This is because emulsions are thermodynamically unstable by nature. In general, the destabilization processes of emulsions are classified into four distinct processes: creaming, flocculation, coalescence, and Ostwald ripening.1) Coalescence and Ostwald ripening are the most serious types of destabilization, whereas creaming and flocculation are subtle destabilization processes.We have been investigating the physical stability of pharmaceutical emulsions using magnetic resonance imaging (MRI).2-4) MRI is one of the most popular molecular imaging methods; it permits the nondestructive monitoring of a sample using the principle of nuclear magnetic resonance (NMR). In addition, MRI can visualize the state of water in a sample by using magnetic resonance (MR) parameters. In a previous study, we established a new method to monitor destabilization processes of pharmaceutical emulsions.4) The key technology is the visualization of the state of water. Water in pharmaceutical emulsions can exist in various states depending on its particular location and microenvironment.2) Once cre...

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