Rationale for Selection of Dissolution Media: Three Case Studies

The selection of media in dissolution method development can sometimes be an arbitrary decision. The case studies in this article give a practical rationale that should help in selecting media, especially surfactants. Three cases were studied: (1) the role of surfactants versus compound stability in the dissolution medium during dissolution method development, (2) the selection of a surfactant based on interactions between the dissolution medium and the drug substance, and (3) the selection of media based on formulation properties. In the first case study, the choice of surfactant in relation to solubility and physical stability of the drug substance is shown. The second revealed an unexpected synergy between polysorbate 20 (Tween) and acetic acid solution that caused an unusual increase in the dissolution rate compared with these media used separately. In the last case study, the medium was modified by addition of surfactant to reflect a change in the formulation. The selection of a dissolution medium should be based on drug substance and formulation characteristics as well as on interactions among components. INTRODUCTION The media typically used in dissolution studies include acidic solutions, buffers, surfactants, and surfactants with acid or buffers (1). Media with bile salts and other relevant physiologically based ingredients, sometimes called biorelevant media, can be used in regulatory tests, but typically are used as research tools or for in vitro–in vivo correlation studies (2). Surfactants are used in dissolution test methods to improve the solubility or wettability of a drug. Sometimes the decision to use a surfactant is based solely on the fact that it will facilitate drug dissolution and not on any further study. It is thus important to understand scientifically the interaction mechanisms between different types of surfactants and drug molecules as well as interactions with excipients. This understanding should guide the analyst in selecting the most appropriate media for methods that will be used in formulation development and drug product dissolution testing. Surfactants reduce solution and surface interfacial tension by replacing water molecules on the surface (3). Surfactant molecules include two distinct components, the head (hydrophilic area) and the tail (hydrophobic area). Surfactants can be classified as anionic (e.g., sodium lauryl sulfate [SLS], also known as sodium dodecyl sulfate [SDS]), cationic (e.g., cetyl trimethyl ammonium bromide [CTAB]), zwitterionic (e.g., alkyl betaine), or nonionic (e.g., Tween or Cremophor EL) (4), as shown in Figure 1. Surfactants exist as monomers at low concentration in solutions. Aggregation occurs with increasing concentration and results in the formation of micelles. The minimum concentration of a monomer at which micelles form is called critical micelle concentration (CMC). The stability of micelles is related to their CMC value: the lower the CMC value of a given surfactant, the more stable the micelles (5) (Table 1). In dissolution testing, the micelle of surfactant molecules mimics the bile acid aggregates in the small intestine; the surfactant facilitates the diffusion and transport of the free solute into the bulk medium. Since dissolution is a combined effect of solubility and diffusivity, the micelle size will have an effect on the dissolution rate of molecules when different surfactants are used. Micellar-driven drug solubilization occurs with an increase in the number of micelles when the surfactant concentration is higher than the CMC value (6). In fact, solubility enhancement is a function of surfactant concentration. This relationship generally can be found for different surfactants and different compounds (3, 7, 8). Micellar drug solubilization is affected by many factors: the nature of the surfactant and the drug substance (e.g., nonpolar molecules are solubilized in the micellar core, whereas those with intermediate polarity are distributed along the surfactant molecules in certain intermediate positions), temperature, pH, and ionic strength (3, 6). For ionic surfactants, the CMC values decrease and the micel*Corresponding author. e-mail: [email protected] dx.doi.org/10.14227/DT200313P6