Applicability boundaries and method-selection strategies for the CMC determination of pharmaceutical surfactants

The Critical Micelle Concentration (CMC) is a crucial Functionality-Related Characteristic (FRC) for pharmaceutical surfactants, fundamentally determining solubilization and thermodynamic stability in formulation design-an indicator increasingly emphasized by global pharmacopoeias. However, a distinct regulatory gap persists: major compendia, including the Chinese Pharmacopoeia (ChP), the United States Pharmacopeia (USP), and the European Pharmacopoeia (EP), currently lack explicit, practical methods for CMC determination. Because different measurement techniques rely on distinct physical principles, they are highly susceptible to environmental factors, leading to significant discrepancies in measurement results. To systematically bridge this methodological gap, this study optimized three mainstream testing techniques for pharmaceutical surfactants across various structural types. These methods were meticulously developed based on practical measurement processes and statistical theory, thereby ensuring their applicability and reliability. Through comparative analysis, we identified the most suitable measurement methods for different categories of pharmaceutical excipients. Importantly, we systematically identified the factors that significantly influence the results of CMC measurement. Ultimately, this study establishes a structure-guided methodological decision framework comprising class-specific method-selection framework for CMC measurement within defined applicability boundaries, thereby providing a practical basis for the quality evaluation of pharmaceutical surfactants and the future development of functionality-related compendial specifications.