Polymeric micelles are potentially efficient in encapsulating and performing the controlled release of various hydrophobic drug molecules. Understanding the fundamental physicochemical properties behind drug–polymer systems in terms of interaction strength and compatibility, drug partition coefficient (preferential solubilization), micelle size, morphology, etc., encourages the formulation of polymeric nanocarriers with enhanced drug encapsulating capacity, prolonged circulation time, and stability in the human body. In this review, we systematically address some open issues which are considered to be obstacles inhibiting the commercial availability of polymer-based therapeutics, such as the enhancement of encapsulation capacity by finding better drug–polymer compatibility, the drug-release kinetics and mechanisms under chemical and mechanical conditions simulating to physiological conditions, and the role of preparation methods and solvents on the overall performance of micelles.

In the current paper, and for the first time, spectrophotometry coupled with a set of factorial designs was executed as a new tool for investigating the interaction between p-synephrine (p-SY) and p-chloranil (p-CHL). Two types of complexes were observed as a result of this interaction. The first complex, an intermolecular charge transfer complex, was measured at 452 nm, while the second, an intramolecular charge transfer complex, was measured at 536 nm. A chemometric assisted screening and optimization of the absorbance at the two wavelengths was scrutinized. As a screening procedure, a 2-level full factorial design (2^k-FFD) was employed. Method variables, such as reaction temperature, heating time, reagent volume, and solvent type were considered and the response was measured at the individual wavelengths. With the help of Pareto analysis, and ANOVA testing (following a response transformation employing Box–Cox treatment), variables ascertained to be significant (p < 0.05) were selected. Significant factors were carefully adjusted, exploiting a response surface methodology (RSM) with a face-centered central composite design (FCCCD). Afterwards, and with the help of the overlaid contour plots, and Derringer's desirability function, the multiple responses (Y₁ and Y₂) were simultaneously optimized and consolidated into a unified performance characteristic. The proposed model denoted the efficacy of experimental designs in adjusting the reaction variables and maximizing the output. Scott's plot, and other models were used to determine the formation constant of a 1 : 1 complex. Validation of the proposed procedure was performed using ANOVA. Linearity, detection and quantification limits as well as accuracy, within-day and intermediate precisions have been assessed following ICH guidelines for evaluation of analytical procedures.