Phase Behavior of Drug–Lipid–Surfactant Ternary Systems toward Understanding the Annealing-Induced Change

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The present study systematically investigates the effect of annealing conditions and the Kolliphor P 407 content on the physicochemical and structural properties of Compritol (glyceryl behenate) and ternary systems prepared via melt cooling (Kolliphor P 407, Compritol, and a hydrophilic API) representing solid–lipid formulations. The physical properties of Compritol and the ternary systems with varying ratios of Compritol and Kolliphor P 407 were characterized using differential scanning calorimetry (DSC), small- and wide-angle X-ray scattering (SWAXS) and infrared (IR) spectroscopy, and hot-stage microscopy (HSM), before and after annealing. The change in the chemical profiles of different Compritol components as a function of annealing was evaluated using 1 H NMR spectroscopy. While no change in the polymorphic form of API and Kolliphor P 407 occurred during annealing, a systematic conversion of the α- to β-form was observed in the case of Compritol. Furthermore, the polymorphic transformation of Compritol was found to be dependent on the Kolliphor P 407 content. As per the Flory–Huggins mixing theory, higher miscibility was observed in the case of monobehenin–Kolliphor P 407, monobehenin–dibehenin, and dibehenin–tribehenin binary mixtures. The miscibility of Kolliphor P 407 with monobehenin and 1,2-dibehenin was confirmed by 1 H NMR analysis. The observed higher miscibility of Kolliphor P 407 with monobehenin and 1,2-dibehenin is proposed as the trigger for the physical separation from the 1,3-diglyceride and triglycerides during melt solidification of the formulations. The phase separation is postulated as the mechanism underlying the formation of a stable β-polymorphic form (a native form of 1,3-diglyceride) of Compritol upon annealing. This finding is expected to have an important implication for developing stable solid–lipid–surfactant-based drug formulations.

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