期刊
MOLECULAR PHARMACEUTICS
卷 19, 期 2, 页码 532-546出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.1c00651
关键词
annealing; lipid polymorphism; thermal miscibility; lipid-surfactant phase behavior; Compritol ATO 888; Kolliphor P 407; H-1 qNMR; BCS Class III API
This study systematically investigated the effect of annealing conditions and Kolliphor P 407 content on the physicochemical and structural properties of solid-lipid formulations. The researchers found that the polymorphic transformation of Compritol was dependent on the Kolliphor P 407 content and identified higher miscibility in certain binary mixtures. The observed higher miscibility of Kolliphor P 407 with specific components was proposed as the trigger for physical separation during melt solidification, with phase separation underlying the formation of a stable beta-polymorphic form of Compritol upon annealing.
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 H-1 NMR spectroscopy. While no change in the polymorphic form of API and Kolliphor P 407 occurred during annealing, a systematic conversion of the alpha- to beta-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 H-1 NMR analysis. The observed higher miscibility of Kolliphor P 407 with monobehenin and 1,2dibehenin 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 beta-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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