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

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 1H 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 ß-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 1H 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 ß-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.

Novel approach for overcoming the stability challenges of lipid-based excipients. Part 2: Application of polyglycerol esters of fatty acids as hot melt coating excipients.

The application of hot melt coating (HMC) as an economic and solvent-free technology is restricted in pharmaceutical development, due to the instable solid-state of HMC excipients resulting in drug release instability. We have previously introduced polyglycerol esters of fatty acids (PGFAs) with stable solid-state (Part 1). In this work we showed a novel application of PGFAs as HMC excipients with stable performance. Three PGFA compounds with a HLB range of 5.1-6.2 were selected for developing immediate-release formulations. The HMC properties were investigated. The viscosity of molten lipids at 100 °C was suitable for atomizing. The DSC data showed the absence of low solidification fractions, thus reduced risk of agglomeration during the coating process. The driving force for crystallization of selected compounds was lower and the heat flow exotherms were broader compared to conventional HMC formulations, indicating a lower energy barrier for nucleation and lower crystallization rate. Lower spray rates and a process temperature close to solidification temperature were desired to provide homogeneous coating. DSC and X-ray diffraction data revealed stable solid state during 6 months storage at 40 °C. API release was directly proportional to HLB and indirectly proportional to crystalline network density and was stable during investigated 3 months. Cytotoxicity was assessed by dehydrogenase activity and no in vitro cytotoxic effect was observed.