TY - JOUR
T1 - Phase Behavior of Drug-Lipid-Surfactant Ternary Systems toward Understanding the Annealing-Induced Change
AU - Kushwah, Varun
AU - Gomes Lopes, Diogo
AU - Saraf, Isha
AU - Koutsamanis, Ioannis
AU - Werner, Bernd
AU - Zangger, Klaus
AU - Roy, Michael C.
AU - Bartlett, Jeremy A.
AU - Frericks Schmidt, Heather
AU - Shamblin, Sheri L.
AU - Laggner, Peter
AU - Paudel, Amrit
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2022/2/7
Y1 - 2022/2/7
N2 - 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- A nd 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 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 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 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.
AB - 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- A nd 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 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 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 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.
KW - H qNMR
KW - annealing
KW - BCS Class III API
KW - Compritol ATO 888
KW - Kolliphor P 407
KW - lipid polymorphism
KW - lipid-surfactant phase behavior
KW - thermal miscibility
UR - http://www.scopus.com/inward/record.url?scp=85122568712&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.1c00651
DO - 10.1021/acs.molpharmaceut.1c00651
M3 - Article
AN - SCOPUS:85122568712
SN - 1543-8384
VL - 19
SP - 532
EP - 546
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 2
ER -