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

Varun Kushwah; Diogo Gomes Lopes; Isha Saraf; Ioannis Koutsamanis; Bernd Werner; Klaus Zangger; Michael C Roy; Jeremy A Bartlett; Heather Frericks Schmidt; Sheri L Shamblin; Peter Laggner; Amrit Paudel

doi:10.1021/acs.molpharmaceut.1c00651

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

Mol Pharm. 2022 Feb 7;19(2):532-546. doi: 10.1021/acs.molpharmaceut.1c00651. Epub 2021 Dec 27.

Affiliations

¹ Research Centre for Pharmaceutical Engineering, Inffeldgasse 13/2, 8010 Graz, Austria.
² Institute of Chemistry, University of Graz, Heinrichstr. 28, 8010 Graz, Austria.
³ Drug Product Design, Worldwide Research and Development, Pfizer Inc, 280 Shennecossett Rd, Groton, Connecticut 06340, United States.
⁴ Institute for Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13/3, 8010 Graz, Austria.

PMID: 34958588
DOI: 10.1021/acs.molpharmaceut.1c00651

Abstract

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 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.

Keywords: 1H qNMR; BCS Class III API; Compritol ATO 888; Kolliphor P 407; annealing; lipid polymorphism; lipid-surfactant phase behavior; thermal miscibility.

MeSH terms

Calorimetry, Differential Scanning
Drug Compounding
Excipients* / chemistry
Phase Transition
Solubility
Surface-Active Agents* / chemistry

Substances

Excipients
Surface-Active Agents