Effect of Compression on the Molecular Arrangement of Itraconazole-Soluplus Solid Dispersions: Induction of Liquid Crystals or Exacerbation of Phase Separation?
Predensification and compression are unit operations imperative to the manufacture of tablets and capsules. Such stress-inducing steps can cause destabilization of solid dispersions which can alter their molecular arrangement and ultimately affect dissolution rate and bioavailability. In this study, itraconazole-Soluplus solid dispersions with 50% (w/w) drug loading prepared by hot-melt extrusion (HME) were investigated. Compression was performed at both pharmaceutically relevant and extreme compression pressures and dwell times. The starting materials, powder, and compressed solid dispersions were analyzed using modulated differential scanning calorimetry (MDSC), X-ray diffraction (XRD), small- and wide-angle X-ray scattering (SWAXS), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and broadband dielectric spectroscopy (BDS). MDSC analysis revealed that compression promotes phase separation of solid dispersions as indicated by an increase in glass transition width, occurrence of a peak in the nonreversing heat flow signal, and an increase in the net heat of fusion indicating crystallinity in the systems. SWAXS analysis ruled out the presence of mesophases. BDS measurements elucidated an increase in the Soluplus-rich regions of the solid dispersion upon compression. FTIR indicated changes in the spatiotemporal architecture of the solid dispersions mediated via disruption in hydrogen bonding and ultimately altered dynamics. These changes can have significant consequences on the final stability and performance of the solid dispersions.
Drug Delivery and Disposition, KU Leuven , Leuven, Belgium.
Abhishek
A
Singh
Soft Matter, Rheology and Technology, Department of Chemical Engineering, KU Leuven , Leuven, Belgium.
Avanish
A
Bharati
Drug Delivery and Disposition, KU Leuven , Leuven, Belgium.
Pauline
P
Frederiks
Polymer Chemistry and Materials, Department of Chemistry, KU Leuven , Leuven, Belgium.
Olivier
O
Verkinderen
Polymer Chemistry and Materials, Department of Chemistry, KU Leuven , Leuven, Belgium.
Bart
B
Goderis
Soft Matter, Rheology and Technology, Department of Chemical Engineering, KU Leuven , Leuven, Belgium.|Polymer Technology, Department of Mechanical Engineering, TU Eindhoven , Eindhoven, The Netherlands.
Ruth
R
Cardinaels
Soft Matter, Rheology and Technology, Department of Chemical Engineering, KU Leuven , Leuven, Belgium.
Paula
P
Moldenaers
Department of Metallurgy and Materials Engineering, KU Leuven , Leuven, Belgium.
Jan
J
Van Humbeeck
Drug Delivery and Disposition, KU Leuven , Leuven, Belgium.
Guy
G
Van den Mooter
D001682:Biological Availability; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004339:Drug Compounding / Q000379:methods; D017964:Itraconazole / Q000737:chemistry*; D050866:Liquid Crystals / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry*; D011208:Powders / Q000737:chemistry; D011312:Pressure; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D013607:Tablets / Q000737:chemistry*; D014961:X-Ray Diffraction / Q000379:methods
D011145:Polyvinyls; D011208:Powders; D013607:Tablets; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D017964:Itraconazole; D011092:Polyethylene Glycols
FTIR; Soluplus; broadband dielectric spectroscopy; compression; itraconazole; liquid crystals; molecular mobility; small-angle X-ray scattering; solid dispersions; tablets