title: Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions.
abstract: It has been technically challenging to specify the detailed molecular interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug-polymer interactions from a molecular perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and physical stability, was selected as a model system. The CLF-HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including ultraviolet-visible (UV-vis), infrared (IR), and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addition, multivariate analysis of spectra was applied to optimize the concentration of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was experimentally investigated from 2D1H-1H homonuclear double quantum NMR spectra by utilizing the ultrafast magic-angle spinning (MAS) technique. The molecular interaction pattern and the critical bonding structure in CLF-HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chemistry calculations. These high-resolution investigations provide critical structural information on active pharmaceutical ingredient-polymer interaction, which can be useful for rational selection of appropriate polymeric carriers, which are effective crystallization inhibitors for amorphous drugs.
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.|Formulation Sciences, Teva Pharmaceuticals , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Haichen
authors.initials: H
authors.lastname: Nie
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Mingtao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.|Global DMPK, Takeda Pharmaceutical Inc. , 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Leone
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , 789 South Limestone Street, Lexington, Kentucky 40536, United States.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Marsac
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Tonglei
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Byrn
mesh_terms: D002991:Clofazimine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry; D025341:Principal Component Analysis; D013055:Spectrophotometry, Infrared
chemical_list: D011108:Polymers; D008747:Methylcellulose; C053309:hydroxypropyl methylcellulose phthalate; D002991:Clofazimine
keywords: acid−base interaction; amorphous; drug−polymer interactions; principal components analysis; solid dispersion; solid-state NMR; ultrafast MAS