title: Investigating the Interaction Pattern and Structural Elements of a Drug-Polymer Complex at the Molecular Level.
abstract: Strong associations between drug and polymeric carriers are expected to contribute to higher drug loading capacities and better physical stability of amorphous solid dispersions. However, molecular details of the interaction patterns and underlying mechanisms are still unclear. In the present study, a series of amorphous solid dispersions of clofazimine (CLF), an antileprosy drug, were prepared with different polymers by applying the solvent evaporation method. When using hypromellose phthalate (HPMCP) as the carrier, the amorphous solid dispersion system exhibits not only superior drug loading capacity (63% w/w) but also color change due to strong drug-polymer association. In order to further explain these experimental observations, the interaction between CLF and HPMCP was investigated in a nonpolar volatile solvent system (chloroform) prior to forming the solid dispersion. We observed significant UV/vis and (1)H NMR spectral changes suggesting the protonation of CLF and formation of ion pairs between CLF and HPMCP in chloroform. Furthermore, nuclear Overhauser effect spectroscopy (NOESY) and diffusion order spectroscopy (DOSY) were employed to evaluate the strength of associations between drug and polymers, as well as the molecular mobility of CLF. Finally, by correlating the experimental values with quantum chemistry calculations, we demonstrate that the protonated CLF is binding to the carboxylate group of HPMCP as an ion pair and propose a possible structural model of the drug-polymer complex. Understanding the drug and carrier interaction patterns from a molecular perspective is critical for the rational design of new amorphous solid dispersions.
authors.affiliation: †Department of Industrial and Physical Pharmacy and ‡Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Haichen
authors.initials: H
authors.lastname: Nie
authors.affiliation: †Department of Industrial and Physical Pharmacy and ‡Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Huaping
authors.initials: H
authors.lastname: Mo
authors.affiliation: †Department of Industrial and Physical Pharmacy and ‡Department of Medicinal Chemistry and Molecular Pharmacology, 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 and ‡Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: †Department of Industrial and Physical Pharmacy and ‡Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Ke
authors.initials: K
authors.lastname: Fang
authors.affiliation: †Department of Industrial and Physical Pharmacy and ‡Department of Medicinal Chemistry and Molecular Pharmacology, 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 Industrial and Physical Pharmacy and ‡Department of Medicinal Chemistry and Molecular Pharmacology, 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 and ‡Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Byrn
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D002991:Clofazimine / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D007917:Leprostatic Agents / Q000737:chemistry; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D007917:Leprostatic Agents; D011108:Polymers; D012997:Solvents; D008747:Methylcellulose; C053309:hydroxypropyl methylcellulose phthalate; D002991:Clofazimine
keywords: amorphous solid dispersion; clofazimine; drug loading capacity; drug polymer interactions; ionic interaction; solution NMR