title: Spectroscopic Investigation of the Formation and Disruption of Hydrogen Bonds in Pharmaceutical Semicrystalline Dispersions.
abstract: We recently found that indomethacin (IMC) can effectively act as a powerful crystallization inhibitor for polyethylene glycol 6000 (PEG) despite the fact that the absence of interactions between the drug and the carrier in the solid state was reported in the literature. However, in the present study, we investigate the possibility of drug-carrier interactions in the liquid state to explain the polymer crystallization inhibition effect of IMC. We also aim to discover other potential PEG crystallization inhibitors. Drug-carrier interactions in both liquid and solid state are characterized by variable temperature Fourier transform infrared spectroscopy (FTIR) and cross-polarization magic angle spinning13C nuclear magnetic resonance spectroscopy (CP/MAS NMR). In the liquid state, FTIR data show evidence of the breaking of hydrogen bonding between IMC molecules to form interactions of the IMC monomer with PEG. The drug-carrier interactions are disrupted upon storage and polymer crystallization, resulting in segregation of IMC from PEG crystals that can be observed under polarized light microscopy. This process is further confirmed by13C NMR since in the liquid state, when the IMC/PEG monomer units ratio is below 2:1, IMC signals are undetectable because of the loss of cross-polarization efficiency in the mobile IMC molecules upon attachment to PEG chains via hydrogen bonding. This suggests that each ether oxygen of the PEG unit can form hydrogen bonds with two IMC molecules. The NMR spectrum of IMC shows no change in solid dispersions with PEG upon storage, indicating the absence of interactions in the solid state, hence confirming previous studies. The drug-carrier interactions in the liquid state elucidate the crystallization inhibition effect of IMC on PEG as well as other semicrystalline polymers such as poloxamer and Gelucire. However, hydrogen bonding is a necessary but apparently not a sufficient condition for the polymer crystallization inhibition. Screening of crystallization inhibitors of semicrystalline polymers discovers numerous candidates that exhibit the same behavior as IMC, demonstrating a general pattern of polymer crystallization inhibition rather than a particular case. Furthermore, the crystallization inhibition effect of drugs on PEG is independent of the carrier molecular weight. These mechanistic findings on the formation and disruption of hydrogen bonds in semicrystalline dispersions can be extended to amorphous dispersions and are of significant importance for preparation of solid dispersions with consistent and reproducible physicochemical properties.
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven , Campus Gasthuisberg O&N2, Herestraat 49 b921, 3000 Leuven, Belgium.|Department of Pharmaceutics, Hanoi University of Pharmacy , 13-15 Le Thanh Tong, Hoan Kiem, Ha Noi, Vietnam.
authors.forename: Tu
authors.initials: T
authors.lastname: Van Duong
authors.affiliation: Applied and Analytical Chemistry, Institute for Materials Research, Hasselt University , Diepenbeek BE-3590, Belgium.
authors.forename: Gunter
authors.initials: G
authors.lastname: Reekmans
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven , Herestraat 49 b1041, 3000 Leuven, Belgium.
authors.forename: Akkaladevi
authors.initials: A
authors.lastname: Venkatesham
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven , Herestraat 49 b1041, 3000 Leuven, Belgium.
authors.forename: Arthur
authors.initials: A
authors.lastname: Van Aerschot
authors.affiliation: Applied and Analytical Chemistry, Institute for Materials Research, Hasselt University , Diepenbeek BE-3590, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Adriaensens
authors.affiliation: Department of Materials Engineering, KU Leuven , Campus Arenberg, Kasteelpark Arenberg 44 b2450, 3001 Heverlee, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Humbeeck
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven , Campus Gasthuisberg O&N2, Herestraat 49 b921, 3000 Leuven, Belgium.
authors.forename: Guy
authors.identifier: 0000-0001-9166-6075
authors.initials: G
authors.lastname: Van den Mooter
mesh_terms: D002152:Calorimetry, Differential Scanning; D006860:Hydrogen Bonding; D007213:Indomethacin / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011092:Polyethylene Glycols / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D011092:Polyethylene Glycols; D007213:Indomethacin
keywords: Fourier transform infrared spectroscopy; X-ray diffraction; amorphous; crystallization; hydrogen bonding; indomethacin; modulated differential scanning calorimetry; nuclear magnetic resonance spectroscopy; polyethylene glycol; solid dispersions