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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/24218

Title: Spectroscopic Investigation of the Formation and Disruption of Hydrogen Bonds in Pharmaceutical Semicrystalline Dispersions
Authors: Duong, Tu Van
Reekmans, Gunter
Venkatesham, Akkaladevi
Van Aerschot, Arthur
Adriaensens, Peter
Van Humbeeck, Jan
Van den Mooter, Guy
Issue Date: 2017
Citation: MOLECULAR PHARMACEUTICS, 14(5), p. 1726-1741
Abstract: We recently found that indomethacin (IMC) can polyethylene glycol 6000 (PEG) despite the fact that the effectively act as a powerful crystallization inhibitor for 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 spinning C-13 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 by C-13 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.
Notes: [Tu Van Duong; Van den Mooter, Guy] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Drug Delivery & Disposit, Campus Gasthuisberg O&N2,Herestr 49 B921, B-3000 Leuven, Belgium. [Tu Van Duong] Hanoi Univ Pharm, Dept Pharmaceut, 13-15 Le Thanh Tong, Hanoi, Vietnam. [Reekmans, Gunter; Adriaensens, Peter] Hasselt Univ, Inst Mat Res, Appl & Analyt Chem, BE-3590 Diepenbeek, Belgium. [Venkatesham, Akkaladevi; Van Aerschot, Arthur] Katholieke Univ Leuven, Rega Inst Med Res, Med Chem, Herestr 49 B1041, B-3000 Leuven, Belgium. [Van Humbeeck, Jan] Katholieke Univ Leuven, Dept Mat Engn, Campus Arenberg,Kasteelpk Arenberg 44 B2450, B-3001 Heverlee, Belgium.
URI: http://hdl.handle.net/1942/24218
DOI: 10.1021/acs.molpharmaceut.6b01172
ISI #: 000400633300038
ISSN: 1543-8384
Category: A1
Type: Journal Contribution
Appears in Collections: Research publications

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