Author:

Keywords:

solid dispersions, crystallization, polyethylene glycol, indomethacin, hydrogen bonding, FTIR, NMR, XRD, DSC, PLM

Abstract:

PURPOSE We recently found that indomethacin (IMC) can effectively act as a crystallization inhibitor for polyethylene glycol 6000 (PEG) despite the fact that the absence of interaction 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 interaction in the liquid state to explain the crystallization inhibition effect of IMC. METHODS Dispersions made up of IMC and PEG were prepared by heating the mixture of the drug and the carrier to above the melting temperatures of both components, followed by solidification of the melt. Drug-carrier interaction in both molten and solid state was characterized by variable temperature Fourier Transform Infrared Spectroscopy (FTIR) and cross-polarization magic-angle spinning 13C nuclear magnetic resonance spectroscopy (NMR). RESULTS FTIR data show the strong IMC-PEG interaction in the molten state that was exhibited by the significant decrease in intensity and then the disappearance of asymmetric carbonyl vibration of the IMC cyclic dimer, suggesting the breaking of hydrogen bonding of the IMC dimer to form an interaction of the IMC monomer with PEG. The drug-carrier interaction was disrupted upon storage and polymer crystallization, resulting in segregation of IMC from PEG crystals that can be observed under polarized light microscopy. This process was further confirmed by NMR since in the liquid (molten) state, when the IMC:PEG unit ratio is below 2:1, almost all signals of IMC are undetectable because of the loss of cross polarization efficiency of too mobile IMC molecules upon attachment to PEG chains via hydrogen bonding. Only signals of carbons with more protons can be observed due to higher cross polarization efficiency. This suggests that each ether oxygen of the PEG unit can form hydrogen bonds with two IMC molecules, possibly owing to the perfect arrangement of drug molecules along the carrier chains that in turn is originating from π-π stacking between the aromatic rings of neighbouring IMC molecules. In molten dispersions containing more IMC e.g. IMC:PEG unit ratio of 3:1 and 6:1, free IMC molecules with lower mobility that do not involve in interaction with PEG can be cross polarized and the signals are visible. The NMR spectrum of IMC shows no change in solid dispersions with PEG upon crystallization, indicating the absence of interaction in the solid state, hence confirming previous studies. The crystallization inhibition of IMC on PEG is independent on the carrier molecular weight. This only depends on the number of hydrogen bonded forming centers i.e. IMC:PEG unit ratio. When the hydroxyl group of IMC is substituted by a methoxy group, no interaction between the new compound and PEG can be detected in both liquid and solid state, and the methoxy derivative of IMC is unable to inhibit crystallization of PEG. CONCLUSION This work demonstrates the formation of hydrogen bonding between IMC and PEG in the liquid state, which is vital for the crystallization inhibition effect on IMC on PEG, and the disruption of the bonds upon crystallization of the carrier, leading to the exclusion of IMC from PEG crystals. Both the presence of a hydrogen bonding forming center and an aromatic ring of IMC are required for the crystallization inhibition effect on PEG.