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 spinning C 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 byC 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.

Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances

“…In pharmaceutical semicrystalline SD, the hydrophilic carrier contains both crystalline and amorphous domains and the API can be amorphous, crystalline, or partially crystalline [ 1 ]. These systems have attracted extensive attention due to their complexity in terms of physical state, as both the carrier and the API can undergo crystalline phase modifications during production of the solid dispersion and/or during storage [ 1 , 2 ]; on one hand, the hydrophilic carrier can accelerate, slow down, or have no effect on the crystallization of the drug [ 3 , 4 ]; on the other hand, the drug can affect the crystallization of the carrier [ 2 ].…”

An Insight into Stabilization Mechanism of a Solid Dispersion of Indomethacin/Partially Hydrolyzed Polyvinyl Alcohol Prepared by Hot–Melt Extrusion

“…The single glass transition indicated the phase homogeneity of IMC and PVOH in IMC/PVOH HME (3 : 7) on a scale of several tens of nanometer. 30) Moreover, the IMC/PVOH HMEs (3 : 7) showed endothermic peaks in the range of 150-200°C. The endothermic peak would be derived from the melting of crystalline phase of PVOH, which was observed in the PXRD patterns (Fig.…”

Hydrophobicity Control in Adaptive Crystalline Assemblies

“…60 nm. Molecular modeling (Figure ) based on SAXS and XRD data reveals that in the best fit model, the long PEG chains are folded five times (Figure a) . The interactions between PDI cores and between perfluoroalkyl chains are responsible for the formation of an ordered lamellar phase (Figure b,c).…”