Crystallization Kinetics of Indomethacin/Polyethylene Glycol Dispersions Containing High Drug Loadings

Abstract

The reproducibility and consistency of physicochemical properties and pharmaceutical performance are major concerns during preparation of solid dispersions. The crystallization kinetics of drug/polyethylene glycol solid dispersions, an important factor that is governed by the properties of both drug and polymer has not been adequately explored, especially in systems containing high drug loadings. In this paper, by using standard and modulated differential scanning calorimetry and X-ray powder diffraction, we describe the influence of drug loading on crystallization behavior of dispersions made up of indomethacin and polyethylene glycol 6000. Higher drug loading increases the amorphicity of the polymer and inhibits the crystallization of PEG. At 52% drug loading, polyethylene glycol was completely transformed to the amorphous state. To the best of our knowledge, this is the first detailed investigation of the solubilization effect of a low molecular weight drug on a semicrystalline polymer in their dispersions. In mixtures containing up to 55% indomethacin, the dispersions exhibited distinct glass transition events resulting from amorphous-amorphous phase separation which generates polymer-rich and drug-rich domains upon the solidification of supercooled polyethylene glycol, whereas samples containing at least 60% drug showed a single amorphous phase during the period in which crystallization normally occurs. The current study demonstrates a wide range in physicochemical properties of drug/polyethylene glycol solid dispersions as a result of the complex nature in crystallization of this system, which should be taken into account during preparation and storage.

Spectroscopic Investigation of the Formation and Disruption of Hydrogen Bonds in Pharmaceutical Semicrystalline Dispersions

“…This process is further confirmed by 13 C 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 13 C NMR spectra of PEG-APIs dispersions were collected in both solid and liquid state at different temperatures. Temperature was calibrated using lead nitrate.…”

“…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 13 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 role of the carrier in the formulation of pharmaceutical solid dispersions. Part I: crystalline and semi-crystalline carriers

“…In addition, depending on the variation between the crystallization rate of PEG and the diffusion rate of indomethacin upon changing the drug loading, the crystallization of the polymer may produce a single amorphous phase or generate amorphous-amorphous phase separation, forming a polymer-rich domain and drugrich domain exhibiting two distinct Tgs. These examples demonstrate that the microstructure and performance of solid dispersions depend not only on the properties of API but also upon characteristics of carrier which both will significantly influence the overall performance of the systems [99].…”

Superiority of amino-modified chiral mesoporous silica nanoparticles in delivering indometacin

“…Poorly water-soluble indometacin (IMC), the acidic nonsteroidal anti-inflammatory drug that can cause irritation of the gastrointestinal mucosa [36], was chosen as guest molecules to construct drug delivery systems. Many formulation techniques, including cyclodextrins [38], microcapsules [39], microemuslsions [25] and solid dispersions [40][41][42][43], have been widely used to establish IMC drug delivery systems. In the current stage, IMC delivery systems constructed by nanotechnology, such as PLGA nanoparticles [44] and nano-solid dispersions [45], have been reported.…”