, Volume 26, Issue 11, pp 2523-2534
Date: 22 Sep 2009

Evaluation of Drug-Polymer Miscibility in Amorphous Solid Dispersion Systems

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ABSTRACT

Purpose

To evaluate drug-polymer miscibility behavior in four different drug-polymer amorphous solid dispersion systems, namely felodipine-poly(vinyl pyrrolidone) (PVP), nifedipine-PVP, ketoconazole-PVP, and felodipine-poly(acrylic acid) (PAA).

Materials and Methods

Amorphous solid dispersion samples were prepared at different drug-to-polymer ratios and analyzed using differential scanning calorimetry (DSC), mid-infrared (IR) spectroscopy, and powder X-ray diffractometry (PXRD). To help with interpretation of the IR spectra, principal components (PC) analysis was performed. Pair Distribution Functions (PDFs) of the components in the dispersion were determined from the PXRD data, and the pure curves of the components were also extracted from PXRD data using the Pure Curve Resolution Method (PCRM) and compared against experimentally obtained results.

Results

Molecular-level mixing over the complete range of concentration was verified for nifedipine-PVP and felodipine-PVP. For felodipine-PAA, drug-polymer immiscibility was verified for samples containing 30 to 70% polymer, while IR results suggest at least some level of mixing for samples containing 10 and 90% polymer. For ketoconazole-PVP system, partial miscibility is suspected, whereby the presence of one-phase amorphous solid dispersion system could only be unambiguously verified at higher concentrations of polymer.

Conclusions

The three techniques mentioned complement each other in establishing drug-polymer miscibility in amorphous solid dispersion systems. In particular, IR spectroscopy and PXRD are sensitive to changes in local chemical environments and local structure, which makes them especially useful in elucidating the nature of miscibility in binary mixtures when DSC results are inconclusive or variable.