2 research outputs found
Phase Separation in Coamorphous Systems: <i>in Silico</i> Prediction and the Experimental Challenge of Detection
Combinatorial
chemistry has enabled the production of very potent drugs that might
otherwise suffer from poor solubility and low oral bioavailability.
One approach to increase solubility is to make the drug amorphous,
which leads to problems associated with drug stability. To improve
stability, one option is to molecularly disperse the drug in a matrix.
However, the primary reason for the failed stabilization with this
approach is phase separation, which has been carefully studied in
polymeric systems. Nevertheless, the amorphous–amorphous phase
separation in coamorphous small molecule mixtures has not yet been
reported. The goal of the present study was to experimentally detect
the amorphous–amorphous phase separation between two small
molecules. A modified <i>in silico</i> method for predicting
miscibility by the Flory–Huggins interaction parameter is presented,
where conformational variations of the studied molecules were taken
into account. A series of drug–drug mixtures, with different
mixture ratios, were analyzed by conventional differential scanning
calorimetry (DSC<sub>conv</sub>) to detect possible amorphous–amorphous
phase separations. The phase separation of coamorphous drug–drug
mixtures was also monitored by temperature modulated DSC (MDSC) and
Fourier transform infrared (FT-IR) imaging at temperatures above <i>T</i><sub>g</sub> for prolonged time periods. Amorphous–amorphous
phase separation was not detected with DSC<sub>conv</sub>, probably
due to the slow kinetics of phase separation. However, the melting
of the separated and subsequently crystallized phases was detected
by MDSC. Furthermore, FT-IR imaging was able to detect the separation
of the two amorphous phases, which demonstrates the ability of this
method to detect small molecule phase separations