A fast and reliable DSC-based method to determine the monomolecular loading capacity of drugs with good glass-forming ability in mesoporous silica

Abstract

The aim of this study was to introduce a fast and reliable differential scanning calorimetry (DSC)-based method to determine the monomolecular loading capacity of drugs with good glass-forming ability in mesoporous silica (MS). The proposed method is based on a solvent-free melting/fusion of drug into the MS during a heat-cool-heat cycle in the DSC. Overloaded drug-MS systems were analyzed in the DSC at different drug ratios (50, 60, 70, 80 and 90% w/w) to quantify the excess drug in the (the fraction not adsorbed to the MS surface). During the first heating, the drug will melt and fuse into the pores of the MS and upon subsequent quench cooling, the drug that is not adsorbed to the surface of the MS will amorphize into a separate phase (as drugs with good glass-forming ability do not crystallize upon quench-cooling from the melt). The drug molecules adsorbed to the MS surface are “immobilized” and will not contribute to a glass transition in the DSC and thus, the excess drug can be quantified simply by determining the change in the heat capacity over the glass transition (ΔCp). Since the ΔCp of overloaded samples decrease linearly with decreasing drug content, the monomolecular loading capacity of the drug in the MS can be determined by extrapolating to zero ΔCp. This value corresponds to the highest drug load at which the drug is monomolecularly adsorbed to the surface of the MS and has no drug-related thermal events (glass transition), i.e. a thermodynamically stable system. Using this method, it was possible to determine the monomolecular loading capacity of four drugs with good glass-forming ability in four different MS. These determinations were in good agreement with the physical stability of the systems during an accelerated stability study, which indicates that the thermoanalytical method enabled fast and reliable determination of the monomolecular loading capacity of drugs in MS.