Purpose: The adsorption of poorly soluble drugs in mesoporous materials to improve the dissolution properties and stabilize the amorphous form is gaining attention in the pharmaceutical field. In this regard, a novel approach has recently been proposed to determine the monomolecular loading capacity of drugs in mesoporous silicas i.e. the loading capacity at which the amorphous drug will be thermodynamically stabilized. The aim of this work was to utilize this method to elucidate the influence of the mesoporous silica properties (surface area and pore volume) on the monomolecular loading capacity.
Methods: In order to study the effect of surface area and pore volume on drug loading capacity, the monomolecular loading capacity of three model drugs celecoxib (CEL), cinnarizine (CIN) and paracetamol (PAR) was determined in five different grades of the mesoporous silica Sylyisa® (S240, S350, S430, S550 and S730). The pore volume, surface area and pore size of the different Sylysia® grades are shown in Table 1. Physical mixtures of drug and mesoporous silica were prepared in fractions of 50-90 w/w% drug using a mortar and pestle. Samples of 4-5 mg were then analyzed in a differential scanning calorimeter (DSC) by annealing the sample 5 °C above the melting temperature (Tm) of the drug for 2 min, followed by a rapid cooling to minimum 40 °C below glass transition temperature (Tg) of the drug. After quenching, the sample was ramped at a rate of 20 °C/min to determine the difference in heat capacity over the glass transition (ΔCp).
Results: By annealing the sample above the Tm of the drug in the DSC, it 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 the drug molecules adsorbed to the MS surface are "immobilized" and will not contribute to a glass transition in the DSC, 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 (see Figure 1). 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. As can be seen in Figure 2, the drug loading capacity generally increase with increasing surface area of the mesoporous silica. However, this trend is not observed for S730 and in fact, for all the drugs the loading capacity in S730 is lower than that in S550, which indicates that surface area is not the only property influencing the drug loading capacity.
Conclusion: The findings of this work show the monomolecular loading capacity generally increase with increasing surface area. However, as the Sylysia® grade with the highest surface area and lowest pore volume (S730) does not follow this general trend, the pore volume may also be limiting of the loading capacity. A possible explanation to this finding could be that even though the surface area may be available for adsorption, the drug cannot access it if (some of) the pores are smaller than the drug molecule.