Formulation of poorly water-soluble drugs with mesoporous silica has become a thriving field of pharmaceutics. The theoretical critical pore diameter has been introduced as a maximum value below which an undesired drug crystallization is suppressed by spatial confinement. Currently, only few values have been reported and study of fast crystallising drugs is missing especially at relevant storage temperatures. This study investigated the critical pore diameter of three model drugs with a poor glass-forming ability (i.e. haloperidol, carbamazepine and benzamide) using different mesoporous carriers (Parteck® SLC 500, Neusilin® US2, Syloid® XDP 3050 and Aeroperl® 300 Pharma) and subsequently monitored physical formulation stability over three months by X-ray powder diffraction. The selected drugs showed clear differences in their estimated critical pore diameters, whereas a temperature dependence was barely relevant for pharmaceutical storage conditions. Superior stability was noted for the formulations containing benzamide in line with its predicted relatively large critical pore diameter of 29.5 nm. Contrarily, impaired physical stability depending on drug loading was observed in the case of haloperidol representing a compound with a rather small critical pore diameter (8.4 nm). These findings confirm the importance of estimating the critical pore diameter, especially for poor glass-forming drugs.

Department of Pharmaceutical Technology Faculty of Pharmacy in Hradec Králové Charles University Akademika Heyrovského 1203 500 05 Hradec Králové Czech Republic

Institute for Pharma Technology University of Applied Sciences and Arts Northwestern Switzerland School of Life Sciences FHNW Hofackerstr 30 4132 Muttenz Switzerland

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