Influence of API physico-chemical properties on amorphization capacity of several mesoporous silica loading methods

The objective of this work was to evaluate the impact of physico-chemical properties of pharmaceutical drugs on the optimal mesoporous silica loading methods. Indeed, a good combination between drug and loading process has to be studied to promote the deepest penetration of the drug inside the mesopores, allowing high drug amorphization. Six molecules, namely lidocaine and its hydrochloride, ibuprofen, ketoprofen, artemether and miconazole, with different physico-chemical properties (the ionized character, the acid-base character, the HBDA number, the solubility in sc-CO₂ and the behavior under subcritical CO₂) were used to produce drug-silica formulations. Different impregnation processes (physical mixing, melting, wetting, sc-CO₂ and subcritical CO₂ impregnations) have been compared for each drug, in terms of drug recovery and crystallinity. Formulations showed drug percentage close to 100% except for supercritical soluble drug formulations impregnated by using sc-CO₂. However, the basic drug character provided less or no drug loss during impregnation. Processing insoluble sc-CO₂ molecule under supercritical conditions led to less crystallinity than the correspondent physical mixture suggesting an interesting repulsive effect that forces the drug penetration within the mesopores. Besides, it has been also highlighted that the HBDA number is not sufficient to predict the final drug loading. Melting methods have high interest considering the drugs tested and subcritical CO₂ could increase the loading, especially for drugs with high molten viscosity. This study showed that a plethora of loading methods can be used to provide high drug loaded MS formulations with a wide choice of equipment.