(81d) Mesoporous Silica Particles Used for Amorphous Pharmaceutical Formulations

In this work, we explore a complex strategy for utilization of well-defined mesoporous silica particles for poorly soluble drug amorphization. The strategy includes, from start to finish, the scale-up of the particles production, the drug loading methods and their scale-up, the loaded particles characterization, the final formulation production and its evaluation.

More and more newly discovered APIs are on one hand very potent, but on the other very poorly soluble. Amorphization of the API in the formulation presents a relatively easy route for increasing the apparent API solubility and thus higher bioavailability in the gastro-intestinal tract. Various methods are being utilized in order to prepare the API in an amorphous form and also to stabilize it. However, most of them either have poor efficiency, high cost of manufacture, need to be tailor-made for each API or suffer from recrystallization upon storage. In comparison, mesoporous silica particles present a very good opportunity to be used as an almost universal, easy to produce and easy to deploy carrier of amorphous APIs.

Due to their very good sorption capabilities, mesoporous silica micro- and nano-particles are often being studied for their possible applications in drug delivery. Most of these studies are focused on possible utilization in the intravenous applications. Only a minority of the works focus on the use of silica particles in the oral delivery area, which poses significantly lower amount of challenges before final deployment, than the complex intravenous delivery route. Since the APIs cannot recrystallize once loaded inside the silica mesopores due to the spatial restrictions, amorphized API present in silica doesn’t need to be further stabilized to prevent recrystallization. Furthermore, the high specific surface area of silica particles and high hygroscopicity of silica particles further promote dissolution of the amorphized payload.

In this work, three different strategies of API loading into the silica particles are explored. The first method relies on impregnation of the silica powder dispersed in saturated solution of the API, relying on sorption equilibrium to achieve loading, or using incipient wetness impregnation, where exact amount of highly concentrated API dissolved in a volatile solvent is injected into the silica powder and then evaporated. In the second method, already prepared placebo tablets containing high amount of empty silica particles are impregnated with a solution of API using ink-jet technology. This involves very precise dosing, which provides the opportunity to tailor the final API dosage for each tablet individually. The presence of free pore volume of the silica particles provides the space needed for the API deposition inside the tablet and also ensures the API amorphization. Also, the fact that the API is dosed after the tablet preparation allows for preparation of the desired pharmaceuticals on-demand. This way, only cheap to produce placebo tablets and pure API need to be stored. Lastly, the third method relies also on pre-prepared tablets, only this time containing crystalline API already in them together with empty silica particles. The API is then amorphized from its crystalline state using microwave heating. The API inside the tablet melts and is absorbed by the silica, where it stays in amorphous form.

Three different types of structured mesoporous silica particles are used throughout the experiments. They were chosen with regards to their suitability for the specific application, the simplicity of their preparation and the possibility to scale-up their production. The scale-up strategies of the particle production were investigated in order to ensure high enough production of experimental material and also to explore the future industrialization possibilities. Several experiments were conducted in order to identify the key scale-up parameters followed by advanced computational modelling of the hydrodynamic conditions in the stirred vessels from small laboratory scale to large reactors. The results were used to identify the conditions needed to achieve successful results on large scales. The API loading scale-up possibilities were also proposed and evaluated.

Model tablet formulations for each of the mentioned methods were developed in relation to be able to accommodate high silica content and provide fast disintegration times in order to further speed up the dissolution process of poorly soluble APIs. The prepared particles, the particles loaded with API and the final formulations were characterized in detail and their performance was evaluated, providing more than satisfactory results.