(95ae) In Situ Drug Amorphisation By Microwave Irradiation Stabilized By Mesoporous Silica

One of the common issues in the pharmaceutical industry is the poor solubility of the newly developed active pharmaceutical ingredients (APIs). The solubility might be significantly enhanced by changing the form of the API from crystalline to amorphous form. The amorphous state is characterized by lower thermodynamic stability and thus better dissolution properties leading to better bioavailability. In addition, the amorphous API in a dosage form (e.g. tablets) must also remain stable and not recrystallize for at least the shelf life of the drug product (usually 2 - 3 years). Various methods are being utilized to prepare and stabilize amorphous formulations in the industry, however they usually involve difficult formulation steps or suffer from poor efficiency, low stability or can be patent obstructed.

In this work a stable amorphous formulation is prepared simply using the standard wet and dry granulation process or direct tableting. Crystalline form of API is used during the initial process. The amorphous form is then prepared in situ and “on demand” either during manufacturing, or by the end user by applying microwave radiation (MW).

To stabilize the API in an amorphous form after the MW, multi-structured mesoporous silica particles were added to the formulation. The particles were prepared using an emulsion synthesis of octylamine in tetraethyl orthosilicate. Using ethanol as an inhibitor instead of the commonly used nitric acid as a catalyst reduces the silica primary nano-particles nucleation rate. The formed nuclei grow larger and then self-assemble around the octylamine droplets and form hollow micro-particles. The prepared microparticles were characterized using the Scanning electron microscopy (SEM) and the Transition electron microscopy (TEM). To characterize the porous structure, nitrogen sorption (BET) analysis was conducted. The results clearly show the particle assemblies contain macropores (cavities), mesopores and micropores and possess very high specific surface area and also very large pore volume. Together with the thermal and chemical stability of silica these properties make the particles well suitable for preserving the melted API in an amorphous form after the MW.

As a proof of concept, initially powder mixtures and later simple tablets composed of Ibuprofen (model API), silica micro-particles and a filler excipient were experimentally investigated. The in situ amorphization of ibuprofen was conducted using a commercial microwave oven. The heating properties of the oven, i.e. the spatial distribution of microwave heating was characterized. Various microwave power input and varying composition of the mixtures (excipient/Ibuprofen ratio) were tested with respect to the melting point of the Ibuprofen. The change from the crystalline to amorphous structure due to MW heating was analyzed by x-ray diffraction (XRD), differential scanning calorimetry (DSC) and FTIR-ATR techniques. The dissolution profiles of ibuprofen from both MW untreated and treated tablets were measured using the High Performance Liquid Chromatography (HPLC).

Based on these initial results, fully formulated tablets were prepared with various API dosage strength using a tablet press. Same compression force and same dwell time was used for all of the tablets. The final tablet composition includes excipient capable of absorption of the MW, which ensures a uniform heating in the whole volume of the tablet. Next it contains the silica microparticles, which by capillary forces absorb the API once melted and stabilize it after cooling down. Lastly, the tablets contain standard filler, lubricant and disintegrant excipients. After the MW application the tablets change their structure due to the melted API intake into the silica micro-particles, forming visible pores in the tablet structure. This has a notable impact on the dissolution and hardness of the resulting tablets. For the final tablet characterization SEM, Texture Analysis, FTIR and Magnetic Resonance Imaging were used.