85 % of drugs are taken orally, and such route of administration ensures the highest acceptance by the patients. 75 % of active pharmaceutical ingredients (API) that are under development are regarded as poorly or practically insoluble, which is one of the main reasons for low bioavailability. To increase absorption through gastrointestinal tract, many solubility enhancing approaches are used, such as formulating salts, using surfactant, cyclodextrins as well as preparation of amorphous solid dispersions (ASDs). Among all the approaches, the most used method for increasing solubility is hot melt extrusion (HME) method for preparation of ASDs. ASDs can be described as a mixture of two or more components in a solid state, i.e. amorphous active pharmaceutical ingredient (API) dissolved in a polymer matrix. Interactions between API and polymer inhibit crystal growth and phase separation, keeping API in a state leading to increased kinetic solubility and dissolution speed.
Processes, (e.g. formation of supersaturated state, colloid particles that contain API and precipitation), during dissolution of ASDs are extremely complex and not well understood. To deepen our understanding of these processes, we relied on advanced scanning electron microscopy (SEM) techniques. Our investigated samples were ASDs of API and polymer hydroxypropyl methyl cellulose acetate succinate (HPMCAS) prepared with HME.
In the scope of this master thesis, we investigated the effect of using different polymer and API ratios and presence or absence of silicon dioxide in ASDs on dissolution, supersaturated state and colloid particles using dissolution media at different pH-values. We assessed different manners of preparation of ASD samples (pure versus extracted from tablet cores and coated tablets) for characterization using developed method of analysis on a SEM.
Developed method of characterization of ASDs during the process of dissolution was used to confirm the usability of coupled SEM-EDS method of analysis of ASD samples, and to confirm the success of ASD isolation from final products. The developed method enables us to perform a more accurate qualitative and quantitavive analysis of the originator’s pharmaceutical form, as it was used to determine its grade of HPMCAS under defined conditions. It also allowed us to better understand the influence of ASD composition, presence and absence of surfactants and excipients on the release mechanism of API in vivo.
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