Acid-base interactions in amorphous solid dispersions: Formulation strategy for tyrosine kinase inhibitors

Using the amorphous state of APIs has become a very beneficial strategy to overcome the solubility challenge faced with an increasing number of newly discovered drug candidates or available APIs. Given the inherent physical instability of amorphous materials, pharmaceutical products are usually formulated by dispersing APIs into polymers utilizing primarily hot melt extrusion or spray drying. The stabilization mechanisms have been discussed over the las three decades. More recently, it has been widely accepted that strong intermolecular interactions between drug and polymer are very important for maintaining the physical stability of the amorphous API. However, the nature of acid-base interaction in the stability of amorphous solid dispersions (ASDs) has not been fully explored. Among the novel small molecule anticancer drugs, tyrosine kinase inhibitor family has led in short time to 20 marketed products. Most of these TKIs are structurally related, and exhibit low to medium bioavailability because of poor water solubility. This dissertation is based on the hypothesis that amorphous solid dispersions exhibiting strong acid-base interactions between acidic polymers and basic TKIs can be exploited to formulate more bioavailable formulations of TKIs. In this study, two TKIs were used as model compound and formulated as ASDs with various acidic polymers to test the hypothesis. In addition, a new methodology, using the powerful analytical technique of XPS, was developed to investigate detail the nature of acid-base interaction of TKIs in ASDs. The most common industrial manufacturing processes for formulation of amorphous solid dispersion are spray-drying and hot melt extrusion. However, there is very limited published information discussing the different effects of these two methods on the properties of formulated ASDs, especially regarding the nature of the acid-base interaction within the TKI and polymer. This study used lumefantrine as a model compound and formulated it with five acidic polymers to explore the manufacturing effects on the acid-base interactions in ASDs. While not commonly used for producing ASDs, ball-milling also can lead to amorphous systems, and the final part of this study investigated how this process impacts the acid-base interactions within ASDs