Investigation of the stability of amorphous solid dispersions

Adequate aqueous solubility of active pharmaceutical ingredients (APIs) is a crucial factor for therapeutic effectiveness. Today, more than fifty percent of the new potential APIs are exhibiting poor aqueous solubility/dissolution rate, leading to low and erratic absorption from the gastro-intestinal (GI) tract and hence low bioavailability. This presents a challenge for pharmaceutical scientists, as many chemicals are abandoned early in the development phase unless there is a reasonable approach to modify or formulate these APIs. Many different formulation strategies have been developed to overcome the solubility problem for poorly water soluble APIs over the past decades. Among those, formulation of amorphous solid dispersions (ASD) is a promising one. Because of the lack of the long range order of molecules (characteristic for crystalline solids), amorphous solids are the most energetic solid state of a material and result in higher solubility and dissolution rate. However, the higher free energy is responsible for inherent thermodynamic instability as structural relaxation, nucleation and crystal growth can occur during storage or dissolution in the GI tract. Therefore, instead of using pure amorphous drugs, in general, the API should be dispersed at a molecular level within an inert carrier in the solid state to form an ASD. The presence of the carrier is necessary to improve the physical stability of amorphous API through inter-molecular interactions, anti-plasticization effect, physical barriers to the nucleation/crystallization process (by increased viscosity) and the reduction in chemical potential of the drug. The aim of the Phd project is to investigate which factors (molecular, formulation, process, storage condition, etc) contribute to the physical stability of the ASD and how a model can be developed to predict crystallization and/or amorphous demixing.