The Importance of Amorphous Stability: Mesoporous Silica for Poor Glass Formers

摘要

Amorphous Formulations: Opportunities and Challenges: Poor drug solubility has become an increasingly important consideration in the development of orally delivered drugs. For example, although it is reported that 60% of approved APIs are poorly soluble, it is hypothesized that up to 90% of candidates in the development pipeline will fall under this category. Therefore, it has become increasingly important to counteract the low bioavailability risks that such poorly soluble compounds can pose. In this area, chemists and formulation scientists have developed a toolkit of strategies that can improve the solubility and subsequent bioavailability of these poorly soluble candidates. These approaches include chemical modifications that can be incorporated into synthesis such as salt formation and prodrugs; or formulation modification approaches such as micelle systems, co-solvents, particle size reduction, complexation and amorphous technology.2 Solid-state modification of the API into the more soluble amorphous form is one of the currently preferred methods for enhancing oral bioavailability of these challenging compounds. Amorphous formulations are especially appealing due to the significant improvement in solubility the amorphous form can provide. By definition, an amorphous solid does not have a long-range order, no crystal structure. Due to this, amorphous solids tend to have substantially higher solubilities than their crystalline counterparts as the strength of intermolecular interactions holding the molecules together, and accordingly the energetic barrier to solvation, are lower. However, amorphous solids are usually thermodynamically unstable due to the high energy associated with this solid-state form. This instability typically leads to re-crystallization driven by a thermodynamic drive to decrease the energy of the system and return to equilibrium. It is important, therefore, to develop and optimize an amorphous formulation to ensure sufficient physical stability over the shelf-life of the product. This is an important consideration, as re-crystallization in the formulation would reduce the effectiveness of the formulation for the patient. As a result, these stability requirements make an important part of the regulatory dossier required for submission of a new molecular entity, the guidelines of which are outlined in ICH Q1.