Current Research Trends In Dielectric Relaxation Studies Of Amorphous Pharmaceuticals: Physical Stability, Tautomerism, And The Role Of Hydrogen Bonding

Alarming statistics showing the continuous increase in the number of drugs and drug candidates with insufficient water-solubility focus scientist's efforts on finding optimal strategy for their formulation. Among the current research trends aimed at improving the solubility of active pharmaceutical ingredients (APIs), amorphization gained notable attention. The replacement of a crystalline API with its amorphous counterpart provides a great opportunity to increase the drug's bioavailability, but at the same time raises stability-related problems as amorphous APIs, from preparation to administration, are inherently driven toward crystallization. The analysis of relaxation processes in glassy and supercooled liquid states of amorphous API with molecular dynamics distributed over many decades in frequency, becomes a powerful tool for addressing many critical problems related to their successfully application. The aim of this article is to outline the contribution of molecular dynamics studies performed using broadband dielectric spectroscopy (BDS) to understanding the key properties of amorphous drugs. Since the problem of stability assessment is the most relevant, most of the article will focus on it. The following questions will be addressed: Can we predict the stability of a drug in a glassy state by measuring its dynamics in a supercooled liquid state? Can we determine the effectiveness of the stabilizer on the basis of relaxation studies? Can we accelerate somehow the stability assessment process? In addition, we will address the problem of tautomerization of amorphous APIs showing how the time-dependent analysis of dielectric response can be utilized to discern the time scale of this phenomenon. We will also briefly discuss the impact of hydrogen bonds on the dynamics of amorphous APIs, which due to their remarkable property deserve closer examination. (C) 2020 Elsevier B.V. All rights reserved.