Thermal analysis in pharmaceutical sciences: a critical narrative review with focus on drug–excipient interactions

Abstract

Abstract Thermal analysis has become an indispensable component of the modern pharmaceutical preformulation toolbox, providing rapid, low-mass, and information-rich answers to questions of identity, purity, polymorphism, thermal stability, and—most critically—drug–excipient compatibility. This narrative review surveys the conceptual and methodological landscape of thermoanalytical techniques most frequently applied in pharmaceutical sciences, with an explicit focus on differential scanning calorimetry (DSC), thermogravimetric analysis (TGA/DTG), differential thermal analysis (DTA), evolved gas analysis hyphenations (TGA–FTIR, TGA–MS), hot-stage microscopy (HSM), and isothermal calorimetric methods (ITC, IMC). Particular emphasis is placed on (i) the kinetic-triplet framework underpinning solid-state stability prediction, in alignment with the most recent recommendations of the ICTAC Kinetics Committee; (ii) the diagnostic logic by which drug–excipient incompatibilities are identified through thermal events (peak shift, broadening, disappearance, enthalpy variation) and corroborated by complementary spectroscopic and diffractometric techniques; and (iii) representative case studies in which these techniques have unambiguously resolved formulation-relevant interactions. The contributions of the Timişoara school of thermal analysis—and in particular the systematic compatibility studies from the present author's group, now set alongside independent case studies from the wider literature—are integrated as illustrative case examples spanning bisphosphonates, antidiabetics, immunosuppressants, central nervous system agents, and cellulose-based polymeric excipients. The review concludes by examining emerging trends, including chemometric and machine-learning-assisted interpretation of thermal data, hyphenated process analytical technology (PAT) for hot-melt extrusion and continuous manufacturing, and the rising relevance of thermal analysis to amorphous solid dispersions, cocrystals, cyclodextrin complexes, and pharmaceutical 3D printing.