Atorvastatin calcium trihydrate (ACT) is a synthetic lipid-lowering agent whose thermal character remains largely unknown or else mischaracterized due to being called both “atorvastatin” and “atorvastatin form I” indiscriminately in the literature. Developing stable drugs, however, requires ensuring and thus understanding the reliable thermal behavior of trihydrate drugs, for pharmaceutical manufacturing can involve temperatures that might cause phase transition and/or the dehydration of the drugs, with implications for its physical characteristics, its chemical characteristics, and/or the pharmaceutical product's bioactivity. Against that background, in our study we investigated both a solid-state and thermal characterization of ACT via powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), and ex situ variable temperature PXRD techniques, all as integral parts of drug development. DSC and TGA curves clarified ACT's thermal stability and dehydration, and the ACT sample was identified as Form I of the trihydrate, which remains stable until approximately 40 °C. DSC showed no significant changes during melting with different heating rates, while the TGA curve revealed the stepwise loss of water molecules following heating. Ex situ PXRD suggested no abrupt changes to the trihydrate's crystal lattice during the dehydration of the first two moles of water molecules. Moreover, HSM clearly showed a unique water loss event never before visualized. Last, HSM confirmed the drug's crystallinity, its crystal shape, and the presence of an isotropic liquid after continuous heating, which remained until cooling to room temperature.
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