The development of microthermal analysis and photothermal microspectroscopy as novel approaches to drug–excipient compatibility studies

The use of microthermal analysis as a novel means of assessing chemical incompatibility between drugs and excipients is assessed using magnesium stearate and acetylsalicylic acid as a model system. Localised thermomechanical analysis (L-TMA), localised differential thermal analysis (L-DTA), nanosampling, thermally assisted particle manipulation (TAPM) and photothermal microspectrometry (PTMS) are developed as a means of allowing extremely small quantities of drug and excipient to be heated in close proximity to each other. Differential scanning calorimetry (DSC), hot stage microscopy (HSM) and temperature controlled attenuated total internal reflection (ATR) FTIR were used as supportive techniques. L-TMA and macroscopic TMA of magnesium stearate indicated that the endothermic DSC peak normally associated with melting does not correspond to significant liquefaction. An optimised method for detecting the interaction at a particulate level of scrutiny was developed whereby the drug is placed on the excipient surface via TAPM and the construct heated, allowing the interaction to be detected in both the L-TMA and L-DTA signal. PTMS allowed spectra to be obtained on nanogram-sized samples and also allowed the interaction to be detected. The study has therefore demonstrated the potential for using TAPM with PTMS for studying interactions at an individual particle level.