The Role of Glass Transition Temperatures in Coamorphous Drug–Amino Acid Formulations

The improved physical stability associated with coamorphous drug–amino acid (AA) formulations may indicate a decrease in mobility of the amorphous drug molecules, compared to the neat amorphous form of the drug. Since the characteristic glass transition temperatures (<i>T</i>_gα and <i>T</i>_gβ) represent molecular mobility in amorphous systems, we aimed to characterize <i>T</i>_gα and <i>T</i>_gβ and to determine their role in physical stability as well as their potential usefulness to determine the presence of an excess component (either drug or AA) in coamorphous systems. Indomethacin (IND)–tryptophan (TRP) and carvedilol (CAR)–TRP were used as model coamorphous systems. The analytical techniques used were X-ray powder diffractometry (XRPD) to determine the solid-state form, dynamic mechanical analysis (DMA) to probe <i>T</i>_gα and <i>T</i>_gβ, and differential scanning calorimetry (DSC) to probe thermal behavior of the coamorphous systems. <i>T</i>_gα analysis showed a gradual monotonous increase in <i>T</i>_gα values with increasing AA concentration, and this increase in the <i>T</i>_gα value is not the cause of the improved physical stability. The <i>T</i>_gβ analysis for the IND–TRP sample with 10% drug had a <i>T</i>_gβ of 226.8 K, and samples with 20–90% drug had similar <i>T</i>_gβ values around 212.5 K. For CAR–TRP, samples with 10–40% drug had similar <i>T</i>_gβ values around 230.5 K, and samples with 50–90% drug had similar <i>T</i>_gβ values around 223.3 K. The similar <i>T</i>_gβ values in coamorphous systems at different drug ratios indicate that they in fact are the <i>T</i>_gβ of the component that is in excess to an ideal drug–AA coamorphous mixture. DSC and XRPD analysis showed that for IND–TRP, IND is in excess if the drug concentration is 30% or above and will eventually recrystallize. For CAR–TRP, CAR is in excess and recrystallizes when the drug concentration is 50% or above. We have proposed a means of estimating, on the basis of <i>T</i>_gβ, which drug to AA ratios will lead to optimally physically stable coamorphous systems that can be considered for further development