The step-wise dissolution method: An efficient DSC-based protocol for verification of predicted API–polymer compatibility

Abstract

The development of an amorphous solid dispersion (ASD) is a promising strategy for improving the low bioavailability of many poorly water-soluble active pharmaceutical ingredients (APIs). The construction of a temperature–composition (T–C) phase diagram for an API–polymer combination is imperative as it can provide critical information that is essential for formulating stable ASDs. However, the currently followed differential scanning calorimetry (DSC)-based strategies for API solubility determination in a polymer at elevated temperatures are inefficient and, on occasions, unreliable, which may lead to an inaccurate prediction at lower temperatures of interest (i.e., T = 25 °C). Recently, we proposed a novel DSC-based protocol called the “step-wise dissolution” (S-WD) method, which is both cost- and time-effective. The objective of this study was to test the applicability of the S-WD method regarding expeditious verification of the purely-predicted API–polymer compatibility via the perturbed chain-statistical associating fluid theory (PC-SAFT) equation of state (EOS). Fifteen API–polymer T–C phase diagrams were reliably constructed, with three distinct API–polymer case types being identified regarding the approach used for the S-WD method. Overall, the PC-SAFT EOS provided satisfactory qualitative descriptions of the API–polymer compatibility, but not necessarily accurate quantitative predictions of the API solubility in the polymer at T = 25 °C. The S-WD method was subsequently modified and an optimal protocol was proposed, which can significantly reduce the required experimental effort.