A combined differential scanning calorimetry and thermogravimetry approach for the effective assessment of drug substance-excipient compatibility

Abstract

AbstractDifferential scanning calorimetry (DSC) is a tool particularly recommended for rapid compatibility screening between active pharmaceutical ingredients (APIs) and excipients, whereas thermogravimetric analysis (TGA), a complementary technique to DSC, is primarily used to assess the thermal stability of APIs and excipients. Both DSC and TGA data can be converted using multivariate statistical methods, which are profitable tools in the detection of compatibility between ingredients. Principal component analysis (PCA) enables identification of compatibility by grouping samples into two clusters in a PCA score plot: acetazolamide and mixture with its highest content, and optionally a 1:1 mixture form one cluster, excipient and mixture with its highest quantity, and optionally a 1:1 mixture the second. Any variation from the arrangement of samples in the abovementioned clusters indicates incompatibility. By using cluster analysis, compatibility can be determined by four clusters, the first consisting of API, the second of groups mixture at the ratio of 7:3 and the third of two mixtures at ratios of 3:7 and 1:1, with the excipient in the remaining fourth cluster. Generally, the combination of DSC and TGA techniques with advanced statistical methods is favorable for the qualitative assessment of compatibility in acetazolamide mixtures with excipients such as mannitol, meglumine, lactose, magnesium stearate, β-cyclodextrin, chitosan, methylcellulose, starch 1500 and PVP K-30. In addition, PXRD revealed that acetazolamide retains its crystalline form after mixing. Accordingly, incompatibilities in acetazolamide mixtures can be attributed to chemical reactions.