Multivariate chemometric approach to thermal solid-state FT-IR monitoring of pharmaceutical drug compound

The study of thermal-related solid-state reaction monitored by spectroscopic method needs the use of advanced multivariate chemometric approach. It is because visual inspection of spectral data on particular functional groups or spectral bands is difficult to reveal the complete physical and chemical information. The spectral contributions from various species involved in the solid-state changes are generally highly overlapping and the spectral differences between reactant and product are usually quite minute. In this article, we demonstrate the use of multivariate chemometric approach to resolve the in situ thermal-dependent Fourier-transform infrared (FT-IR) mixture spectra of lisinopril dihydrate when it was heated from 24 to 170 degrees C. The collected FT-IR mixture spectra were first subjected to singular value decomposition (SVD) to obtain the right singular vectors. The right singular vectors were rotated into a set of pure component spectral estimates based on entropy minimization and spectral dissimilarity objective functions. The resulting pure component spectral estimates were then further refined using alternating least squares (ALS). In current study, four pure component spectra, that is, lisinopril dihydrate, monohydrate, anhydrate, and diketopiperazine (DKP) were all resolved and the relative thermal-dependent contributions of each component were also obtained. These relative contributions revealed the critical temperature for each transformation and degradation. This novel approach provides better interpretation of the pathway of dehydration and intramolecular cyclization of lisinopril dihydrate in the solid state. In addition, it can be used to complement the information obtained from differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).