Revealing Kinetics of Paracetamol Crystallization Using Time-Resolved Raman Spectroscopy, Orthogonal Time-Lapse Photography, and Non-Negative Matrix Factorization (OSANO)

Crystallization is a complex phenomenon with far-reachingimplicationsfor the production and formulation of active pharmaceutical ingredients.Understanding this process is critical for achieving control overkey physicochemical properties that can affect, for example, the bioavailabilityand stability of a drug. In this study, we were able to reveal intricateand diverse dynamics of the formation of metastable intermediatesof paracetamol crystallization varying with the choice of solvent.We demonstrate the efficacy of our novel approach utilizing an objectivefunction-based non-negative matrix factorization technique for theanalysis of time-resolved Raman spectroscopy data, in conjunctionwith time-lapse photography. Furthermore, we emphasize the crucialimportance of integrating Raman spectroscopy with supplementary experimentalinstrumentation for the mathematical analysis of the obtained spectra. This study revealed the complex kineticsof metastable intermediatephases in paracetamol crystallization depending on the solvent. Ournovel method uses objective function-based non-negative matrix factorization(NMF) to analyze time-resolved Raman spectroscopy data with time-lapsephotography. We further stress the need of an orthogonal experimentalsetup for accurate investigation of relative concentrations and spectralinformation.