Quantifying API polymorphs in formulations using X-ray powder diffraction and multivariate standard addition method combined with net analyte signal analysis

Abstract The direct quantification of Active Pharmaceutical Ingredients in solid formulations is a challenging open issue. A consolidated analytical technique based on X-ray Powder Diffractionis available, being the definitive test for the identification of polymorphs and crystal phases. However, its application for quantitative analysis is hindered by matrix effects: refinement methods (e.g. Rietveld method) require a complete knowledge of samples' composition, while univariate calibration methods require the matrix effect to be studied and severely suffer from the co-presence of crystalline and amorphous phases in the sample. Multivariate analysis is the only way to bypass problems affecting refinements procedures and univariate calibration. In particular, the multivariate standard additionmethod (SAM) is promising; however, it is straightforward only when the analytical blank (matrix devoid of analyte) is available: in that case SAM is applied by simply extrapolating the SAM model to the matrix experimental signal. In this work, the quantitative analysis of polymorphic forms of Active Pharmaceutical Ingredients based on X-ray Powder Diffractionis performed for the first time by a method based on multivariate standard additionmethod combined with net analyte signalprocedure; it allows for reliable quantification of polymorphs of active principles in solid formulations, which are rapidly analyzed without any sample pre-treatment. Two test cases are presented: quantification of two polymorphs of piracetamin binary mixtures (forms II and III), and quantification of paracetamol (form I) in Tachifludec®.