Many substances can have more than one crystalline form. Each of these is called polymorphic form and can have different physical and chemical properties. For this reason, determining and monitoring polymorphic transformations has become very important, especially in the pharmaceutical industries. Spectroscopic and imaging techniques enable in situ, non-destructive and fast quantitative measurements of polymorphic mixtures in solid samples and suspensions.

Raman, PVM and IR spectroscopy have already been used singularly to detect nucleation and polymorphic transformations during crystallization processes as well as to analyse powder mixtures of multiple polymorphic forms. However, a comprehensive study and comparison between those techniques used simultaneously during polymorphic transformation has not been performed yet. One of the aims of the present work is to compare the effectiveness of Raman, NIR and PVM to detect nucleation and polymorphic transformations during crystallization processes. Focused beam reflectance measurement (FBRM) and UV probes were also used simultaneously in the same system to validate and integrate the results obtained by the other probes.

The model compound used for the experiments is ortho-aminobenzoic acid which has three different polymorphic forms. The transformation studied is the one from metastable form II to stable form I. Experiments were performed using all the probes at the same time in order to compare the signals and combine the different results. Chemometrics techniques (such as principal components analysis) were exploited to obtain qualitative and quantitative information about the solute concentration, solid concentration and polymorphic concentration. The pre- and post-processing of the data have been done with Matlab, Excel, TQ Analyst and iC Raman.

In conclusion, Raman, NIR and PVM were successfully used to detect, monitor and quantify polymorphic transformation during crystallization. UV and mid-IR were used to measure solute concentration while FBRM could give information about the solid phase (nucleation, growth, CSD). The results from the different probes were combined and integrated in order to have a complete knowledge of the most important parameters for crystallization processes.

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