Fast real-time monitoring of entacapone crystallization and characterization of polymorphs via Raman spectroscopy, statistics and SWAXS

Crystallization of the drug entacapone from binary sol-vent mixtures was monitored in situ using a Raman opticalprobe. The recorded Raman spectra and statistical ana-lysis, which included the principal components methodand indirect hard modeling made it possible to estimatethe starting point of crystallization, to assess crystalliza-tion temperatures and to provide information on the poymorphic content of the mixture. It was established thatcrystallization temperatures were proportional to the vol-ume content of the solvent in mixtures. The samples werealso evaluated off-line via Raman spectroscopy and SWAXS.The collected data showed the presence of forms b and gin all solvent mixtures. In a toluene/methanol 30:70 mix-ture, in addition to forms b and g, at least one of the formsA, D or a was also indicated by SWAXS. The results haveshown that the presence of a particular polymorph isstrongly dependent on the nature and portion of the sol-vent in the binary solvent mixture.