Paracetamol Crystallization Using Laser Backscattering and ATR-FTIR Spectroscopy: Metastability, Agglomeration, and Control

A systematic approach is developed for the in situ control of the crystal size distribution, and is applied to the aqueous crystallization of paracetamol (acetaminophen) as a model pharmaceutical system. This involves the determination of the solubility curve and the metastable limit, and the operation of concentration-controlled batch crystallization. The solution concentration and the solubility curve of paracetamol in water are determined using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy coupled with chemometrics. The metastable zone width of paracetamol is determined using laser backscattering and ATR-FTIR spectroscopy. Seeded batch crystallizations of paracetamol following a desired supersaturation profile near the metastable limit are carried out using in situ solution concentration measurements obtained from ATR-FTIR spectroscopy. The in situ chord length distributions of crystals obtained from laser backscattering are related to characteristics of the crystal size distribution. Product crystals where the supersaturation temporarily exceeded the metastable limit during operation contained agglomerates and exhibited large size variation. Larger product crystals of more uniform size and shape are obtained from operation where supersaturation was successfully controlled to stay within the metastable limit.