(737b) Thermodynamic Properties of Paracetamol Impurities and Their Impact on the Crystallisation of Paracetamol from Solution

The impact of additives and impurities on active pharmaceutical ingredients is an essential yet poorly understood area in crystallization research. Paracetamol, which is one of the most widely used model systems in crystallization, is typically produced with trace amounts of unwanted impurities. However, it remains unclear how the main impurities 4-nitrophenol (NP) and 4’chloroacetanilide (CA) affect the solubility and polymorphism of paracetamol.

This work describes the solid- and solution characterisation of the main impurities of paracetamol. Temperature-dependent solid-liquid properties of 4-nitrophenol (NP) and 4’chloroacetanilide (CA) were obtained in four different alcohols and their effect as impurities on the crystallisation and solubility of paracetamol (PA) will be presented. HPLC measurements were used to determine the solution stability of these compounds. The solubility of NP appeared to be significantly higher than PA whereas the solubility of CA was lower than PA. The solubility difference between the impurities could be rationalised based on their molecular structure and hydrogen bonding interactions. Despite these significant differences between the impurities, their effect on the solubility of PA is the same, as each impurity slightly increases the solubility of PA. The solubility data was modelled using the empirical modified apelblat equation and thermodynamic models, which include the Margules, van-Laar, Wilson and NRTL models. The quality of fit of the tested thermodynamic models to the experimental data increases in the order Margules < van-Laar < Wilson < NRTL < Apelblat.

XRPD measurements were conducted to establish the polymorhpism of the compounds used in this study. Recrystallisation of PA from solution containing the highly soluble NP impurity resulted in small uniformly sized high purity PA form I crystals whereas the presence of the poorly soluble CA impurity induced the formation of large needle shaped crystals of PA form I. These differences in crystallisation are a consequence of the solubility difference and the different functional groups of PA and its impurities. The effect of the impurities on the nucleation kinetics of paracetamol was investigated using induction time measurements and showed that the nucleation process is inhibited for both impurities.

The presentation will cover experimental and modelling data and describes the effect of impurities on the solubility, crystallization and nucleation kinetics of paracetamol. Overall this work presents fundamental information for the development of crystallisation approaches for the purification of paracetamol from its main impurities.