The importance of impurity on pharmaceutical processes

peer-reviewed ; Solution crystallization processes are widely treated as binary systems consisting of a solute and a solvent. For real systems, additional components such as additives and impurities may significantly impact crystallization processes even when present in very small amounts. An understanding of the mechanistic role of additives and impurities is therefore essential to design and control crystallization processes. This thesis first describes the solubility and crystallization of pure active pharmaceutical ingredients (API’s) from solution. Subsequently, it discusses the thermodynamic, kinetic and crystallization effects, caused by impurities. Eventually, these knowledge were applied to optimize impurity removal processes by using a combined experimental-modelling approach to investigate a mother-liquor recycle operation and improve properties on the processability of API. The gravimetric solubility method and how solubility models cope with industrially-relevant complex products belonging to the α-Thio-β-chloroacrylamide family which is a class of highly versatile synthetic intermediates was examined. One of the drawbacks of the gravimetric method is the evaporation of solvents which is due to elevated operating temperature or the volatile nature of the solvent itself. Solubility data at higher temperatures, beyond the atmospheric boiling point of solvents, allows for an increase in crystallization yield. A pressurized-synthetic methodology was presented as a new technique for determining high-temperature solubility data even beyond the atmospheric boiling point. With the gravimetric method in combination with HPLC analysis, the effect of impurities (4-nitrophenol and 4’-chloroacetanilide) on the solubility of paracetamol has been determined and modelled. To study the effect of volume on the nucleation kinetics of paracetamol, an automated FBRM-method was applied to record induction times. The shear rate was rationalized to be the part of the kinetic parameter that changes most significantly when ...