University of Limerick
Keshavarz_2019_Importance.pdf (5.28 MB)

The importance of impurity on pharmaceutical processes

Download (5.28 MB)
posted on 2022-10-13, 11:51 authored by Leila Keshavarz
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 changing the crystallizer type, up to a specific volume beyond which the effect becomes negligible. Induction time experiments were used in combination with the classical nucleation theory and demonstrated that the impurities employed reduced the nucleation rate. The impurities did not affect the solid−liquid interfacial energy but significantly reduced the kinetic factor. The poor compression ability of paracetamol is well known. The crystal habit of paracetamol was altered in the present of structurally similar impurity (4’-chloroacetanilide) to improve the compaction behaviour of the paracetamol crystals. An experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. As a result, it was feasible to accurately control the compressibility and the amount of 4’-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the solvent for crystallization. In crystallization process, recycle of mother liquor allows for reduced waste and increased yield with complete control of the impurity concentration. A sequence of batch-cooling crystallization experiments was demonstrated to investigate how a mother liquor recycle operation affects the crystallization of paracetamol as a result of the gradual build-up of the impurity 4-nitrophenol. The results can be used as a guide to estimate the optimum mother liquor recycle conditions that would lead to reduced product and solvent waste and improved process efficiency. The result of this thesis addresses a number of challenges in the crystallization of API’s and impurities and leads to improved impurity removal processes. To obtain high yield as well as specific crystal quality attributes while maintaining a control on impurities, techniques strategies including continuous crystallization with recycle and pressurized methods were developed. Furthermore, rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications.



  • Doctoral

First supervisor

Frawley, Patrick J.



Other Funding information




Also affiliated with

  • Bernal Institute

Usage metrics

    University of Limerick Theses


    No categories selected


    Ref. manager