Restricted Access. Restriction lift date: 9999-12-31
Studies of impurities in crystalline pharmaceuticals and related compounds
Loading...
Files
Date
2025
Authors
McGrath, Michael
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
The occurrence of and management of impurities in batches of drug products is a constant challenge faced by chemists in the pharmaceutical industry. While the inclusion of many process related impurities can be controlled and removed to safe levels and levels specified by regulatory bodies by techniques such as crystallization, some impurities may prove difficult to remove and may not be adequately removed using crystallization. In these cases the process may need to be changed to reduce the formation of these difficult to remove impurities. Crystallizations are of particular importance as purification methods. The methods by which an impurity incorporates into and is purged from a crystalline Active Pharmaceutical Ingredient (API) are not often fully understood. Furthermore, the distribution of the impurity may not be uniform, within single crystals or within the batch as a whole and information on the distribution would be valuable in the design of an effective impurity management strategy.
This research focuses on a number of aspects of impurities in drug-like crystalline solids. One is the generation of phase-diagrams to assist in understanding the phase behaviour of two-component binary systems, which in turn helps to investigate the methods by which impurities incorporate into host crystals. Building on this we examine how different crystallization conditions affect the impurity purge and impurity rejection during crystallization, utilizing recently developed metrics for that purpose which optimize the use of HPLC data. Finally, the distribution of impurities during crystal growth is examined and placed on a sound footing through the use of uncertainty evaluation.
Chapter one provides a summary of impurities in pharmaceuticals, the methods by which they incorporate into host crystals and different methods by which impurities are removed from drug products in the pharmaceutical industry. Background into crystal structure, crystal morphology and polymorphism are introduced. The concept of crystal growth is discussed. In this chapter the effects of impurities on a host crystal are introduced. Finally, this chapter gives a summary of various solid-state analytical techniques of most relevance to the project, and analysis by High-Performance Liquid Chromatography (HPLC) as it is central to the project work.
Chapter two focuses on the selection of the systems that will be used in this research, outlining why each host and impurity was chosen. The synthetic routes employed to access the chosen compounds, and the development of the analytical techniques used to characterise their behaviour is outlined. The development of the various HPLC methods used is described. The development of crystallization methods used throughout this research is also discussed in this chapter.
Chapter three details the use of Tammann plots and binary phase diagrams to investigate the phase behaviour of our chosen study systems. This information is used to help to identify the methods by which the impurities incorporate into the host crystals. Formation of eutectics and eutectics with solid solutions are reported as well as modifications of these behaviours due to polymorphism.
Chapter four is concerned with the application of a set of calculations and parameters based on HPLC data to quantify impurity rejection and impurity purge during crystallization. This chapter also discusses the effects of solvent choice and impurity level present on crystal morphology, utilizing the impurity rejection and purge metric for that purpose.
Chapter five looks at the distribution of impurities throughout the crystal at different stages of crystal growth. A detailed uncertainty analysis of the HPLC methods developed in this research will be introduced in this chapter and its applications outlined. That approach is then used to evaluate the relative levels of impurity incorporation at earlier and later stages of crystal growth for the system under study.
Chapter six provides a summary of the conclusions for each project undertaken and presented in this thesis followed by an appendix chapter containing supplemental PXRD data and an in-depth explanation of the use of Excel for chapter five is provided. Chapters two to five all have an introduction section which will be followed by the experimental section for that chapter.
Description
Restricted Access
Keywords
Impurities , Crystalline , Pharmaceuticals
Citation
McGrath, M. 2025. Studies of impurities in crystalline pharmaceuticals and related compounds. PhD Thesis, University College Cork.
Link to publisher’s version
Copyright
© 2025, Michael McGrath.