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Crystallization science : addressing nucleation, growth and continuous manufacturing
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Date
2026-02
Abstract
Crystallization is one of the most important unit operations for the purification and isolation of the active pharmaceutical ingredients from their crude material. Despite its critical role, process development in this area is still guided by the rule of thumb. Fundamentally, crystallization is a supersaturation-driven process in which the desired compound is separated from the solution. This can be achieved either through nucleation, a phase transformation process, or through crystal growth, where seed crystals are introduced to guide the selective isolation of the target compound with the desired polymorph, controlled size distribution and morphology. While both strategies are well established and routinely applied in industry, several fundamental aspects of crystallization remain poorly understood. Crystallization is a well-established technique, with many of its theoretical foundations, such as the classical nucleation theory developed in the 1920s and 1930s and the Burton-Cabrera-Frank model, dating back to 1951. Although these theoretical models have greatly enhanced our understanding of nucleation and growth mechanisms, several important aspects of crystallization remain unclear and only partially understood. Experimentally, various key challenges still remain, particularly the absence of reliable methods to control nucleation kinetics (inferred from the induction time) and the lack of theory-driven protocols for designing continuous crystallization processes. In this work, we address seven persistent issues in crystallization, covering both theoretical gaps in nucleation and growth understanding and practical challenges, such as the lack of reliable experimental methods for pharmaceutical process development. These issues are highly relevant to crystallization fundamentals and highlight the barriers that limit progress in both academic research and industrial applications. We make a genuine attempt to address these challenges by combining theoretical insights with experimental perspectives. Chapter 2 outlines each of these problems in detail and provides an overview of proposed strategies to overcome them. The following chapters (3–8) then address each issue sequentially, examining each one in depth and discussing potential solutions, ending with recommendations for future work.
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University of Limerick
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Sustainable Development Goals
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Attribution-NonCommercial-ShareAlike 4.0 International