Primary and secondary crystal nucleation of pharmaceutics

• Main Author: Briuglia, Maria Lucia
• Published: University of Strathclyde 2017
• Subjects: 660
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.736849

Control of the crystallisation process is essential in the consistent and reliable production of many particulate materials in the pharmaceutical and chemical industries. Crystal Nucleation defines the crystal size distribution of the obtained crystal population affecting downstream operations. The literature agrees on crystal nucleation division as primary and secondary nucleation depending on the conditions of the used supersaturated solution. Primary nucleation occurs in a clear supersaturated solution, while secondary nucleation is induced by at least one parent crystal present in the solution. Despite the large amount of research conducted on this field, several challenges for primary and secondary nucleation fundamental understanding are still identifiable. The aim of this thesis is to develop meticulous and accurate methods to measure primary and secondary nucleation in order to systematically study nucleation mechanisms relevant to industrial scales. This thesis is constituted of two main parts: one part studies primary nucleation and develops a method for control and measure primary nucleation rate within the metastable zone width (Chapter 2) using different volumes and hydrodynamics (Chapter 3). The second part concerns studies of secondary nucleation under well-controlled conditions providing a systematic method to measure secondary nucleation rates (Chapter 4), which can be integrated in industrial workflows (Chapter 5) and applied to study the chiral outcomes (Chapter 6). The developed methods decouple primary and secondary nucleation events improving crystallisation processes understanding. The reliability and reproducibility of the novel proposed methods offer an appropriate process control strategy to address existing challenges on crystal nucleation.