Crystal nucleation of griseofulvin as a model of medium-sized, flexible, and polymorphic active pharmaceutical ingredient (API)
Creators: name: Diniz, Mariana Oliveira
Publisher: name: University of Limerick
Year: 2025
Subjects: classificationCode: 34
subject: Chemical sciences
subject: FOS: Chemical sciences

description: Crystallisation is an important purification and separation step for pharmaceutical industries. It can help to control desired properties such as solid-state, crystal habit and particle size, which can influence the bioavailability and manufacturability of the drug. Crystallisation is a two-step process involving nucleation, where a stable nucleus separates out of solution, and crystal growth, where the nucleus grows into the final crystal. The aim of this thesis is to investigate the crystal nucleation of griseofulvin as a model medium-sized, flexible, and polymorphic active pharmaceutical ingredient. In this work, we evaluated the effect of solvent, volume and agitation on the nucleation kinetics of griseofulvin. We also analysed the resulting solid form of griseofulvin crystallising in selected solvents.Griseofulvin nucleates fastest in acetonitrile, followed by n-butyl acetate and slowest in methanol. Analysis with classical nucleation theory indicates that both the pre-exponential factor and interfacial energy values were higher in methanol, followed by n-butyl acetate and lower in acetonitrile. The interfacial energy is well correlated to the order of ease of nucleation. Mesoscale clusters are present at the start of nucleation in acetonitrile and n-butyl acetate but not in methanol aligning with a non-classical nucleation theory mechanism. The larger size and higher concentration of mesoscale clusters in acetonitrile led to faster nucleation than in n-butyl acetate.For griseofulvin in methanol, volume and agitation process parameters do not impact the interfacial energy, as expected, but the pre-exponential factor does vary. The induction time for experiments at 100 mL are well correlated to energy dissipation with the incorporation of a term for critical supersaturation. Higher shear rate and energy dissipation lead to a decrease in induction times when examined within the same vessel. However, no clear correlation is observed between nucleation rate and mixing-related parameters when experiments across different systems are considered.Griseofulvin nucleates as the stable form I in methanol, as a previously reported solvated form in acetonitrile and as an unreported solvated form in n-butyl acetate. The desolvation of the solvated form in acetonitrile resulted in an unreported polymorphic form after drying at low humidity and room temperature. This new polymorphic form has a crystal structure related to most of the reported solvated forms of griseofulvin and can act as a host to specific guest species.In conclusion, solvent, volume and agitation are important parameters for the design of crystallisation processes and the knowledge of the solid form landscape is important for the development of new formulations of active pharmaceutical ingredients. Classical theory remains a valuable framework for understanding the crystallisation process and can be effectively supplemented by non-classical approaches when it fails to offer a satisfactory explanation. Although there has been some progress in understanding the scaling-up of crystallisation within similar crystallisers, comparing scales with different agitation mechanisms and detection methods remains a significant challenge.<br><br>