Investigating secondary nucleation at the microscale

Secondary nucleation of crystals is a ubiquitous phenomenon in pharmaceutical manufacturing processes and other applications and natural phenomena where crystallization is important. Already formed primary crystal nuclei generate new secondary nuclei in response to a varied range of stimuli such as mechanical disturbance, shear stress from flow and the presence of impurities. In manufacturing uncontrolled secondary nucleation can lead to difficulties managing key process variables and outcomes parameters including crystal solid form, growth rates and particle sizes. Secondary nucleation has been shown to be exquisitely sensitive to conditions including slight variations in mechanical disturbance and flow, presenting significant challenges for applications. The fundamental reasons for this sensitivity must lie in microscopic processes of detachment and addition of molecular material from and to existing nuclei, but there is little deep understanding of how these processes influence nucleation.
Most work on secondary nucleation has focussed on macroscopic bulk response eg to flow and agitation, as well as how the process then scales up to industry-relevant volumes, for example in secondary crystal generation from seed crystals in pharmaceutical manufacture. Much of the current industry knowhow and strategy is based on and limited by these empirical and trial-and-error approaches. This project will instead take a direct microscopic scale approach to improve our understanding of how microscale mechanical disturbance and shear flow influence secondary nucleation. We propose using a novel approach based on a particle trapped and manoeuvred by an optical tweezer to provide controlled micron-scale mechanical disturbance of a seed crystal acting as the source of secondary nucleation. Direct optical observation then provides data on formation of secondary nuclei including nucleation and growth rates and spatial distribution of new crystals relative to seed and disturbance location. By controlling disturbance force, and rate and type (eg 'direct' or glancing impact on the seed crystal, or 'scraping' the disturber particle along the seed surface) we can then investigate how micron-scale events trigger secondary nucleation and how mechanical factors influence later crystal growth.
Optical tweezers (whose invention gained Art Ashkin a share of the 2018 Nobel Prize in Physics) use a focussed laser beam to trap a micron-sized probe particle suspended in a liquid. Steering of the trapping beam can be used to manipulate the probe and apply local forces in a controlled way. Furthermore the probe also acts as measuring device: so-called 'passive' mode of the tweezer can be used to measure changes in local viscosity and density of the suspending medium due to release of material from the seed, by tracking the particle position within the trap and inferring from the harmonic strength of the optical trap the local force balance. Therefore by alternately steering the particle to create a disturbance, and subsequently tracking the 'passive' particle to measure local change in viscosity and density, we combine disturber and measurer in one device.
The experiment is carried out in an optical microscope, which provides focussing of the trapping/steering beam, position tracking of the particle, imaging to reveal local changes in optical contrast (refractive index) indicating early stage crystal nucleation, and direct observation of later stage crystal growth including growth shapes, once secondary nuclei are greater than around 5-10 microns and can be optically resolved. In order to develop further quantitative interpretation of the response based on the applied forces, we will also undertake hydrodynamic modelling of the disturbed flow field, using recently developed in-house hydrodynamic molecular dynamics codes. Finally we will also explore the potential for detailed molecular modelling of the response of the crystal seed surface to external force