1. Optimisation of crystallisation processes using simulation and experimental methods
- Author
-
Sun, Zhuang
- Subjects
660 ,Crystallisation control ,Population balance equation ,Design of Experiments ,optimisations - Abstract
Crystallisation is an important unit operation for separation and purification in the pharmaceutical and food industrials. Crystallisation affects the product properties of an active pharmaceutical ingredient (API), such as purity, crystallisation size distribution (CSD) and crystal shape. Therefore, the crystallisation process, especially process kinetics should be understood and well controlled to produce the required size, shape and purity crystals. The purpose of this research is to design the trajectory through the phase diagram to control the relative rates of various kinetics mechanisms using (a) digital tools and (b) structured experimental investigations. Paracetamol (PCM) in propanol/water mixture solvent and Compound X offered by Takeda Pharmaceutical Company in methanol/water were used as the model system in this work. Experiments on each process were real-time monitored by Process Analysis Technology (PAT) tools, such as focused beam reflectance measurement (FBRM) for nucleation detection, particle vision and measurement (PVM) for crystal morphology detection (crystal growth and agglomeration) and attenuated total reflectance (ATR)UV/vis spectroscopy for measuring solute concentration (supersaturation which is the driving force of a crystallisation process). In addition, the availability of a mathematical model is necessary to improve a crystallisation process by implementing advanced modelbased optimisation and control of the desired product properties, which can also minimise the use of API and save cost; developing a model can be challenging due to the complexity of the process kinetics and corresponding parameter estimation (kinetics expression form and parameter number).This thesis addresses these issues for the first model system. A sequential design of experiment was applied to isolate the different kinetics in different batches by controlling supersaturation levels and seeds loading; then different kinetic mechanisms can be understood from each experiment and the corresponding mathematical expressions can be determined. PCM in propanol/water system was used as case system to demonstrate this method. Agglomeration and breakage were studied first in saturated solution to separate the growth; the experiments demonstrated agglomeration and breakage simultaneously occur and the sum kernel and symmetric daughter distribution were applied to simulate the agglomeration and breakage. In series of growth experiments, seeds were added to a low supersaturation solution to avoid secondary nucleation. A size-independent power law expression was used to describe the growth. The estimated parameters were fixed for the nucleation study. A higher seeds loading and a higher supersaturation level was applied to study secondary nucleation. Secondary nucleation rates were found to be dependent on the second moment. Unseeded cooling experiments were designed to study the primary nucleation; a power-law expression involving the supersaturation was applied to describe the kinetics. In addition, a model-based design of experiments method was applied to improve the precision of kinetic parameters for unseeded process and seeded process which include four parameters and six parameters, respectively. A D-optimal criterion was used to optimise the temperature cooling profile and sampling points to obtain the most informative process data, resulting in a reduction in the confidence intervals for the parameter estimates. Using the kinetics from the previously described batch experiments, the steady state operation of a cascade mixed-suspension, mixed-product removal (MSMPR) continuous crystallisation process was optimised using the process model to control the nucleation and growth in different stages and hence control the crystal size. To produce crystals with larger mean size, a relative smaller nucleator with higher temperature was optimised to restrict the primary nucleation and secondary nucleation, so that the remaining longer mean residence time was used for crystal growth. The start-up time was also optimised to reduce the time to reach the steady state, for stages starting full of feed solution or empty. An industrial API, Compound X which crystallised from a sequential antisolvent and cooling batch process was studied in the final section. The purpose was to design the sequence of crystallisation stepsto reduce agglomeration in the final product. Crystals with narrower product CSD and reduced agglomeration, were achieved by applying feedback-controlled temperature cycling after the wet milling (by dissolving undesired fine crystals) with an improved sequence of antisolvent and cooling. The approaches provide a systematic framework to study and control process kinetics for CSD design. The methodologies developed include applying sequential design of experiments and model-based design of experiments for estimation of kinetic parameters, optimising the continuous process by separating nucleation and growth and applying wet-milling and temperature cycle to reduce the degree of crystal agglomeration. The trajectory through the phase diagram determines the generation of supersaturation which affects the process kinetics, and in turn determines the consumption of the supersaturation and properties of the crystals such as the mean size.
- Published
- 2020
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