Crystallization is an important process used in a wide range of industries, which has made it the main process in the primary manufacturing stage, and thereby the quality of crystals produced has a major impact on downstream processes such as filtration, milling and drying, as well as transport and storage processes. Organic reactive crystallization, which is widely used in the production of active pharmaceutical ingredients (APIs), has many unique features that make it different from cooling or anti-solvent crystallization, even leading to some concepts and methods not directly applicable to this process.
A survey of the literature reveals that previous research on reactive crystallization has mainly been conducted for inorganic materials which are known to be simpler than crystallization of organic materials. For example, it is known that compared with inorganic materials, organic materials tend more to aggregation and form amorphous. In addition, the published literature in this research area is often concerned with laboratory scale crystallization, rather than industrial scale processes.
The focus of this research project is to carry out research on the process design, optimization, simulation and scale-up of organic reactive pharmaceutical crystallization. The objective is to research the process and crystallizer design which takes advantage of the features of the reactive crystallization process and on simulation, optimization and scale-up techniques with the aim of manufacturing high quality products measured by the products’ crystallinity, stability, purity, and processability. Process analytical technology (PAT) is used as a supporting tool to achieve the above stated objectives. An off-patent drug, sodium cefuroxime which is considered as a second generation antibiotic, is used as the case study drug.
Firstly, on-line Attenuated Total Reflection-Fourier Transform InfraRed spectroscopy (ATR-FTIR) was used to monitor the change in the supersaturation in order to optimize the flow rate of the anti-solvent during the anti-solvent re-crystallization process of sodium cefuroxime. The solubility of sodium cefuroxime under various temperatures T, pH values and solvents was measured and correlated in models. The effect of the anti-solvent (95% ethanol) flow rate on crystallinity was examined and the results showed that appropriate anti-solvent flow rate could improve the stability of sodium cefuroxime. The optimized anti-solvent re-crystallization process provided a new method to obtain high-quality seeds of sodium cefuroxime.
Secondly, Process Analytical Technology (PAT) based on Focused Beam Reflectance Measurement (FBRM) was used to optimize the parameters of the reactive synthesis process of sodium cefuroxime, such as the feed order, the reaction temperature, the stirring speed, the feed rate/speed and the amount of seeds. An impinging jet mixer, which could provide rapid mixing effectiveness of reactants, was applied and optimized. After that, the optimized process was scaled-up from 1L to 10L with a volumetric scaling-up factor of 10. The product had superior crystallinity, uniform size distribution, higher stability and purity, which indicated that this optimization methodology and impinging jet mixer design could be applied in other similar reactive crystallization processes.
Finally, Process Analytical Technology (PAT) including Ultraviolet–Visible Spectrometry (UV) and FBRM was used to study the reaction kinetics and the mechanism of crystal growth in the reactive synthesis process of sodium cefuroxime. A process and crystallizer was designed based on the data obtained above. This process provided two reactors in series for conducting a rapid reactive crystallization process of pharmaceutical compounds in continuous mode. It involved a tank reactor with the use of an impinging jet mixer and stirrer to create intensive mixing of the reactants before nucleation and a tubular reactor with suitable length to avoid back mixing of the products. The results showed that by using this process, the product had uniform size distribution, higher stability and superior crystallinity, in both laboratory scale and 50L scaled-up processes.
