Progress of Pharmaceutical Continuous Crystallization

Crystallization is an important unit operation in the pharmaceutical industry. At present, most pharmaceutical crystallization processes are performed in batches. However, due to product variability from batch to batch and to the low productivity of batch crystallization, continuous crystallization is gaining increasing attention. In the past few years, progress has been made to allow the products of continuous crystallization to meet different requirements. This review summarizes the progress in pharmaceutical continuous crystallization from a product engineering perspective. The advantages and disadvantages of different types of continuous crystallization are compared, with the main difference between the two main types of crystallizers being their difference in residence time distribution. Approaches that use continuous crystallization to meet different quality requirements are summarized. Continuous crystallization has advantages in terms of size and morphology control. However, it also has the problem of a process yield that may be lower than that of a batch process, especially in the production of chirality crystals. Finally, different control strategies are compared.

Crystallization Growth of Single Crystal Cu by Continuous Casting

Crystallization growth of single-crystal Cu by continuous casting has been investigated using self-designed horizontal continuous casting equipment and XRD. Experimental results showed that the crystallization plane of (311), (220) and (ill) were eliminated sequentially in evolutionary process. The final growth plane of crystal was (200), the direction of crystallization was [100], the growth direction of both sides of the rod inclined to axis, and the degree of deviation of direction [100] from the crystal axis was less than 10°. In order to produce high quality single crystal, the solid-liquid interface morphology must be smooth, even be planar.

Reaction Crystallization of Struvite in a Continuous FB MSZ Type Crystallizer with Jet Pump Driven by Compressed Air

The results of struvite reaction crystallization from diluted water solutions of phosphates （V） （0.20 mass% of PO43-） by means of magnesium and ammonium ions are presented. Continuous FB MSZ crystallizer with jet pump driven by compressed air was used. Influence of pH and mean residence time of suspension on the crystal product quality was determined. Increase in pH from 9 to 11 resulted that mean crystal size decreased nearly two-time： from 27.1 to 15.1μm for mean residence time of suspension 900 s. Elongation of this time from 900 to 3,600 s influenced struvite crystal size advantageously-it increased from 27.1 to 41.2 μm at pH 9. From the population density distributions nucleation and growth rates of struvite were calculated based on the simplest SIG model of mass crystallization kinetics in MSMPR crystallizer. Linear growth rate ofstruvite crystals decreased nearly two-time with the increase in environment pH from 9 to 11, and more than 2.5-time with the elongation of mean residence time of crystal suspension in a crystallizer from 900 to 3,600 s from 1.34× 10-8 m/s （pH 9, τ= 900 s） to 2.60×10-9 m/s （pH 11, τ= 3,600 s）.

Controlling Nonlinear Dynamics in Continuous Crystallizers

Crystallization is used to produce vast quantities of materials. For several applications, continuous crystallization is often the best operation mode because it is able to reproduce better crystal size distributions than other operation modes. Nonlinear oscillation in continuous industrial crystallization processes is a well-known phenomenon leading to practical difficulties such that control actions are necessary. Nonlinear oscillation is a consequence of the highly nonlinear kinetics, different feedbacks between the variables and elementary processes taking place in crystallizers units, and the non-equilibrium thermodynamic operation. In this paper the control of a continuous crystallizer model that displays oscillatory behavior is addressed via two practical robust control approaches： （i） modeling error compensation, and （ii） integral high order sliding mode control. The controller designs are based on the reduced-order model representation of the population balance equations resulting after the application of the method of moments. Numerical simulations show good closed-loop performance and robustness properties

Deep learning-based on-line image analysis for continuous industrial crystallization processes

In situ microscopic imaging is a useful tool in monitoring crystallization processes,including crystal nucleation,growth,aggregation and breakage,as well as possible polymorphic transition.To convert the qualitative information to be quantitative for the purpose of process optimization and control,accurate analysis of crystal images is essential.However,the accuracy of image segmentation with traditional methods is largely affected by many factors,including solid concentration and image quality.In this study,the deep learning technique using mask region-based convolutional neural network(Mask R-CNN)is investigated for the analysis of on-line images from an industrial crystallizer of 10 m^(3) operated in continuous mode with high solid concentration and overlapped particles.With detailed label points for each crystal and transfer learning technique,two models trained with 70,908 and 7,709 crystals respectively are compared for the effect of training data amount.The former model effectively segments the aggregated and overlapped crystals even at high solid concentrations.Moreover,it performs much better than the latter one and traditional multi-scale method both in terms of precision and recall,revealing the importance of large number of crystals in deep learning.Some geometrical characteristics of segmented crystals are also analyzed,involving equivalent diameter,circularity,and aspect ratio.

Continuous synthesis of dolutegravir sodium crystals using liquid-gas heterogeneous microreactor

In this work, a liquid-gas heterogeneous microreactor was developed for investigating continuous crystallization of dolutegravir sodium(DTG), as well as revealing reaction kinetics and mixing mechanism with 3-min data acquisition. The reaction kinetics models were established by visually recording the concentration variation of reactants over time in the microchannel via adding pH-sensitive fluorescent dye. The mixing intensification mechanism of liquid-gas flow was quantified through the fluorescent signal to indicate mixing process, demonstrating an outstanding mixing performance with a mixing time less than 0.1 s. Compared with batch crystallization, continuous synthesis of dolutegravir sodium using liquid-gas heterogenous microreactor optimizes crystal distribution size, and successfully modifies the crystal morphology in needle-like habit instead of rod-like habit. The microreactor continuous crystallization can run for 5 h without crystal blockage and achieve D90 of DTG less than 30 μm. This work provides a feasible approach for continuously synthesizing dolutegravir sodium, and can optimize the existing pharmaceutical crystallization.

Numerical Simulation and Prediction for Sticking Type Breakout Behavior in Slab Contiuous Casting

A two-dimensional heat transfer model was developed to calculate the mould wall temperature field under normal operations condition and to determine its changing behavior when breakout occured. On the numerical simulation of sticking type breakout process and the breakout related wall temperature evolution, parameters of prediction were suggested.

Comparison of two position sensitive gamma-ray detectors based on continuous YAP and pixellated NaI(TI) for nuclear medical imaging applications

Dedicated position sensitive gamma-ray detectors based on position sensitive photomultiplier tubes （PSPMTs） coupled to scintillation crystals, have been used for the construction of compact gamma-ray imaging systems, suitable for nuclear medical imaging applications such as small animal imaging and single organ imaging and scintimammography. In this work, the performance of two gamma-ray detectors： a continuous YAP scintillation crystal coupled to a Harnamastu R2486 PSPMT and a pixellated NaI（TI） scintillation array crystal coupled to the same PSPMT, is compared. The results show that the gamma-ray detector based on a pixellated NaI（TI） scintillation array crystal is a promising candidate for nuclear medical imaging applications, since their performance in terms of position linearity, spatial resolution and effective field of view （FOV） is superior than that of the gamma-ray detector based on a continuous YAP scintillation crystal. However, a better photodetector （Hamamatau H8500 Flat Panel PMT, for example） coupled to the continuous crystal is also likely a good selection for nuclear medicine imaging applications.