Batch crystallization development

Farrell, R.J. and Yen-Cheng Tsai, 1994. Nonlinear controller for batch crystallization Development and experimental demonstration. In American Institute of Chemical Engineers National meeting. Atlanta, Paper 89e. 

Neglecting agglomeration and breakage, the population of particles in a batch crystallizer develops overtime simply by the growth of the particles (Equation 9.13) ... 

Mathews and Rawlings (1998) successfully applied model-based control using solids hold-up and liquid density measurements to control the filtrability of a photochemical product. Togkalidou etal. (2001) report results of a factorial design approach to investigate relative effects of operating conditions on the filtration resistance of slurry produced in a semi-continuous batch crystallizer using various empirical chemometric methods. This method is proposed as an alternative approach to the development of first principle mathematical models of crystallization for application to non-ideal crystals shapes such as needles found in many pharmaceutical crystals. 

Using piecewise constant control profiles and orthogonal collocation on finite elements, this approach was further developed by Renfro (Renfro, 1986 Renfro et al, 1987) to deal with much larger problems. More recent simultaneous applications that involve SQP, orthogonal collocation, and piecewise constant control profiles have been presented by Patwardhan et al (1988) for online control, and by Eaton and Rawlings (1988) for optimization of batch crystallizers. These studies have shown that simultaneous approaches can be applied successfully to small-scale applications with complex constraints. 

The design and operation of industrial crystallizers is where developments in the laboratory are confirmed and their practical significance determined. In recent years, crystallization processes involving specialty chemicals and pharmaceuticals have increased. This has led increased interest in batch crystallization operation, optimization and desigrt At the same time, the advent of powerful computers and their routine avaUabilily has stimulated interest in the area of on-line control of crystallization process (both batch and continuous). Progress in batch crystallization is surrunarized in a number of recent papers and reviews 173-801. In this section I will discuss two areas which I think will have an impact in the next decade. 

Tavare and Garside ( ) developed a method to employ the time evolution of the CSD in a seeded isothermal batch crystallizer to estimate both growth and nucleation kinetics. In this method, a distinction is made between the seed (S) crystals and those which have nucleated (N crystals). The moment transformation of the population balance model is used to represent the N crystals. A supersaturation balance is written in terms of both the N and S crystals. Experimental size distribution data is used along with a parameter estimation technique to obtain the kinetic constants. The parameter estimation involves a Laplace transform of the experimentally determined size distribution data followed a linear least square analysis. Depending on the form of the nucleation equation employed four, six or eight parameters will be estimated. A nonlinear method of parameter estimation employing desupersaturation curve data has been developed by Witkowki et al (S5). 

The crystallization literature is replete with theoretical developments of batch crystallizer models and techniques to estimate their parameters. However, most of the schemes are constrained to specific crystallizer configurations and model formulations. 

The dynamic model used in predicting the transient behavior of isothermal batch crystallizers is well developed. Randolph and Larson (5) and Hulburt and Katz (6) offer a complete discussion of the theoretical development of the population balance approach. A summary of the set of equations used in this analysis is given below. 

As an alternative to multistage batch crystallization processes with their attendant problems of material handling and losses, several types of continuous column crystallizers have been developed, in which the product crystals are washed with their own melts in countercurrent flow. Those illustrated in Figures 16.14-16.17 will be described. Capacities of column purifiers as high as 500gal/(hr) (sqft) have been reported but they can be less than one-tenth as much. Lengths of laboratory size purifiers usually are less than three feet. 

On-line particle sizing by ultrasonic (acoustic attenuation) spectroscopy was developed for use during batch crystallization processes.14 Crystallization of the alpha polymorph of (l) -glutamic acid from aqueous solution was monitored by continuously pumping the crystallizing solution through an on-line ultrasonic spectrometer. The method enabled measurement of the crystal size distribution and solid concentration throughout the... 

A population balance can be used to follow the development of a crystal size distribution in batch crystallizer, but both the mathematics and physical phenomena being modeled are more complex than for continuous systems at steady state. The balance often utilizes the population density defined in terms of the total crystallizer volume, rather than on a specific basis n = nVj. Accordingly, the general population balance given by Eq. (51) can be modified for a batch crystallizer to give ... 

The rate of cooling, or evaporation, or addition of diluent required to maintain specified conditions in a batch crystallizer often can be determined from a population-balance model. Moments of the population density function are used in the development of equations relating the control variable to time. As defined earlier, the moments are... 

It is clear that stringent control of batch crystallizers is critical to obtaining a desired crystal size distribution. It is also obvious that the development of a strategy for generating supersaturation can be aided by the types of modeling illustrated above. However, the initial conditions in the models were based on properties of seed crystals added to the crystallizer. In operations without seeding, initial conditions are determined from a model of primary nucleation. 

More recently, batch crystallizations have been rejuvenated by the development of mi-crobatch robots and by the groups of Chayen (7), DeTitta (8), and D Arcy (9). 

Sensors for particle size characterization used for crystallization include ultrasound attenuation measurement/ " laser diffraction/ and laser backscatteiing/ commercially called focused beam reflectance measurement (FBRM). Ultrasonic attenuation spectroscopy has been used to monitor the crystallization process parameters such as the crystal size distribution, concentration, and the onset of nucleation during batch crystallization of L-glutamic acid/ Off-line laser diffraction has been used to measure the crystal size distribution in the development of the crystallization process for a pharmaceutical intermediate/ ... 

Determination of metastable zone is usually the first step in the development of a batch crystallization process. Recent advances in in-process sensor technology enabled the determination of metastable zone to be carried out in an automated A typical... 

A common approach in the pharmaceutical industry for the development of a batch crystallization process... 

Trends in the crystallization process development in the pharmaceutical industry is to carry out measurements at a small scale in addition to utilizing automation and high throughput systems as exemplified by the use of automated metastable zone measurement for 1 mL samples. It is expected that the future batch crystallization recipes will be designed based on the data collected from much smaller scale crystallizers than what is currently used in industry. 

Perhaps the most troublesome aspect of batch crystallizers is the difficulty associate ciystal size distributions in going from one batch to the next. This may be overcome and control of mixing conditions. In general, however, the development of methods for design and analysis of batch crystallizers lags those for cortinuous systems. 

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