Automated metastable zone measurement

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. 

Parsons, A.R., Black, S.N., Colling, R., 2003, Automated Measurement of Metastable Zones for Pharmaceutical Compounds, Trans IChemE, 81, 700-704. 

The use of ATR-FTIR spectroscopy is not a requirement for the determination of the metastable zone. If the goal is the determination of metastable zone or solubility curve alone, then there are less technically complicated methods, such as the gravimetric method for solubility measurement and observation by eye for detection of the metastable limit. Even for the automation of the system, ATR-FTIR spectroscopy is not a requirement. Automated determination... 

Polythermal methods have in common that a suspension containing known amounts of solvent and solute in excess is heated and the temperature where last particles dissolve is detected. For detection, visual observation (e.g., under a microscope), turbidity measurements, particle-detecting inline probes (e.g., FBRM probe (Lasentec , Mettler Toledo GmbH)), or calorimetry may be used. Since it is a dynamic method, the results depend on dissolution kinetics of the particular system. In general, polythermal measurements are easier to automate since just a temperature has to be followed and no special analytical technique is required. The above-mentioned Crystall6 multiple reactor system can also be used to perform such kind of measurements. To detect both the dissolution process for derivation of saturation temperatures (clear points) and the formation of particles (cloud points) for determination of the metastable zone width, the... 

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