Seeded Batch Cooling Crystallization with Temperature Cycling for the Control of Size Uniformity and Polymorphic Purity of Sulfathiazole Crystals Mohd R. Abu Bakar, Zoltan K. Nagy,* and Chris D. Rielly Department of Chemical Engineering, Loughborough UniVersity, Loughborough, Leicestershire LE11 3TU, United Kingdom Abstract: An experimental study has been conducted to evaluate the capability of a seeded batch cooling crystallization with a tem- perature cycling method to produce a narrow crystal size distribu- tion and grow a desired polymorphic form of sulfathiazole crystals. The study used focused beam reflectance measurement (FBRM), and attenuated total reflectance ultraviolet/visible (ATR-UV/vis) spectroscopy for the in situ monitoring and control of the process. Based on the FBRM readings, the process was driven using a feedback control approach that employs alternating cycles of heating and cooling phases so that the number of counts, corre- sponding to the number of seed particles, is maintained, whilst the square-weighted chord length distribution, indicating the dynamic progress of the growth of the seeds in the system, is increased. Results of the experiments show that the temperature cycling method promoted Ostwald ripening, which helped in accelerating the growth and enhancing the size uniformity of the product. The method also has a good prospect to be implemented for the control of polymorphic purity. Seeds of Form I and Form II could be grown from n-propanol and water, respectively. Form I seeds in water were first transformed into Form II and/or swamped by nuclei of Form II, before the growth of the newly formed crystals took place. Seeds of Form II and Form III in n-propanol, however, were not able to grow at all. This study confirmed that the nucleation and growth of sulfathiazole crystals are solvent-mediated, and the insight into these phenomena was captured very well by the in situ monitoring tools. 1. Introduction Crystallization is an important unit operation used in many chemical process or pharmaceutical industries. The objective of the operation is to generate crystals with desired qualities including crystal size distribution (CSD), habit, purity and polymorphic form. In order to achieve this objective, a careful selection of the crystallization operation and control method is required. The application of process analytical tools has led to novel control approaches for pharmaceutical crystallization, which can yield significant product quality improvements. Alongside supersaturation control 1-9 and, more recently, a direct nucleation control, 10 the method of seeding also plays an important role in defining the properties of the crystals produced. Seeding is widely used in the control of CSD 11-15 and has been successfully applied in the control of polymorphism. 16-18 Generally, the technique involves the introduction of seed crystals in a supersaturated solution, and the operating curve afterward should remain within the metastable zone. 19,20 During the process, secondary nucleation is expected to take place, and the supersaturation is mainly used for the growth of seeds. This type of seeding technique circumvents the uncertainties in the spontaneous primary nucleation since the system is not allowed to become labile. 6 Seed crystals can be generated either directly from recrys- tallization or from subsequent particle-size reduction processes including sifting, screening, sonication, supercritical fluid extraction and particle-size reduction followed by ripening (ageing). These processes, however, may not eliminate, and may even promote, the uncertainty in the size uniformity of the produced seed crystals. 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