Optimization of batch antisolvent crystallization

Batch antisolvent crystallization is a commonly used crystallization method in the pharmaceutical industry, which produces very pure crystals with a narrow particle size distribution and high yields. It is also an effective method to crystallize heat sensitive materials, since the crystallization can be achieved at low temperatures.; The objectives of this research were to study the effect of the antisolvent addition rate on various crystallization parameters, including operational parameters and product specification parameters, and to find an operating procedure that produces a desired particle size distribution. The monitoring of the system is done in situ using attenuated total reflection Fourier transform infrared (ATR FTIR) spectroscopy.; Since antisolvent crystallisation involves two solvents, the polarity behavior of binary systems is addressed first. This involved the introduction of a spectroscopic method to estimate polarities of pure solvents. The same method was applied to binary mixtures. It was shown that even small amounts of antisolvent will cause significant nonideality in the polarity of the system. This should be accounted for in antisolvent crystallization.; The chosen crystallization was I-lysine monohydrochloride purification using water as a solvent and ethanol as an antisolvent. The solubility data for I-lysine monohydrochloride in water, ethanol, and mixtures of water and ethanol were determined. The addition of ethanol decreased the solubility of I-lysine monohydrochloride in water significantly.; The growth kinetics of I-lysine monohydrochloride were estimated from nucleation cell and seeded laboratory scale experiments. These data were used to predict nucleation rates. It was shown that the nucleation rate is very high throughout the crystallization.; The effect of the antisolvent addition rate on bulk supersaturation and particle size was studied. ATR FTIR spectroscopy was used to study the bulk supersaturation. It was shown that the bulk supersaturation was not a function of antisolvent concentration. Sieving showed that the particle size was strongly dependent on the antisolvent addition rate.; This dissertation employed a spectroscopic method for studying solvent polarity behavior. The feasibility of ATR FTIR spectroscopy for monitoring batch antisolvent crystallization was demonstrated. Also, an operating scheme for producing the desired particle size was presented.