Crystallization Behaviour Of Zinc Lactate In Presence Of Impurities

Crystallization is an important separation and purification process used widely in food, fine chemical and pharmaceutical industries. Especially in the pharmaceutical industry, crystallization processes are often carried out as the final purification step in the manufacturing of active pharmaceutical ingredients (APIs), enabling one to obtain solid products with high purity at low costs.Crystallization is a very complicated process as it involves many concomitant phenomena such as nucleation, growth, breakage and agglomeration of crystals, and the purity and physical properties (morphology, crystal size distribution, bulk density, product filterability, and dry solid flow properties) of the crystals are significantly influenced by the selection of the crystallization process (e.g. cooling, evaporation, or antisolvent addition). The control of the manipulated "input" variables during the crystallization process (e.g. stirring, cooling or evaporation rates, seed amount, rate of antisolvent addition, etc.) also plays a key-role in the determination of the final dispersed solid properties. Despite the long history and widespread application of crystallization, a large number of unsolved problems remain concerning modeling, design and control of the industrial processes, which requires an in-depth and improved understanding of the mechanisms of nucleation, growth, breakage and agglomeration, and of the influence of the process variables on these mechanisms.Industrial solutions are almost invariably impure, by any definition of the term, and in many cases, small amounts of impurities present in the solution can have a dramatic effect on solubility, nucleation, crystal growth, and morphology. Furthermore, product purity is probably the most important index of product quality, and is obviously of paramount concern for pharmaceuticals because small amounts of impurities are likely to result in reduced drug efficacy and harmful side effects. Understanding the effect of impurity on the crystallization and controlling the process to reduce as much as possible the impurity content of the main crystallizing product is therefore of significant engineering importance.In this dissertation, crystallization behaviour of zinc lactate in presence of impurities was investigated. The main work and results are listed as follows:(1) NaCl, HC1 and four other generic organic acid/salt including succinic acid, citric acid, malic acid and sodium oxalate are selected as impurities to investigate the effects of pH and impurities on the solubility of zinc lactate. Moreover, effect of malic acid on the position and width of zinc lactate metastable zone was also studied. The results show that the solubility of zinc lactate is a combined effect of pH and intermolecular interaction between impurity and host species which is mainly due to the formation of metal-organic complexes. In our system, the solubility of zinc lactate slightly increases with decreasing pH. And the solubility of zinc lactate increases in presence of organic acid, while decreases in presence of sodium oxalate. On this basis, a model is proposed for the prediction of effects of impurities on solubility at different initial concentration, which is able to fit the experimental data satisfactorily. Besides, the presence of malic acid increases both the solution solubility and supersaturation limit, and consequently, changes the position and width of metastable zone.(2) Primary nucleation kinetics of zinc lactate in presence of impurities including malic acid, succinic acid and sodium oxalate were investigated. The results show that the solubility, energy barrier for the formation of nuclei and intermolecular binding energy are influenced in presence of impurities. The position and width of metastable zone are consequently changed. The primary nucleation rate depends on the combination effects of molecular binding energy and solute concentration, which will transform with increasing the supersaturation in aqueous solution.(3) A method concerning on-line monitoring of solution concentration during cooling crystallization process by using conductivity meter was proposed. Furthermore, four cooling crystallization processes of zinc lactate were performed, and the variations of concentration were measured on-line based on this method. And the accuracy was verified by comparing with the experimental results measured off-line by HPLC. On this basis, a simple numerical simulation model, which can be used to predict the nucleation and crystal growth kinetics during crystallization process, was proposed by combining the revised Kubota and PBE model. The results show that this model was successfully adopted to obtain kinetic expressions for both nucleation and crystal growth as a function of supersaturation. Moreover, the presence of malic acid led to a reduction in the overall nucleation and growth kinetics of zinc lactate. And the reductions to the nucleation and growth kinetics were more pronounced when the malic acid concentration increased.(4) Batch cooling crystallization of zinc lactate in the presence of malic acid was carried out at different operating conditions to show the influence of secondary nucleation and the rate of crystal growth on the purity, crystal size, yield and crystal structure of the final products. The results show that appropriate amount and size of seed crystals should be chosen to get the final product with high average volume crystal size and purity. Moreover, other operating parameters such as seeding temperature, cooling rate and terminated temperature were also shown to exert some influence on the crystallization process. Concerning the crystal shape, crystals grown in impure media appeared to be substantially different.(5) Adsorption of impurities including malic acid and succinic acid on the crystal surface of zinc lactate was investigated using molecular modeling. The results show that the binding energies of malic acid and succinic acid molecules on the surface of zinc lactate are higher than that of zinc lactate molecules. With respect to malic acid, the binding energies of which on surface (002) and (100) of zinc lactate are slightly higher than that on surface (110), the crystal then mainly growth in the direction of surface (110), and the crystal habit exhibits rather thin anisotropic shape. While the binding energies of succinic acid on surface (002) and (110) of zinc lactate are significantly higher than that on the surface (100) of zinc lactate. The crystal habit therefore exhibits a laminar shape. All these predictions are conincident with the results obtained from experiments.