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This study investigates the effects of key process parameters of continuous mixing-induced supersaturation on the antisolvent crystallization of lactose using D-optimal Design of Experiments (DoE). Aqueous solutions of lactose were mixed isothermally with antisolvents using a concentric capillary mixer. Process parameters investigated were the choice of antisolvent (acetone or isopropanol), concentration of lactose solution, total mass flow rate, and the ratio of mass flow rates of lactose solution and antisolvent. Using a D-optimal DoE a statistically significant sample set was chosen to explore and quantify the effects of these parameters. The responses measured were the solid state of the lactose crystallized, induction time, solid yield and particle size. Mixtures of α-lactose monohydrate and β-lactose were crystallized under most conditions with β-lactose content increasing with increasing amount of antisolvent. Pure α-lactose monohydrate was crystallized using acetone as the antisolvent, with mass flow ratios near 1:1, and near saturated solutions of lactose. A higher resolution DoE was adopted for acetone and was processed using multivariate methods to obtain a crystallization diagram of lactose. The model was used to create an optimized process to produce α-lactose monohydrate and predicted results agreed well with those obtained experimentally, validating the model. The solid state of lactose, induction time, and solid yield were accurately predicted.

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This study combines reactive and antisolvent crystallization concepts via mixing-induced supersaturation to demonstrate a wider range of options for solvent system selection in multicomponent crystallization. This approach was applied to investigate continuous crystallization of 1:1 and 2:1 cocrystals of benzoic acid and isonicotinamide. Design of Experiments was used to identify conditions where pure cocrystal phases are obtained and a continuous mixing-induced cocrystallization process was implemented to selectively produce either 1:1 or 2:1 cocrystals.

Preferential crystallization is a technique used to separate enantiomers and is usually performed in batch mode. For a continuously operated preferential crystallization process from a supersaturated racemic solution, however, nucleation and growth of the unwanted counter enantiomer eventually becomes inevitable, and a controlling measure should be taken. Through the use of polarimetry as an effective monitoring tool to detect the crystallization of the unwanted enantiomer, a novel strategy to eliminate the unwanted enantiomer crystals in a continuous cooling preferential crystallization process is presented. The strategy involves switching from the racemic feed solution to an enantiopure feed solution upon detection of the counter enantiomer crystals. This allows selective dissolution of the counter enantiomer crystals while the preferred enantiomer crystals continue to crystallize. After all of the counter enantiomer crystals are dissolved by decreasing the counter enantiomer solution concentration sufficiently below its solubility, the feed is switched back to the racemic solution. Through the use of this modelfree controlling action the continuous process does not have to be terminated. Instead, this method rectifies the situation to the initial metastable steady state by using a portion of the produced enantiomer product. The process can therefore operate at higher supersaturations compared with existing processes for longer periods of time since the control action does not rely on the dissolution kinetics of the system but rather on the thermodynamics of the phase diagram. We show that this new approach is an effective and scalable control strategy for achieving enantiopure product in a continuous preferential crystallization process.

The free radical emulsion copolymerization of methyl methacrylate and ethyl acrylate initiated by ammonium persulfate at 60 "C in the presence of a blend of anionic and non-ionic emulsifiers was investigated. In the interval 2 the rate of copolymerization is approximately proportional to the 0,6th power of the total emulsifier concentration. The number of final polymer particles is proportional to the 0,5th power of the total emulsifier concentration. The dependence of the rate of copolymerization on the composition of the emulsifier system is described by a curve with a maximum at a mole fraction of non-ionic emulsifier of about 03. The mean particle size keeps a constant value until the maximum of the polymerization rate is reached. Beyond this maximum the particle size abruptly increases (mole fraction of non-ionic emulsifier =0,5). The rate of copolymerization, the conductivity and stability of the polymer latex increase, whereas the particle size and interfacial tension of latex and the number-average molecular weight of copolymer decrease with increasing total concentration of the emulsifier blend.

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