Crystallization is an important unit operation within many pharmaceutical processes for the separation and purification of intermediate compounds and active pharmaceutical ingredients. There has been a growing interest in the use of process intensification methods for pharmaceutical crystallization to strongly improve the manufacture of pharmaceuticals. Solvents have a significant impact on crystalline product attributes, operating costs and sustainability. In view of this important role of solvents, this thesis aims to analyze and develop novel process intensification methods for pharmaceutical crystallization with a focus on optimal solvent selection and solvent operation. In particular, three research topics are covered.

First, a process model for a continuous membrane-assist...[ Read more ]

Crystallization is an important unit operation within many pharmaceutical processes for the separation and purification of intermediate compounds and active pharmaceutical ingredients. There has been a growing interest in the use of process intensification methods for pharmaceutical crystallization to strongly improve the manufacture of pharmaceuticals. Solvents have a significant impact on crystalline product attributes, operating costs and sustainability. In view of this important role of solvents, this thesis aims to analyze and develop novel process intensification methods for pharmaceutical crystallization with a focus on optimal solvent selection and solvent operation. In particular, three research topics are covered.

First, a process model for a continuous membrane-assisted crystallization process based on a full population balance equation is developed and analyzed. Membrane-assisted crystallization is a hybrid separation technology combining crystallization for solid formation and membranes for solvent removal. The region for attainable crystal product qualities of such crystallization process and design space for specified crystal product qualities are identified via a novel optimization-based method. The results reveal that augmenting a crystallization process with membranes can lead to a more robust operation with guaranteed quality, which is the result of increased process flexibility via well-controlled solvent removal.

Second, a novel integrated process and solvent design method is proposed for a continuous antisolvent crystallization process with solvent separation and recycling. The type of solvents to be used and process variables are optimized simultaneously, which is important in view of the strong interdependence between the selection of solvents and the operation of processes. The PC-SAFT model is adopted for the prediction of all relevant thermodynamic properties such as solubility, vapor-liquid-equilibrium and residual enthalpy. The continuous mapping method is adopted as the solution strategy to convert the original mixed integer nonlinear program problem into a nonlinear program problem, which is much easier to solve computationally.

Third, a novel method for the manufacture of pharmaceutical crystals is proposed. In particular, an emulsion is adopted as the solvent system and cooling is used for achieving supersaturation for crystallization, which is a new combination. The influence of emulsion droplet size on crystal product size and induction time is systematically investigated. The results show that a control on crystal size by confining crystal growth in emulsion droplets can be achieved for certain droplet size range.