Emilie Gagnière

Chapter 9:Co-crystallization in Solution and Scale-up Issues

This chapter focuses on the co-crystallization process in organic compounds. The operation is performed in batch mode in order to meet regulatory requirements. The industrial manufacturing process is carried out in solution for economical reasons. When a co-crystal form is chosen from among the different screened solid forms of an API, the development of such a co-crystallization process starts on the lab scale in a thermostated mechanically stirred reactor, since it is representative of the most popular apparatus used in the chemical and pharmaceutical industry. We recall that the nucleation, growth and dissolution mechanisms involved in the crystallization of a mono-component crystal are similarly acting in the co-crystallization of a multi-component crystal. The development process starts after co-crystal screening with the construction of a thermodynamic phase diagram of the system API/co-crystallizing agent/solvent. The definition of the operating conditions requires taking into account the possible kinetic pathway in the phase diagram during the run since other solid forms (single component crystal or another co-crystal form) may appear and compete against the co-crystal form. Several solid phases may appear concomitantly or consecutively during the process, some of them may disappear whereas others continue to grow. The choice of a “safe” operating region combined with a seeding strategy ensures the presence and development of only the desired co-crystal form all along the run. However in the case of a final co-crystal phase mixed with another crystalline phase due to a process deviation, it is possible to trigger a solution-mediated phase transition in suspension by manipulating the concentration of one of the co-crystal components, in order to suppress this unexpected solid phase and to fulfill the crystalline purity requirements.

Hybrid Modeling of Phase Transition for Evaporators and Condensers in Chillers

Abstract A novel hybrid dynamic model for two-phase heat exchangers is described in this paper. This model is developed for dynamic modeling of chillers and heat pumps. It permits to represent over time the spatial distribution of the state variables such as the mass fraction, the mass density, the temperature and the pressure. A switching procedure between different regimes based on a phase stability test is applied to ensure the continuity of the system evolution. This switching is performed by matrix operations, which permit to achieve a global and very compact representation of the system. The manipulated matrices are analytically determined from a thermodynamic model of the refrigerant based on an equation of state. A simulation program is developed using the Matlab software. Simulation tests with step-type inputs are provided, which show the relevance of the model as well as its high flexibility since one can switch automatically from an evaporation situation to a condensation situation and vice-versa.