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.