The use of Process Analytical Technologies (PATs) recommended by the Food and Drug Administration (FDA) has significantly increased during the past years in the design, control and monitoring of pharmaceutical or chemical manufacturing processes [1]. Nowadays PAT is also commonly used in Good Manufacturing Practices (GMPs). Some PAT techniques employ on-line fiber-optic sensors to acquire non-destructive measurements of physical properties and kinetic information of dissolved and solid fraction of molecular substances in slurries in real time [2].

The main objective of this project is to develop a global model for DuPont’s sulfonylurea coupling reaction for monitoring purposes (e.g. detect process upset, detect endpoint, and forecast changes). The global model will allow us to estimate the kinetics of the reaction, the kinetics of nucleation, the kinetics of dissolution, and the kinetics of crystallization.

Before such complex model can be developed, it is necessary to conduct experiments in a simpler system (e.g. salicylic acid in water-ethanol mixture). These experiments allow us to control critical parameters and establish precisely known conditions. In addition, they are designed so the process of dissolution and the process of crystallization can be observed independently one another, and independently of chemical reactions. Consequently, we will be able to develop an appropriate model for each process in our small-scale semi-batch reactor.

For the simpler system, this study uses attenuated total reflectance ultra-violet visible (ATR UV-vis) spectroscopy for kinetic modeling of the dissolution and crystallization of salicylic acid in ethanol-water. The dissolution model, which relies on a power-law equation, can be obtained by adding aliquots of an ethanol-water mixture into a salicylic acid slurry. Near-infrared (NIR) diffuse reflectance spectroscopy is used to detect the degree of saturation, quantify the solid fraction present in a slurry using a calibration, and for verification and validation purposes. A temperature probe is also used to monitor heat changes involved in this dissolution.

[1] Fevotte G., International Journal of Pharmaceutics 241 (2002) 263-278
[2] Gemperline et al, Analytical Chemistry 76 (2004) 2575-2582