Thermodynamics and kinetic studies for crystallization of carboxylic acids (para-methoxyphenylacetic acid and benzoic acid): measurement and mathematical modeling
Creators: name: TANGIRALA, Ramesh
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 400406
subject: Powder and particle technology
classificationCode: 400409
subject: Separation technologies

description: Crystallization is a unit operation widely used to isolate and purify products in the pharmaceutical and chemical industries. The crystallization step directly influences product attributes such as crystal size, shape, yield, purity, and these attributes play an essential role in the drug formulations,  uptake and efficacy of pharmaceutical products. Optimal design of a crystallizer is critical to improve both the quality of the final product and the efficiency of the process, but the required  crystallization process and kinetics of many pharmacologically important products are little understood.
  
The focus of the work is generating precise crystallization data and understanding the crystallization process to facilitate the design of an optimal crystallizer for Active Pharmaceutical Ingredients (APIs) to achieve high purity and yield of the final product.  The model drug used in this study was para-methoxyphenylacetic acid, which is being used to treat and as a novel diagnostic biomarker for early detection of non-small cell lung cancer. It is also used as a building block material to produce essential drugs such as dextromethorphan, an anticough medicine, and penicillin. Commercially available para-methoxyphenylacetic acid particles are suitable for synthetic organic chemistry as an intermediate but do not achieve high sensitivity and specificity as potential biomarkers due to product purity issues.
  
This investigation aimed to elucidate the solute-solvent molecular interactions, nucleation mechanism involved during cooling crystallization of para-methoxyphenylacetic acid in various pure and binary solvents. Furthermore, developing novel methods to replace conventional approaches and developing precise crystallization engineering data for controlled crystallization and design an optimal industrial crystallizer.

Primarily, a new solid-liquid phase equilibrium data of para-methoxyphenylacetic acid in pure and mixed organic and aqueous solvent systems was obtained at common conditions of industrial practice. The modified Apelblat equation, ¿h (Buchowski) equation, and nonrandom two-liquid (NRTL) activity coefficient model was used to correlate the experimental solubility data in pure solvents, whereas the binary solvent systems were modeled using the van't Hoff-Jouyban-Acree, Apelblat-Jouyban-Acree, and NRTL models, among which the NRTL model exhibited better goodness of fit. Furthermore, for insight into the molecular interactions in the solvent systems, the enthalpy of dissolution has been being evaluated.

Then, the metastable zone widths (MSZW) were estimated for p-Methoxyphenylacetic acid in the water, isopropanol, and toluene using the polythermal method by focused beam reflectance measurement, in situ analytical process tool (PAT). In addition, the effect of solvent, cooling rate, and initial saturation temperature on metastable zone width was studied. In the way of elucidating the nucleation mechanism involved during the crystallization of para-methoxyphenylacetic acid in different solvents, the MSZW data were correlated with the Nývlt equation, self-consistent Nývlt like equation, and Sangwal's 3D classical nucleation approach and determined nucleation kinetic parameters.

Estimating crystallization data for high-value products using conventional methods requires vast quantities of chemicals and time, which is not always recommendable. In contrast to conventional methods, an improved methodology was developed to estimate seeded crystal growth kinetics by using the differential scanning calorimeter with milligrams of samples in a shorter time. To validate this method, benzoic acid in water and ethanol mixture was used for this study, and estimated kinetic parameters were compared with the literature and found good agreement. This method's additional advantage is to perform experiments and generate crystallization data at higher temperatures and pressure using appropriate DSC pans.

Furthermore, summarizing crystallization data measured in this study and understanding the crystallization mechanism involved, the process design of an industrial crystallizer for para-methoxyphenylacetic acid was suggested.