Design of co-crystallization processes with regard to particle size distribution

• Published in: Chemical engineering science 2015-05, Vol.128, p.36-43
• Main Authors: Holaň, Jan, Ridvan, Luděk, Billot, Pascal, Štěpánek, František
• Format: Article
• Language: English
• Subjects: Co-crystal; Cooling crystallization; Needle shaped particles; Particle size distribution; Population balance model; Seeding
• ISSN: 0009-2509; 1873-4405
• DOI: 10.1016/j.ces.2015.01.045

Many active pharmaceutical ingredients (APIs) are poorly soluble and therefore poorly bioavailable. Advances in crystal engineering have motivated research into the design of pharmaceutical co-crystals. This study examines the formation of agomelatine–citric acid co-crystal in a batch cooling crystallization. Three linear cooling profiles (10°C, 20°C and 30°C/h) were applied for both unseeded and seeded crystallization and the effect of the seeding temperature on the final crystal size distribution was systematically investigated. A mathematical model of the crystallization process, consisting of the population and mass balance, was formulated and solved using the finite difference method. The growth and nucleation rate constants were evaluated iteratively by the comparison of measured and simulated crystal size distributions. The similarities and differences between classical single-component crystallization and co-crystallization were discussed. [Display omitted] •Co-crystallization of agomelatine and citric acid in batch cooling crystallization.•Effect of cooling profile and seeding temperature on crystal size distribution.•On-line process monitoring by FBRM.•Population balance model for the evaluation of kinetic parameters.•Unusual trends in apparent orders for crystal growth and nucleation.