University of Limerick
Long_2020_Investigating.pdf (2.27 MB)

Investigating process variables and additive selection to optimize polymorphic control of carbamazepine in a CO2 antisolvent crystallization process

Download (2.27 MB)
journal contribution
posted on 2020-05-14, 13:41 authored by Barry Long, Kevin M. RyanKevin M. Ryan, Luis PadrelaLuis Padrela
Supercritical CO2 antisolvent crystallization typically promotes the formation of metastable polymorphic forms of pharmaceutical drugs. However, using this technological approach in combination with the use of distinct molecular additives can provide further control over the final polymorphic form obtained. The work presented herein investigates the influence of critical processing variables of a CO2 antisolvent crystallization process in the presence of molecular additives with respect to the polymorphism of carbamazepine (CBZ), a highly polymorphic BCS class II drug. A Design of Experiments (DoE) approach was performed to assess the outcome of CBZ polymorphism, impacted by CO2 antisolvent processing variables such as pressure, temperature, and CO2 addition rate when anionic additives (sodium stearate or sodium dodecyl sulfate) were selected. Statistical analysis revealed that the combination of temperature and CO2 addition rate show statistically significant impact (p < 0.05) on the final CBZ polymorphic form obtained when no additive was present during short hold studies. However, when using 5% w/w additive in the CBZ methanol solutions, CBZ samples produced from CO2 antisolvent crystallization correspond to form II (when using sodium stearate as the additive) or form III (when using sodium dodecyl sulfate as the additive) for most samples, regardless of the processing conditions used. An investigation into the polymorphic stability of these CBZ samples was undertaken, allowing the precipitated CBZ to remain immersed in the supercritical media (supercritical CO2 and methanol) for a prolonged period (60 h). Carbamazepine samples that were initially form II began to convert to the stable form III at lower temperature (40 °C), while samples that were initially form III showed almost no conversion.



Organic Process Research and Development; 24 (6), pp. 1006-1017


American Chemical Society



Other Funding information



© 2020 Royal Society of Chemistry. Personal use of this material is permitted. Permission from Royal Society of Chemistry must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works



Usage metrics

    University of Limerick


    No categories selected


    Ref. manager