Propranolol resolution using enantioselective biphasic systems

abstract

The commercialization of chiral drugs is an increasing concern in the pharmacological field since the differences in the pharmacological activities of enantiomers may result in serious problems in the treatment of diseases using racemates. The resolution of chiral drugs is important for the development of safer and more active pharmaceuticals. This work aims to develop an enantioseparation platform for the resolution of propranolol (R/S-PRP) resorting to esters of tartaric acid and chiral ionic liquids (CILs) as chiral selectors in biphasic systems. More specifically, the efficiency of enantioselective liquid-liquid extraction (ELLE) systems, both aqueous and nonaqueous biphasic systems, are here studied, aiming to do a direct comparison between these two types of systems for the resolution of R/S-PRP. Studies were carried to evaluate the proper phase forming components of ELLE, R/S-PRP:chiral selector ratio, the potential of CILs over esters of tartaric acid, and the most suitable alkyl chain length for the esters of tartaric acid. It was found that the selected organic phase formers of ELLE, 1,2-dichloroethane and ethyl acetate, greatly impact the potential of the enantiorecognition of the system. The most efficient biphasic system identified was composed of 1,2-dichloroethane-water, and dipentyl-L-tartrate and boric acid as chiral selectors, with a enantioselectivity of 2.54. This system was further employed for the resolution of R/S-PRP in centrifugal partition chromatography, to assess its scalability potential, being shown that it was possible to increase the purity of R-PRP from 59% to 75%.

keywords

AQUEOUS 2-PHASE SYSTEMS; CHIRAL IONIC LIQUID; COUNTER-CURRENT CHROMATOGRAPHY; GRIGNARD-REAGENTS; AMINO-ALCOHOLS; L-TARTRATE; SEPARATION; EXTRACTION; ENANTIOMERS; RECOGNITION

subject category

Engineering, Chemical

authors

Carreira, ARF; Ferreira, AM; Almeida, MR; Coutinho, JAP; Sintra, TE

Groups

G4 - Renewable Materials and Circular Economy
G5 - Biomimetic, Biological and Living Materials

Projects

Separação de fármacos quirais por cromatografia de partição centrífuga usando sistemas aquosos bifásicos enantioseletivos. (ChiResus)

CICECO - Aveiro Institute of Materials (UIDB/50011/2020)

CICECO - Aveiro Institute of Materials (UIDP/50011/2020)

Rede Nacional de Ressonância Magnética Nuclear (PTNMR)

acknowledgements

This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, financed by national funds through the FCT/MEC and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement. This work was also financially supported by the project POCI-01-0145-FEDER-030750 (PTDC/EQU-EPQ/30750/2017) -funded by FEDER, through COMPETE2020 -Programa Operacional Competitividade e Internacionalizacao (POCI), and by national funds (OE), through FCT/MCTES. The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). The authors thanks Mara G. Freire for allowing the use of the CPC equipment. Ana R. F. Carreira acknowledges FCT for the Ph.D. grant SFRH/BD/143612/2019.