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Strategies for multicomponent separation of Nadolol stereoisomers by simulated moving bed and jo processes

Publication . Ribeiro, António E.; Graça, Nuno S.; Arafah, Rami; Rodrigues, Alírio; Pais, Luís S.

The Simulated Moving Bed (SMB) chromatography is an interesting alternative technique for the production of fine chemicals and pharmaceuticals. The pioneer classical SMB concept was designed for the separation of binary mixtures or to the recovery of one single component from a multicomponent mixture. In recent years, this technology has undergone through several important technical developments, allowing the exploitation of better preparative separation performances. The introduction of a wide range of new and more powerful preparative stationary phases allied to the development of new and more versatile strategies and modes of SMB operation are now a reality. Several configurations have been proposed in order to extend the SMB technology to the separation of multicomponent mixtures by using a cascade of SMBs in series or other complex SMB related techniques like multi-zone SMB, intermittent SMB and JO processes [1-3]. Nadolol is a pharmaceutical drug marketed as a mixture of its four stereoisomers and its prescription is related with some severe risks such as heart failure. This four component mixture will be used as a case study for the development of chromatographic strategies for multicomponent separation. Recently, our research group reported the pseudo-binary separation of nadolol stereoisomers by SMB chromatography [4]. A SMB pilot unit with Chiralpak AD chiral stationary phase was used to obtained the more retained stereoisomer 100% pure. A different strategy was also recently published based on a three column intermittent SMB unit [5]. A new methodology for the design, optimization and experimental implementation of the multicomponent separation will be introduced, including the use of different chiral and achiral adsorbents, the screening and choice of the best adsorbent-solvent combinations, and the use of different SMB operating modes and strategies.

2016Conference object

Open access

Separation of nadolol stereoisomers by fixed-bed and continuous preparative liquid chromatography using C18 columns

Publication . Ribeiro, António E.; Arafah, Rami; Rodrigues, Alírio; Pais, Luís S.

In recent years, the authors have focused in the preparative separation of chemical drugs by chiral SMB chromatography. Different case studies have been considered, including the separation of non-steroidal anti-inflammatory drugs (ketoprofen and flurbiprofen enantiomers) [1-4], and the pseudo-binary separation of nadolol stereoisomers, a beta-blocker pharmaceutical drug [5]. While the first two case studies are typical examples of binary chiral mixtures (a pair of enantiomers), the last is an example of a quaternary mixture, composed by two pairs of enantiomers. This considerably increases the complexity and the difficulty of the separation process, asking for new strategies for the complete resolution of all the four components.

2016Conference object

Open access

Preparative separation of multicomponent mixtures by simulated moving bed liquid chromatography

Publication . Ribeiro, António E.; Graça, Nuno S.; Arafah, Rami; Rodrigues, Alírio; Pais, Luís S.

Direct racemic resolution of enantiomers by means of liquid chromatography using chiral stationary phases is nowadays a very popular technique. This popularity is mainly due to development of new chiral stationary phases and also by exploring and developing new and more efficient modes of operation. The use of chiral liquid chromatography through the simulated moving bed (SMB} technology has gained a renewed interest as an alternative technique for the production of fme chemicals and pharmaceuticals. The classic SMB process is a continuous process to separate binary (or pseudo-binary) mixtures or to recover one single component from a multicomponent mixture. Several modified SMB processes have been introduced to separate multicomponent mixtures. Among then, the cascade SMB, the intermittent SMB, the JO processes and other complex multi-zone SMB related techniques, are often applied to the separation of multicomponent mixtures. The JO technology allows the separation of ternary mixtures through a cyclic process constituted by two discrete steps [1 ]. Nadolol is a pharmaceutical drug marketed as a mixture of four stereoisomers, used to treat cardiovascular diseases. However, its prescription is also related with some severe risks such as heart failure. It is well known that pure enantiomer separation is important to control chiral drugs safety. Recently, our research group reported the pseudo-binary separation of nadolol by SMB chromatography [2]. Using the classic SMB mode of operation, the complete separation of nadolol stereoisomers was achieved using Chiralpa.k AD chiral stationary phase (CSP). The more retained stereoisomer was collected 100% pure in the extract and a mixture of the other three stereoisomers was collected in the raffmate. In this work, we will present different strategies for multicomponent separation, using different solvent compositions, other CSP and SMB related techniques. Namely, (a) The use of Chiralpak lA, that comparing to AD CSP, allows the use of a wider range of solvents and therefore better separation performances; (b) The use of the JO process to achieve a final ternary separation, using the mixture of the three stereoisomers that eo-eluted in the raffinate in the separation previously referred and (c) The separation ofthe two pairs ofnadolol enantiomers using an achiral C18 material, followed by two parallel classic SMB binary enantioseparation processes.

2015Conference object

Open access

Separation of Nadolol Stereoisomers by Fixed-Bed and Continuous Preparative Liquid Chromatography using C18 Columns

Publication . Ribeiro, António E.; Arafah, Rami; Rodrigues, Alírio; Pais, Luís S.

Continuous preparative liquid chromatography is nowadays a well-established technology used for the separation of a wide range of chemical mixtures. Among theseContinuous preparative liquid chromatography is nowadays a well-established technology used for the separation of a wide range of chemical mixtures. Among these techniques, the simulated moving bed (SMB) technology has gained an increasing interest to the industry in the production of fine chemicals and pharmaceuticals. This growing is due to the development of new and more versatile stationary phases, as well as new operating schemes for SMB and other continuous chromatographic processes. In recent years, the authors have focused in the preparative separation of chemical drugs by chiral SMB chromatography. Different case studies have been considered, including the separation of non-steroidal anti-inflammatory drugs (ketoprofen and flurbiprofen enantiomers) [1-4], and the pseudo-binary separation of nadolol stereoisomers, a beta-blocker pharmaceutical drug [5]. While the first two case studies are typical examples of binary chiral mixtures (a pair of enantiomers), the last is an example of a quaternary mixture, composed by two pairs of enantiomers. This considerably increases the complexity and the difficulty of the separation process, asking for new strategies for the complete resolution of all the four components. Experimental and simulation results have been recently presented considering a first step of a pseudo-binary separation by SMB (the more retained component being obtained pure in the extract and the other three co-eluting in the raffinate), followed by a ternary separation through a JO process [6]. This work introduces a different strategy using an achiral C18 stationary phase under reversed-phase mode to perform a first SMB separation step. The C18 achiral adsorbent allows the separation of the two pairs of nadolol diastereomers, i.e., the first racemate (composed by the nadolol compounds 2 and 3) co-eluting in the raffinate, and the second racemate (composed by the nadolol compounds 1 and 4) to be obtained in the extract SMB stream. After this preliminary achiral separation step, two parallel SMB runs must be carried out using a chiral stationary phase to achieve the complete separation of all the four nadolol stereoisomers.

2016Conference object

Open access

Separation of Nadolol Stereoisomers Using Chiralpak IA Chiral Stationary Phase

Publication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.

Chiralpak IA adsorbent is used for both analytical and preparative chromatographic separation of nadolol stereoisomers. The results include a complete screening of the mobile phase composition for both the baseline resolution of all four nadolol stereoisomers (analytical separation) and the simulated moving bed (SMB) pseudo-binary separation of the most retained stereoisomer. The experimental results show that analytical baseline resolution of nadolol stereoisomers can be achieved using alcohol/hydrocarbon and alcohol/acetonitrile solvent mixtures. The 10%ethanol/90%acetonitrile mixture is presented as the one that presents baseline resolution with lower retention. For the preparative pseudo-binary separation, pure ethanol, pure methanol, alcohol/acetonitrile, and alcohol/tetrahydrofuran mixtures proved to allow good separation results. The 100%methanol/0.1%diethylamine solvent composition was selected to perform the experimental SMB separation. Using a 10 g/L total feed concentration, the more retained stereoisomer was recovered at the extract outlet stream with 99.5% purity, obtaining a system productivity of 1.98 gL-1 h-1 and requiring a solvent consumption of 3.13 L/g of product. Comparing these results with the ones recently presented by Ribeiro et al. (2013), this work shows that the Chiralpak IA chiral adsorbent is an interesting alternative to Chiralpak AD for the separation of nadolol stereoisomers at both analytical and preparative scales.

2016Journal article

Restricted access