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- Separation of nadolol racemates by high pH reversed-phase simulated moving bed chromatographyPublication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.Nadolol is a pharmaceutical drug marketed as a mixture of four stereoisomers, used to treat cardiovascular diseases. This drug is a mixture of two pairs of racemates, therefore, its complete separation represents a challenging task. Recently, our research group reported the pseudo-binary separation of nadolol by SMB chromatography using both coated Chiralpak AD and Chiralpak IA immobilized chiral stationary phases. In this work, we present an alternative strategy, implementing a first achiral separation step, by using C18 columns to perform the separation of the two pairs of nadolol racemates under reversed-phase mode. Extensive experimental and simulation results will be presented including solvent screening, measurement of equilibrium and kinetic data, and both fixed-bed and SMB preparative separations. Extensive experimental and simulation results will be presented, including solvent screening, measurement of equilibrium adsorption isotherms, breakthrough measurements, and SMB (FlexSMB-LSRE unit) experimental preparative separation using C18 columns.
- Preparative separation of nadolol racemates using reversed-phase liquid chromatographyPublication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.Nadolol is a nonselective beta-adrenergic receptor antagonist ( -blocker) pharmaceutical drug, widely used in the treatment of cardiovascular diseases, such as hypertension, ischemic heart disease (angina pectoris), congestive heart failure, and certain arrhythmias. Its chemical structure has three stereogenic centers which allows for eight possible stereoisomers. However, the two hydroxyl substituents on the cyclohexane ring are fixed in the cis-configuration, which precludes four stereoisomers; in fact, two pairs of enantiomers. Nadolol is presently marketed as an equal mixture of the four stereoisomers, designated as the diastereoisomers, There are still few published works concerning the separation of nadolol stereoisomers. Most of these works refer the resolution at analytical scale and few refer the separation at preparative scale using the simulated moving bed (SMB) technology [2-4]. This technology is generally based on the use of chiral adsorbents which must have enough recognition for all the chiral species.
- Complete separation of the quaternary mixture of nadolol stereoisomers using preparative and simulated moving bed chromatographyPublication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.The separation and purification of high added value products by liquid chromatography is a very popular technique. The development of more stable and efficient stationary phases, together with the design of innovative and more flexible separation processes, enhanced the use of chromatographic processes, particularly at preparative and industrial scales through fixedbed and simulated moving bed (SMB) technologies. Fixed-bed and SMB techniques are more and more used in the separation of a wide range of products for the pharmaceutical, fine chemistry, biotechnology and food industries. In this context, one of the actual main challenges concerns the design and optimization of these chromatographic processes for challenging multicomponent separations. This includes the development of new and innovative chromatographic processes, combining different design strategies and modes of operation, with different types of stationary and mobile phases.
- Separation of Nadolol Stereoisomers Using Chiralpak IA Chiral Stationary PhasePublication . 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.
- Enantioseparation of the four nadolol stereoisomers by fixed-bed and simulated moving bed chromatographyPublication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, L.S.In the last decades, the separation and purification of high added value products by liquid chromatography has been a very popular technique. The development of more stable and efficient stationary phases, together with the design of innovative and more flexible separation processes, enhanced the use of chromatographic processes, particularly at preparative and industrial scales through simulated moving bed (SMB) technology and allied techniques. Nowadays, preparative and SMB related techniques are more and more used in the separation of a wide range of high added value products of interest for the pharmaceutical, fine chemistry, biotechnology and food industries. In this context, one of the actual main challenges concerns the design and optimization of these chromatographic processes for multicomponent separations. This includes the development of new and innovative chromatographic processes, combining different design strategies and modes of operation, with different types of stationary and mobile phases. This communication will introduce the multicomponent separation challenge using the commercial pharmaceutical drug of nadolol stereoisomers. The nadolol represents a very interesting case-study of multicomponent chiral separation since it is composed by four stereoisomers, arranged in two pairs of enantiomers. In this way, it introduces the possibility of alternative strategies, using different kind of separation sequences and techniques, the use of different packings (chiral and achiral stationary phases), and the correspondent mobile phase optimization at both normal and reversed phase modes. An extensive set of experimental results obtained at fixed-bed and SMB operations will be presented. The complete methodology will be explained and applied for the pseudo-binary enantioseparation of the more retained and active stereoisomer (1+2+3)/(4), and for the (2)/(3) and (1)/(4) binary enantioseparations after a first achiral pseudo-binary separation of the two nadolol racemates.
- Preparative separation of nadolol racemates by fixed-bed and SMB liquid chromatography using C18 columnsPublication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.Nadolol is one representative beta-blocker pharmaceutical drug prescribed worldwide for relieve of several diseases mainly related with the cardiovascular system. However, like other pharmaceutical drugs, it is also related with some severe risks, such as depression, insomnia and cardiovascular failure, among others. Some authors refer that this problem is related, or could be related, to the fact that nadolol drug is still marketed as a mixture of equal amounts of its four stereoisomers. In the pharmaceutical industry and in terms of preparative scale, there are two main strategies to obtain pure enantiomer drugs. The first strategy is based on traditional methods of selective organic synthesis that allows the attainment of large amounts of a single product but with the disadvantage of being large time consuming. The other preparative strategy makes use of continuous separation processes based on multicolumn and cyclic adsorptive liquid chromatographic techniques to achieve the resolution of a racemic mixture. The use of such technologies allows, in a short period of time, the obtaining of enough amounts of pure enantiomers needed to perform the main pharmacological studies in the first steps of drug development. Lately, our research group reported the pseudo-binary separation of RSR-nadolol stereoisomer, referred in the literature as being the one responsible of the nadolol drug therapeutic action, by means of simulated moving bed (SMB) chromatography using both coated Chiralpak AD and Chiralpak IA immobilized chiral stationary phases (CSP).1,2 This technology is generally based on the use of chiral adsorbents which must have enough recognition for all the chiral species. In this work it is proposed an alternative strategy, implementing a first achiral separation step, to be followed by two subsequent parallel chiral separation steps.3-5 In this first achiral step, C18 columns are used to perform the separation of the two pairs of nadolol enantiomers (“racemate A” from “racemate B”) under reversed-phase mode. 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. Extensive experimental and simulation results will be presented including solvent screening, measurement of equilibrium adsorption isotherms, breakthrough measurements, and both fixed-bed (Azura prep LC unit) and SMB (FlexSMB-LSRE unit) preparative separations using C18 columns.
- High pH reversed-phase preparative chromatographic separation of nadolol racemates using C18 adsorbentsPublication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.In recent years, the continuous improvement of preparative liquid chromatographic techniques, make easier the resolution of complex multicomponent chiral drugs, into single pure stereoisomers, by means of combining different strategies and using chiral and achiral adsorbents. Nadolol is one representative beta-blocker pharmaceutical drug prescribed worldwide for relieve of several diseases related with the cardiovascular system. This pharmaceutical chiral drug represents a very interesting case-study since it is composed by four stereoisomers, being a mixture of two racemates, i.e., a mixture of two pairs of enantiomers. The complete separation of all the four nadolol stereoisomers can be achieved using alternative strategies, different types of separation sequences and techniques, such as, the use of different adsorbents (chiral and achiral stationary phases), and the correspondent mobile phase optimization at both normal and reversed-phase modes [1-3]. In this work, a large set of experimental results will be presented for the separation of the two nadolol racemates using a commercial Azura preparative HPLC system, equipped with two 250 mL/min pump heads. The fixed-bed separation was carried out through a sequence of multiple injections, optimized by taking into account the retention time of both racemates using an XBridge Prep OBD C18 column with preparative dimensions (250mm ID x 30mm L) and with a particle size diameter of 10 m [4]. Experimental results will show the optimization of the mobile phase composition and injection time. The experimental results presented in this work stresses out the advantage of using a first achiral reversed-phase chromatographic separation step to perform the separation of the two nadolol racemates.
- Separation of Nadolol Stereoisomers by Fixed-Bed and Continuous Preparative Liquid Chromatography using C18 ColumnsPublication . 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.
- Separation of nadolol stereoisomers by liquid chromatography using Chiralpak IA chiral stationary phasePublication . Arafah, Rami; Pais, Luís S.; Ribeiro, António E.The main objective of this work is to study the chiral separation of stereoisomers of nadolol by preparative liquid chromatography. In this report it is presented the state of the art and experimental results obtained for optimizing the methodology for preparative scale separation of nadolol stereoisomers using an immobilized chiral stationary phase (Chiralpak® IA). The screening of the solvent composition is based on the best solvent or solvents mixture to perform the pseudo-binary separation (1+2+3/4) of the more retained stereoisomer using the simulated moving bed technology. The three least retained components (1, 2 and 3) co-elute in the raffinate outlet stream and the more retained component (4) will elute in the extract outlet stream. After the solvent composition optimization, 100%methanol:0.1%diethylamine solvent composition was selected to perform the experimental SMB separation. Experimental results also include adsorption equilibrium isotherm and breakthroughs measurements followed by SMB experimental operation. Using a 2 g/L total feed concentration, the more retained stereoisomer was totally recovered at the extract outlet stream with 100% purity, obtaining a system productivity of 0.31 gtarget product/(Lbed.hr) and requiring a solvent consumption of 27.71 Lsolvent/gtarget product. Another SMB run was performed using a considerable higher feed concentration of 10 g/L and an improvement in the performance parameters were observed. For the more retained stereoisomer in the extract outlet stream, a purity of 99.5%, and a recovery of 97.6% was obtained, with a productivity of 1.98 gtarget product/(Lbed.hr) and a solvent consumption of 3.13 Lsolvent/gtarget product. The extract and raffinate SMB outlet streams were collected and used to perform additional adsorption equilibrium isotherm and breakthroughs experiments. These results were used to evaluate the differences in the adsorption equilibrium dynamics for pure and racemic nadolol feed mixtures. This work introduced new alternative results for the separation of nadolol stereoisomers and contributed for a future objective of the complete separation of the four nadolol stereoisomers by SMB technology using different modes of SMB operation, adsorbents and solvent compositions.
- Multicomponent separation of nadolol stereoisomers combining different preparative technologies and chiral and achiral-chiral strategiesPublication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, L.S.Nadolol is a common prescribed pharmaceutical drug for the relieve of several cardiovascular diseases and represents a very interesting case-study of multicomponent chiral separation since it is composed by four stereoisomers, being two pairs of enantiomers. In this way, it introduces the possibility of alternative strategies, using different kind of preparative separation sequences and techniques, the use of different packings (chiral and achiral stationary phases), and the corresponding mobile phase optimization at both normal and reversed-phase modes. When considering preparative and multicomponent separation, the complexity deeply increases by introducing the necessity of multi-step separation sequences (or a much more complex multi-region separation process), by opening the possibility to combine chiral and achiral stationary phases (when in presence of stereoisomers instead of just one pair of enantiomers) and to combine different separation techniques (fixed-bed and simulated moving bed (SMB) related processes). The design of the complete preparative separation of nadolol stereoisomers asks for a global experimental and simulation methodology considering both the characterization and optimization of each separation step and its sequences to achieve the four nadolol components pure. New strategies using combinations of achiral and chiral stationary phases and sequences of different separation techniques will be presented. Extensive experimental and simulation results for the complete separation of all the four nadolol stereoisomers using Chiralpak IA (chiral) and different Waters C18 (achiral) stationary phases will be presented.
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