Separation of a quaternary chiral mixture using different simulated moving bed strategies

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 multicolumn chromatography (M CC) processes, such as modified SMB processes have been introduced to separate multicomponent mixtures. Among then, the cascade SMB, the intermittent SMB, the JO processes (also called pseudo-SMB) 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 ,2]. 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 using both coated Chiralpak AD and Chiralpak lA inunobilized chiral stationary phases (CSP) [3,4]. Using the classic SMB mode of operation, the complete separation of nadolol stereoisomers was achieved using both CSP. The more retained stereoisomer was collected 100% pure in the extract and a mixture of the other three stereoisomers was collected in the raffinate. In this work, we will present different strategies for multicomponent separation, using different solvent compositions, different 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 of the two pairs of nadolol enantiomers using an achiral C18 material, followed by two parallel classic SMB binary chiral enantioseparation processes. The application of these different approaches represents possible SMB strategies for the complete separation of the quaternary nadolol chiral mixture.This work was financially supported by Project POCI-01-0145-FEDER-006984-Associate Laboratory LSRE-LCM funded by FED ER funds through COMPETE2020 - Programa Operacional Competitividade e Internacionali~ao (POCI) - and by national funds through FCT - Fundação para a Ciência e a Tecnologia. This work was also eo-financed by QREN, ON2 and FEDER through Project NORTE-07-0162-FEDER-000050.info:eu-repo/semantics/publishedVersio

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

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.Financial support by the Portuguese R&D foundation FCT (Fundação para a Ciência e a Tecnologia) and European Community through FEDER (project PTDC/EQUEQU/ 119025/2010) is gratefully acknowledged. This work was co-financed by FCT/MEC and FEDER under Program PT2020 (Project UID/EQU/50020/2013) and by QREN, ON2 and FEDER (Project NORTE-07-0162-FEDER-000050).info:eu-repo/semantics/publishedVersio

Mengenali Kecanduan Situs Porno pada Remaja: Gambaran Mengenai Faktor Penyebab dan Bentuk Kecanduan Situs Porno Remaja

Adolescence is a phase where people want to experience new things in their life that this phase is vulnerable for their development. Various vulnerabilities can effect adolescence, which one of them is addicted and accessing to porn sites. This research used a mixed method approach between qualitative and quantitative research using descriptive form that aims to obtain an overview of the causes and forms of addiction to porn sites that experienced by adolescence. Informants in this research were 112 adolescence who consisted of 59 men and 53 women who were located in the city of Makassar aged 15-18 years old and never access porn sites, where researches used purposive sampling. This research used a addicted to porn sites scale that was adapted by the author based on Porn Addiction Assessment of Young as well as a questionnaire prepared by the researcher using a literature review regarding addiction porn sites as a research instrument. The data obtained will be analyzed using qualitative analysis model with a content analysis form and then processed using statistical methods of frequency distribution. The results in this research shows that pornographic in adolescent males is higher than adolescent girls. Factors that causes a person becomes addicted to porn sites are divided into external and internal, which external factors in this case is from friends, is the biggest factor that causes porn sites addiction in adolescents. However, internal factors, such as their own desires and curiosity will also affect adolescents addicted to porn sites. In addition, most teenagers in Makassar are classified as a compulsive sexual user. The researchers also found a new characteristic of user, namely defensive user based on the informants responses

PENGARUH PENERAPAN MODEL PROJECT BASED LEARNING TERHADAP KEMAMPUAN PEMECAHAN MASALAH MATEMATIS DITINJAU DARI DISPOSISI MATEMATIS PADA SISWA SMA/MA DI PEKANBARU

Penelitian ini bertujuan untuk mengetahui terdapat atau tidak pengaruh penerapan model project based learning terhadap kemampuan pemecahan masalah matematis ditinjau dari disposisi matematis pada siswa SMA/MA di Pekanbaru. Penelitian ini merupakan penelitian dengan menggunakan desain factorial eksperiment. Populasi dalam penelitian adalah seluruh siswa kelas X SMA Negeri 8 Pekanbaru tahun ajaran 2024/2025. Sampel penelitian ini dipilih dengan menggunakan cluster random sampling, terpilih kelas X.6 sebagai kelas eksperimen dan kelas X.7 sebagai kelas kontrol. Adapun teknik pengumpulan data yang digunakan pada penelitian ini adalah tes, angket, observasi dan dokumentasi. Instrumen pengumpulan data berupa soal tes kemampuan pemecahan masalah matematis, lembar angket disposisi matematis, lembar observasi dan foto pelaksanaan kegiatan penelitian. Sedangkan teknik analisis data yang digunakan adalah uji anova dua arah. Berdasarkan hasil analisis data hasil penelitian dapat diambil kesimpulan bahwa: 1) Terdapat perbedaan kemampuan pemecahan masalah matematis antara siswa yang diajar menggunakan model project based learning dengan siswa yang diajar menggunakan model pembelajaran konvensional. 2) Terdapat perbedaan kemampuan pemecahan masalah matematis antara siswa yang memiliki disposisi matematis tinggi, sedang dan rendah. 3) Tidak terdapat pengaruh interaksi antara model pembelajaran dan disposisi matematis terhadap kemampuan pemecahan masalah matematis siswa. Berdasarkan uraian kesimpulan tersebut, secara umum dapat disimpulkan bahwa model project based learning berpengaruh terhadap kemampuan pemecahan masalah matematis ditinjau dari disposisi matematis pada siswa SMA/MA di Pekanbaru

Complete separation of the quaternary mixture of nadolol stereoisomers using preparative and simulated moving bed chromatography

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.info:eu-repo/semantics/publishedVersio

Strategies for the global multicomponent separation of nadolol stereoisomers by chiral and achiral fixed-bed and simulated moving bed chromatography

The design and optimization of a chiral binary separation process is based on a careful selection of the proper combination between the chiral stationary phase and the mobile phase composition to separate a specific chiral binary or pseudo-binary mixture. When considering 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 SMB related processes). The nadolol pharmaceutical drug 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 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. The design of the complete 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 nadolol stereoisomers using Chiralpak IA (chiral) and different Waters C18 (achiral) stationary phases will be presented. The results recently obtained by our research team for this topic [1-3] clearly supports the capacity to enhance the knowledge on the chromatographic separation of chiral pharmaceuticals using preparative and SMB chromatography. In this communication we will introduce original and innovative challenges through the real separation of multicomponent (quaternary) chiral mixtures which will represent an important step forward for the pharmaceutical industry.This work is a result of project "AIProcMat@N2020 - Advanced Industrial Processes and Materials for a Sustainable Northern Region ofPortugal2020", with the reference NORTE-01-0145-FEDER-000006, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the Portugal2020 Partuership Agreement, through the European Regional Development Fund (ERDF), and of project POCI-01-0145-FEDER-006984- Associate Laboratory LSRE-LCM funded by ERDF through COMPETE2020 - Programa Operacional Competitividade e Intemacionaliz~iio (POCI) - and by national funds through FCT - Fundação para a Ciência e a Tecnologiainfo:eu-repo/semantics/publishedVersio

Separation of nadolol racemates by high pH reversed-phase preparative fixed-bed chromatography: comparison of C18 materials

Fixed-Bed technology will be used for the multicomponent preparative separation of a pharmaceutical beta-blocker chiral drug. New strategies using different achiral stationary phases will be presented. Nadolol is a quaternary mixture of equal amounts of four stereoisomers and will be used as case-study. A new methodology for the design, optimization and experimental implementation of the multicomponent separation will be introduced, including the use of three different achiral adsorbents, the screening and choice of the best adsorbent-solvent combination, taking in account the final preparative separation using the fixed-bed technology. Extensive experimental and simulation results will be presented, including solvent screening, measurement of equilibrium adsorption isotherms, breakthrough measurements, and fixed-bed (Azura prep HPLC unit) experimental preparative separation using C18 columns under reversed-phase mode.“AIProcMat@N2020 - Advanced Industrial Processes and Materials for a Sustainable Northern Region of Portugal 2020”, with the reference NORTE-01-0145-FEDER-000006, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and of project POCI-01-0145-FEDER-006984 – Associate Laboratory LSRE-LCM funded by ERDF through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI) – and by national funds through FCT - Fundação para a Ciência e Tecnologia.info:eu-repo/semantics/publishedVersio

Separation of nadolol racemates by high pH reversed-phase fixed-bed and simulated moving bed chromatography

The separation of nadolol racemates under high pH reversed-phase using both the fixed-bed (FB) and the simulated moving bed (SMB) preparative chromatographic techniques is reported after the previous published work [1] where the Waters XBridge C18 adsorbent and an ethanol:water:diethylamine solvent mixture were validated to allow the separation of the multicomponent feed mixture composed by four nadolol stereoisomers into two pure racemates (two pairs of enantiomers). In this work, the experimental preparative separations using one commercial fixed-bed preparative HPLC Azura system equipped with one sole column of preparative dimensions (30 mm ID × 250 mm L) and one labscale SMB apparatus (the FlexSMB-LSRE pilot unit) equipped with six semi-preparative columns (19 mm ID × 100 mm L) are presented. Both systems use the Waters XBridge C18 adsorbent of 10 μm particle diameter. The screening of the mobile phase composition elected the 30:70:0.1 (v/v/v) ethanol:water:diethylamine solvent mixture to perform both FB and SMB preparative operations. A large set of experimental, modelling and simulation results are presented, including pulses, measurement and modelling of the adsorption equilibrium isotherms, and its validation through breakthroughs measurements. The modelling and simulation steps allowed the prediction and the optimization of both the FB and SMB operating conditions. For FB, using a feed concentration of 9 g/L of an equimolar mixture of the two nadolol racemates, both were recovered almost pure (at least 99.9 %), with a global system productivity of 3.06 gfeed/(Lbed.hr) and a solvent consumption of 4.21 Lsolvent/gfeed. For SMB, the pilot unit’s pressure drops limits imposed a maximum internal flow-rate of only 5 mL/min and, for a nadolol feed concentration of 2 g/L, both racemates were recovered 100 % pure, with a system productivity of 0.13 gfeed/(Lbed.hr) and a solvent consumption of 6.19 Lsolvent/gfeed. Additional simulation results showed that a SMB preparative unit can perform the 9 g/L nadolol racemate separation with a system productivity of 3.61 gfeed/(Lbed.hr) and a solvent consumption of only 1.95 Lsolvent/gfeed using the same average internal flow-rate as in FB operation. Even better SMB productivities can still be obtained using the same feed or solvent flow-rates as in FB operation if the internal SMB flow-rates are allowed and not limited by the system pressure drop. The experimental results presented in this work validate the strategy of separating a four nadolol stereoisomers mixture into two pure nadolol racemates, each one composed by a pair of nadolol enantiomers, using an achiral C18 adsorbent through FB and SMB chromatographic techniques. Each nadolol racemate can later be purified into pure nadolol stereoisomers using standard binary chiral FB and SMB chromatography. In this way, this works introduces a real and experimental solution for the complete multicomponent preparative separation of the four nadolol stereoisomers.The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) for financial support through national funds FCT/MCTES (PIDDAC) to CIMO (UIDB/00690/2020 and UIDP/00690/ 2020) and SusTEC (LA/P/0007/2020). National funding by FCT, Foundation for Science and Technology, through the individual research grant (SFRH/BD/137966/2018) of Rami S. Arafah is also acknowledged.info:eu-repo/semantics/publishedVersio

High pH reversed-phase preparative chromatographic separation of nadolol racemates using C18 adsorbents

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.AIProcMat@N2020 - Advanced Industrial Processes and Materials for a Sustainable Northern Region of Portugal 2020”, with the reference NORTE-01-0145-FEDER-000006, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and of project POCI-01-0145-FEDER-006984 – Associate Laboratory LSRE-LCM funded by ERDF through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI) – and by national funds through FCT - Fundação para a Ciência e Tecnologia.info:eu-repo/semantics/publishedVersio

Separation of nadolol racemates by high pH reversed-phase fixed-bed and simulated moving bed chromatography

Nadolol is a pharmaceutical chiral drug worldwide prescribed to the relief of some diseases mainly related with the cardiovascular system. Although some studies refer that the therapeutic effect of this drug is related with only one enantiomer, nadolol is still being marketed as a mixture of four stereoisomers, in a form of a racemic mixture of two racemates. The separation of all the four stereoisomers, despite being a very challenging task, will be very helpful to provide the pharmaceutic industry of any amounts of pure compounds to perform individual pharmaceutic and pharmacologic studies. Recently, our research group reported the pseudo-binary separation of RSR-nadolol stereoisomer by simulated moving bed (SMB) technology using both coated Chiralpak AD and immobilized Chiralpak IA chiral stationary phases, with an eluent normal-phase mode. 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 nadolol racemates under reversed-phase mode. This introduces much more deep and new challenges involving selection of the packing to be used, optimization of the solvent composition, and the strategy design for defining the different separation steps and its sequences. Different separation strategies can be designed and optimized, enlarging the packing materials possibilities, from fully chiral (Chiralpak) to achiral (C18) – chiral (Chiralpak) separation combinations and, so, the use of both normal and reversed-phase chromatography. For each step, the optimization of the solvent composition will be carried out, using pure alcohol, alcohol-hydrocarbon and alcohol-water mixtures, all with a basic modifier, considering the strong basic nature of the nadolol stereoisomers. The separation technology to be used will also be tested, including fixed-bed and SMB liquid chromatography. The different alternatives will be evaluated in terms of the real capacity to achieve complete separation of all the four nadolol stereoisomers and in terms of system productivity and solvent consumption. Considering the previous tasks, both modelling-simulation and experimental tools will be fully used, namely in what concerns the knowledge of the equilibrium adsorption isotherms, kinetic data (axial dispersion and resistance to mass transfer), and the prediction of preparative fixed-bed and SMB performances. This chemical engineering approach will allow the deep knowledge of all the separation processes and its optimization at preparative scale. Extensive experimental and simulation results will be presented, including solvent screening, measurement of equilibrium adsorption isotherms, breakthrough measurements, preparative HPLC (Azura pilot unit) and SMB (FlexSMB-LSRE unit) experimental separations of nadolol racemates using C18 columns. At the end is expected the clear definition of the best separation strategy for the complete separation of nadolol stereoisomers and the experimental availability of all the four pure stereoisomers [1-4].This work is a result of: Project •AIProcMat@N2020- Advanced Industrial Processes and Materials for a Sustainable Northern Region of Portugal 2020", with the reference NORTE-Q1-0145-FEDER-000006, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); Associate laboratory LSRE-LCM - UID/EQU/50020/2019- funded by national funds through FCT/MCTES (PIDDAC). Rami S. Arafah is supported by a PhD Grant of Fundação para a Ciência e a Tecnologia (SFRH/BD/137966/2018).info:eu-repo/semantics/publishedVersio