The growing demand for sustainable technologies for cannabinoid purification has driven the development of advanced methods that balance efficiency and reduced environmental impact. This thesis confronts these challenges by proposing the implementation of innovative multicromatographic processes based on Alternative Pump Recycling (APR) and Simulated Moving Bed (SMB) techniques, with a focus on the use of green solvents such as ethanol. The goal is to improve the separation of bioactive compounds such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), while ensuring a significant reduction in solvent consumption, waste generated and energy costs. In the first part of the paper, APR is explored, using ethanol as the mobile phase for the removal of THC from CBD-rich matrices. Through the combined use of numerical simulations and practical experimentation, APR has been shown to achieve high levels of CBD purity and recovery, ensuring effective separation even under critical co-eluting conditions. Simulations based on mathematical models optimized the number of recycles, reducing the time and resources required for the process. Results show that the technique is comparable or superior to traditional batch chromatography in terms of performance. In the second part, the thesis focuses on the application of SMB technology, considered one of the most efficient techniques for continuous, industrial-scale separations. Two distinct approaches were taken: the first uses normal-phase (NP) chromatography for cannabigerol (CBG) purification, exploiting a combination of heptane and ethanol to ensure high loading capacities and efficient separation. The second approach, operating in reverse phase (RP), employed an ethanol-water mixture for complete THC depletion from complex matrices, making the process suitable for stringent regulatory and environmental standards. In both cases, the SMB system showed significant advantages over traditional techniques, with up to a 15 times reduction in solvent consumption and a 54% increase in productivity. Finally, the thesis explores the chiral separation of cannabinoids by analyzing the behavior of six compounds on nine chiral stationary phases derived from polysaccharides under both NP and RP conditions. The results revealed distinct interaction mechanisms based on stationary phase configuration, offering valuable insights for optimizing enantiomeric separations and characterizing novel bioactive compounds. The entire study emphasizes the importance of combining innovative technologies, numerical approaches, and sustainable methodologies to meet the growing needs of the cannabinoid industry. The techniques developed in this thesis represent an important step toward the adoption of more environmentally friendly practices while maintaining high standards of quality and performance. This research not only contributes to improved industrial purification operations but also opens new opportunities for the production of analytical standards and the exploration of cannabinoids with potential therapeutic applications.
La crescente domanda di tecnologie sostenibili per la purificazione dei cannabinoidi ha spinto lo sviluppo di metodi avanzati che bilanciano l'efficienza con la riduzione dell'impatto ambientale. Questa tesi affronta queste sfide proponendo l'implementazione di processi cromatografici innovativi basati sulle tecniche di Alternative Pump Recycling (APR) e Simulated Moving Bed (SMB), con un focus sull'uso di solventi green come l'etanolo. L'obiettivo è migliorare la separazione di composti bioattivi della Cannabis come il cannabidiol (CBD) e il tetraidrocannabinolo (THC), garantendo al contempo una significativa riduzione del consumo di solventi, dei rifiuti generati e dei costi energetici. Nella prima parte del lavoro, viene esplorato l'APR, utilizzando l'etanolo come fase mobile per la rimozione del THC da matrici ricche di CBD. Grazie all'uso combinato di simulazioni numeriche e sperimentazioni pratiche, l'APR ha dimostrato di raggiungere elevati livelli di purezza e recupero del CBD, garantendo una separazione efficace anche in condizioni critiche di co-eluzione. Le simulazioni basate su modelli matematici hanno ottimizzato il processo, riducendo il tempo e le risorse necessarie. I risultati mostrano che la tecnica è comparabile o superiore alla cromatografia tradizionale in termini di prestazioni. Nella seconda parte, la tesi si concentra sull'applicazione della tecnologia SMB, considerata una delle tecniche più efficienti per separazioni continue su scala industriale. Sono stati adottati due approcci distinti: il primo utilizza la cromatografia in fase normale (NP) per la purificazione del cannabigerolo (CBG), sfruttando una combinazione di esano ed etanolo per garantire elevate capacità di carico e separazioni efficienti. Il secondo approccio, operante in fase inversa (RP), ha impiegato una miscela di etanolo e acqua per l'eliminazione completa del THC da matrici complesse, rendendo il processo adatto a rigorosi standard normativi ed ecologici. In entrambi i casi, il sistema SMB ha mostrato vantaggi significativi rispetto alle tecniche tradizionali, in termini di consumo di solventi e un aumento della produttività. Infine, la tesi esplora la separazione chirale dei cannabinoidi, analizzando il comportamento di sei cannabinoidi su nove fasi stazionarie chirali derivate da polisaccaridi, sia in condizioni di NP che di RP. I risultati hanno rivelato distinti meccanismi di interazione in base alla configurazione della fase stazionaria, offrendo preziose informazioni per ottimizzare le separazioni enantiomeriche e per caratterizzare nuovi composti bioattivi. L'intero studio enfatizza l'importanza di combinare tecnologie innovative, approcci numerici e metodologie sostenibili per soddisfare le crescenti esigenze dell'industria dei cannabinoidi. Le tecniche sviluppate in questa tesi rappresentano un passo importante verso l'adozione di pratiche più ecologiche, mantenendo al contempo elevati standard di qualità e prestazioni. Questa ricerca non solo contribuisce a migliorare le operazioni industriali di purificazione, ma apre anche nuove opportunità per la produzione di standard analitici e per l'esplorazione dei cannabinoidi con potenziali applicazioni terapeutiche.
Greening Cannabinoids Purification Through Advanced Multicolumn Preparative Chromatography Methods
COMPAGNIN, Greta
2025
Abstract
The growing demand for sustainable technologies for cannabinoid purification has driven the development of advanced methods that balance efficiency and reduced environmental impact. This thesis confronts these challenges by proposing the implementation of innovative multicromatographic processes based on Alternative Pump Recycling (APR) and Simulated Moving Bed (SMB) techniques, with a focus on the use of green solvents such as ethanol. The goal is to improve the separation of bioactive compounds such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), while ensuring a significant reduction in solvent consumption, waste generated and energy costs. In the first part of the paper, APR is explored, using ethanol as the mobile phase for the removal of THC from CBD-rich matrices. Through the combined use of numerical simulations and practical experimentation, APR has been shown to achieve high levels of CBD purity and recovery, ensuring effective separation even under critical co-eluting conditions. Simulations based on mathematical models optimized the number of recycles, reducing the time and resources required for the process. Results show that the technique is comparable or superior to traditional batch chromatography in terms of performance. In the second part, the thesis focuses on the application of SMB technology, considered one of the most efficient techniques for continuous, industrial-scale separations. Two distinct approaches were taken: the first uses normal-phase (NP) chromatography for cannabigerol (CBG) purification, exploiting a combination of heptane and ethanol to ensure high loading capacities and efficient separation. The second approach, operating in reverse phase (RP), employed an ethanol-water mixture for complete THC depletion from complex matrices, making the process suitable for stringent regulatory and environmental standards. In both cases, the SMB system showed significant advantages over traditional techniques, with up to a 15 times reduction in solvent consumption and a 54% increase in productivity. Finally, the thesis explores the chiral separation of cannabinoids by analyzing the behavior of six compounds on nine chiral stationary phases derived from polysaccharides under both NP and RP conditions. The results revealed distinct interaction mechanisms based on stationary phase configuration, offering valuable insights for optimizing enantiomeric separations and characterizing novel bioactive compounds. The entire study emphasizes the importance of combining innovative technologies, numerical approaches, and sustainable methodologies to meet the growing needs of the cannabinoid industry. The techniques developed in this thesis represent an important step toward the adoption of more environmentally friendly practices while maintaining high standards of quality and performance. This research not only contributes to improved industrial purification operations but also opens new opportunities for the production of analytical standards and the exploration of cannabinoids with potential therapeutic applications.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
