Μεταξύ των χρήσιμων συστατικών των παραπροϊόντων των υγρών εκροών ενός ελαιοτριβείου είναι οι φαινολικές ουσίες οι οποίες χαρακτηρίζονται από την υψηλή αντιοξειδωτική τους δράση. Οι φαινολικές ενώσεις, εφόσον ανακτηθούν, είναι δυνατόν να αξιοποιηθούν εμπορικά, αφού μπορούν να χρησιμοποιηθούν σε πολύ σημαντικούς τομείς όπως στην προστασία της υγείας του ανθρώπου (προστασία από τον διαβήτη, τον καρκίνο), στην βιομηχανία τροφίμων, στην κοσμετολογία κλπ.. Στην παρούσα εργασία, εξετάστηκε ο διαχωρισμός και η ανάκτηση των φαινολικών ενώσεων με τη μέθοδο της κρυστάλλωσης με ψύξη, από υδατικά διαλύματα. Οι φαινολικές ενώσεις που επιλέχθηκαν για μελέτη ήταν η φαινόλη κινναμικό οξύ [trans-cinnamic acid (TCA)] και η φαινόλη φερουλικό οξύ [ferulic acid (FA)]. Η επιλογή τους έγινε γιατί η χαμηλή διαλυτότητα τους, σε σύγκριση με τις αντίστοιχες της τυροσόλης και της υδροξυτυροσόλης, καθιστά πιο εύκολη τη διερεύνηση της επιλεκτικής τους κρυστάλλωσης στην ψυχόμενη επιφάνεια. Η πειραματική διαδικασία πραγματοποιούταν σε αντιδραστήρα διαλείποντος έργου όγκου, με διπλότοιχα τοιχώματα σε σταθερή θερμοκρασία η οποία ρυθμιζόταν με την βοήθεια θερμοστάτη ανακυκλοφορίας. Το προς κρυστάλλωση διάλυμα εισαγόταν στον αντιδραστήρα και θερμαινόταν σε σταθερή θερμοκρασία. Η κρυστάλλωση λάμβανε χώρα πάνω σε μια ψυχόμενη κυλινδρική επιφάνεια ανοξείδωτου χάλυβα που εμβαπτιζόταν στο διάλυμα. Η θερμοκρασία στην κυλινδρική επιφάνεια διατηρούνταν σταθερή. Ακολούθως, μετά το πέρας του κύκλου κρυστάλλωσης, οι κρύσταλλοι συλλέγονταν για την περαιτέρω ανάλυσή τους. Τα ποσοστά ανάκτησης των πολυφαινολών που επιτεύχθηκαν στην παρούσα εργασία, ήταν ιδιαίτερα υψηλά και ειδικότερα στα πειράματα που περιλάμβαναν διαλύματα υψηλού υπερκορεσμού και χαμηλής θερμοκρασίας ψυχόμενης επιφάνειας. Η παρακολούθηση της μεταβολής της θερμοκρασίας από την ψυχρή επιφάνεια προς τα τοιχώματα του αντιδραστήρα (στην ακτινική διεύθυνση) ως συνάρτηση του χρόνου, δίνει πληροφορίες για το σημείο έναρξης και για την ολοκλήρωση της διεργασίας της κρυσταλλικής ανάπτυξης. Σκοπός της παρούσας εργασίας είναι η κατάστρωση και επίλυση των ισοζυγίων μάζας και ενέργειας καθώς και ο προσδιορισμός (θεωρητικός και πειραματικός) του πάχους του αποτιθέμενου στερεού στην ψυχόμενη επιφάνεια. Η επίλυση των μερικών διαφορικών εξισώσεων δίνει αναλυτικές λύσεις για την κατανομή του προφίλ της υπέρψυξης και της συγκέντρωσης ως προς τα φαινολικά κλάσματα κατά μήκος του αντιδραστήρα. Δεδομένου ότι η υπέρψυξη αποτελεί και την κινούσα δύναμη για την κρυσταλλική ανάπτυξη, παρατηρήθηκε ότι ήταν δυνατή η αριστοποίηση της ανάκτησης των φαινολικών ενώσεων από υπέρθερμα διαλύματα με τη μέθοδο της κρυστάλλωσης με ψύξη. Το ποσοστό ανάκτησης που επιτεύχθηκε ήταν περίπου . Παράλληλα εξετάστηκε επίδραση της συναγωγής στην κρυσταλλική ανάπτυξη. Αυξανομένης της γωνιακής ταχύτητας, ευνοείται η κρυστάλλωση στο κυρίως διάλυμα και παρουσιάζεται μια μείωση στο τελικό ανακτώμενο στερεό μιας και τα moles της προς κρυστάλλωση ουσίας δεν έχουν τον απαραίτητο χρόνο να διαχυθούν και να κρυσταλλωθούν επιλεκτικά στην περιοχή όπου παρουσιάζεται διαφορά συγκέντρωσης. Η τελική σειρά πειραμάτων αφορούσε πειράματα κρυστάλλωσης με ψύξη μίγματος πολυφαινολών καθώς και προκαταρκτικών πειραμάτων αποβλήτου ελαιοτριβείου με σκοπό τη διερεύνηση της δυνατότητας ανάκτησης των πολυφαινολών από διάφορα διαλύματα και άπο το απόβλητο αντίστοιχα. Σε όλα τα παραπάνω, ο προσδιορισμός της υγρασίας στο στερεό κρυσταλλικό στρώμα ήταν υψίστης σημασίας για τον έλεγχο της καθαρότητας των ανακτώμενων κρυστάλλων. Το ποσοστό υγρασίας που προσδιορίστηκε ήταν πολύ μικρό και περίπου ίδιο με το αντίστοιχο ποσοστό των συνθετικών φαινολών / Phenolic compounds are among, the most complex and the most difficult to remove compounds from the by-products of olive mill wastewaters (OMW). Due to significant properties, including stability and anti-oxidative activity, the recovery of poly-phenols (PP) from OMW is of paramount importance. In the present work, trans-cinnamic acid and ferulic acid, model compounds for the PP present in OMW were removed by cooling crystallization from aqueous solutions. Cooling crystallization experiments were done in a batch reactor kept at constant temperature. Solutions of the two tested PP were prepared in the reactor and were allowed to equilibrate. Crystallization took place on the surface of a cylindrical stainless steel (SS) metal tube immersed into the supercooled solution. The SS surface was cooled at a lower temperature with respect to the respective melting point. With respect to each of the PP studied, the respective solubilities as a function of temperature were measured. The formation of PP crystal layers on the SS tube surface took place without any appreciable induction time. In the series of experiments done, the temperature and concentration profile in the batch reactor in the presence of the cooled SS surface were calculated on the basis of mass and heat transport equations for unstirred systems. The imposed super-cooling from the cold surface to the bulk solution, which is the driving force for the crystallization of the phenolic compounds on the SS surface, was thus estimated.

Eine kalorimetrische Kristallisationsuntersuchung unter dynamischer Abkühlung ist bisher noch nicht erfolgt, auch weil die klassischen DSC-Messsysteme hierfür thermisch zu träge sind und die Einschwingzeiten zu lang sind. Durch die Weiterentwicklung der Prüftechnik, insbesondere auf dem Gebiet der Hochgeschwindigkeitskalorimetrie, erscheint es jedoch erstmals möglich, das dynamische Abkühlverhalten prozessnah nachbilden zu können und die Auswirkung auf die Kristallisation zu untersuchen. Im Rahmen dieser Arbeit wurde daher versucht die dynamische Abkühlung einer Kunststoffschmelze aus PBT kalorimetrisch in Abhängigkeit der Werkzeugtemperatur und der Bauteilgeometrie nachzubilden, jeweils bei Betrachtung verschiedener Bauteiltiefen. Hierfür wurden numerisch nichtlineare Kühlratenverläufe bestimmt, die im Anschluss durch Segmentierung linearisiert und somit in ein FSC-Programm überführt werden konnten. Anhand der resultierenden Wärmestromverläufe konnte gezeigt werden, dass eine Interpretation der kalorimetrischen Erfassung unter dynamischer Abkühlung möglich ist und der Verlauf der Kristallisation in verschiedenen Bauteiltiefen in Abhängigkeit der weiteren Randbedingungen nachvollzogen werden kann. / A calorimetric investigation of the crystallization of thermoplastics under dynamic cooling has not performed yet, also because the classical DSC measuring systems are thermally too slow for this purpose and the corresponding settling times are too long. However, as a result of the further development of testing technology, especially in the field of high-speed calorimetry, it seems possible to simulate the dynamic cooling behavior of real processing and to investigate its effects on crystallization. In this work the dynamic cooling of a polymer melt was simulated calorimetrically depending on the tool temperature and the part geometry, in each case considering the different cooling behavior of different part depths. Therefore, numerically nonlinear cooling rate profiles were determined, which could then be linearized by segmentation and thus converted into a calorimetric program. On the basis of the resulting heat flow characteristics it could be shown that an interpretation of the calorimetric detection under dynamic cooling is possible and the course of the crystallization in different part depths can be reconstructed in dependence on the further boundary conditions.

<p>Crystallization is a key solid-liquid separation and purification technique used in pharmaceutical industry. Some of the critical quality attributes (CQAs) of a product from crystallization process include crystal size distribution (CSD), purity, polymorphic form, morphology, etc. Different size and polymorphs of a drug substance may have different dissolution profiles and different bioavailability, which can have adverse effect on human health. Therefore, it is important to design and control crystallization process to meet product CQAs. In recent years, drug substances are becoming more complex, often being heat sensitive, which may limit the temperature that can be used in the crystallization step. Consequently, the traditional cooling only crystallization may not be well suited to recover the high value drug substances. For these systems, antisolvent crystallization is typically employed to improve the yield. On the other hand, the solvent composition can significantly impact the polymorphic outcome. Therefore, designing combined cooling and antisolvent crystallization (CCAC) processes to solve the challenges of active pharmaceutical ingredient (API) crystallization in a highly regulated environment is a complex engineering problem. </p> <p>With rising energy costs and intense price competition from generic pharmaceutical companies, the pharmaceutical industry is looking for ways to reduce the cost of manufacturing via process intensification (PI). This thesis focuses on different PI techniques for CCAC of drug substances. Continuous or smart manufacturing is gaining popularity due to its potential to lower the cost of manufacturing while maintaining consistent quality. Continuous crystallization is an important link in the continuous manufacturing process. The first part of the thesis shows PI of a commercial drug substance, Atorvastatin calcium (ASC) for target polymorph development via continuous CCAC using an oscillatory baffled crystallizer (OBC). An existing batch CCAC process for ASC was compared with the continuous CCAC in OBC and it was found the continuous process 30-fold more productive compared to the batch process. An array of process analytical technology (PAT) tools was used in this work to assess key process parameters that affect the polymorphic outcome and CSD. The desired narrower CSD product was obtained in the OBC compared to that from a batch crystallizer.</p> <p>The next part of the thesis focused on model-based PI technique for efficient determination of crystallization kinetics of a polymorphic system in CCAC. A novel experimental design was proposed which significantly reduced the number of experiments required to determine crystallization kinetics in a CCAC process. The kinetic parameters were validated, and a validated polymorphic model was used to perform an in-silico design of experiment (DoE) to develop a design space that can be used to identify operating conditions to achieve a desired crystal size and polymorphic form. </p> <p>The final part of the thesis combines the experimental and model-based approach for designing a continuous CCAC process for ASC in a cascade of Coflore agitated cell reactor (ACR) and three-stage mixed suspension mixed product removal (MSMPR). A combined artificial neural network (ANN) and principal component analysis (PCA) method was used to calibrate an ultraviolet (UV) probe which was used to monitor ASC solute concentration in the cascade process. The crystallization kinetic parameters were estimated in ACR and MSMPR which was used to build a digital model of the cascade process. The digital model was then used to obtain a design space with different temperature profile in the three-stage MSMPR that yielded narrow CSD of ASC form I. Overall, this thesis demonstrates the benefits of applying PI in the CCAC of drug substances using a holistic approach including novel equipment, application of an array of PAT tools, and model-based digital design to achieve desired CQAs of the product.</p>

In thisproject, solubility of butyl paraben in 7 puresolvents and 5 ethanol aqueous solvents has been determined at from 1 ℃to 50 ℃. Thermodynamic properties of butyl paraben have been measured by DifferentialScanning Calorimetey. Relationship between molar solubility of butyl paraben in6 pure solvents and thermodynamic properties has been analyzed. Thisrelationship suggests a method of estimating activity of solute at equilibrium fromcombining solubility data with DSC measurements. Then, activity coefficient accordingto the solubility at different temperatures can be estimated. Duringthe solubility measurements in ethanol aqueous solvents, it is found that whenbutyl paraben is added into aqueous solutions with certain proportion ethanol,solutions separates into two immiscible liquid layers in equilibrium. Water andethanol are primary in top layer, while the butyl paraben is primary in bottomlayer, but the solution turns to cloudy when two layers of solution are mixed. Theaim of this work was to present the phase behaviour of liquid-liquid-phaseseparation for (butyl paraben + water + ethanol) ternary system from 1 ℃ to 50 ℃at atmospheric pressure. Thearea of liquid-liquid-phase separation region in the ternary phase diagram increaseswith the increasing temperature from 10 ℃to 50 ℃. In thisstudy, more than several hundreds of nucleation experiments of butyl paraben havebeen investigated in ethyl acetate, propanol, acetone and 90% ethanol aqueoussolution. Induction time of butyl paraben has been determined at 3 differentsupersaturation levels in these solvents, respectively. Free energy ofnucleation, solid-liquid interfacial energy, and nuclei critical radius havebeen determined according to the classical nucleation theory. Statistical analysis ofinduction time reveals that the nucleation is a stochastic process with widevariation even at the same experiment condition. Butyl paraben nucleates most difficultlyin 90 % ethanol than in other 3 solvents, and most easily in acetone. The interfacialenergy of butyl paraben in these solvents tends to increasing with decreasemole fraction solubility in these solvents. Coolingcrystallizations with different proportions of butyl paraben, water and ethanolhave been observed by Focused Beam Reflectance Method, Parallel VirtualMachine, and On-line Infrared. The FBRM, IR curves and the PVM photos show someof the solutions appeared liquid-liquid phase separation during coolingcrystallization process. The results suggest that if solutions went throughliquid-liquid phase separation region during the cooling crystallizationprocess the distribution of crystals crystal was poor. Droplets from solutions withsame proportion butyl paraben but different proportions of water and ethanolhave been observed under microscope. Induction time of the droplets has been determinedunder the room temperature. Droplets from top layer or bottom layer of solutionwith liquid-liquid phase separation on small glass or plastic plates were alsoobserved under microscope. The microscope photos show that the opposite flows ofcloudy solution on the glass and the plastic plate before nucleation. The resultsof the cooling and evaporation crystallization experiments both revealed thatnucleation would be prevented by the liquid-liquid phase separation. / QC 20110630

In this work, the solubility of butyl paraben in 7 pure solvents and in 5 different ethanol-water mixtures has been determined from 1 ˚C to 50 ˚C. The solubility of ethyl paraben and propyl paraben in various solvents has been determined at 10 ˚C. The molar solubility of butyl paraben in pure solvents and its thermodynamic properties, measured by Differential Scanning Calorimetry, have been used to estimate the activity of the pure solid phase, and solution activity coefficients. More than 5000 nucleation experiments of ethyl paraben, propyl paraben and butyl paraben in ethyl acetate, acetone, methanol, ethanol, propanol and 70%, 90% ethanol aqueous solution have been performed. The induction time of each paraben has been determined at three different supersaturation levels in various solvents. The wide variation in induction time reveals the stochastic nature of nucleation. The solid-liquid interfacial energy, free energy of nucleation, nuclei critical radius and pre-exponential factor of parabens in these solvents have been determined according to the classical nucleation theory, and different methods of evaluation are compared. The interfacial energy of parabens in these solvents tends to increase with decreasing mole fraction solubility but the correlation is not very strong. The influence of solvent on nucleation of each paraben and nucleation behavior of parabens in each solvent is discussed. There is a trend in the data that the higher the boiling point of the solvent and the higher the melting point of the solute, the more difficult is the nucleation. This observation is paralleled by the fact that a metastable polymorph has a lower interfacial energy than the stable form, and that a solid compound with a higher melting point appears to have a higher solid-melt and solid-aqueous solution interfacial energy. It has been found that when a paraben is added to aqueous solutions with a certain proportion of ethanol, the solution separates into two immiscible liquid phases in equilibrium. The top layer is water-rich and the bottom layer is paraben-rich. The area in the ternary phase diagram of the liquid-liquid-phase separation region increases with increasing temperature. The area of the liquid-liquid-phase separation region decreases from butyl paraben, propyl paraben to ethyl paraben at the constant temperature. Cooling crystallization of solutions of different proportions of butyl paraben, water and ethanol have been carried out and recorded using the Focused Beam Reflectance Method, Particle Vision and Measurement, and in-situ Infrared Spectroscopy. The FBRM and IR curves and the PVM photos track the appearance of liquid-liquid phase separation and crystallization. The results suggest that the liquid-liquid phase separation has a negative influence on the crystal size distribution. The work illustrates how Process Analytical Technology (PAT) can be used to increase the understanding of complex crystallizations. By cooling crystallization of butyl paraben under conditions of liquid-liquid-phase separation, crystals consisting of a porous layer in between two solid layers have been produced. The outer layers are transparent and compact while the middle layer is full of pores. The thickness of the porous layer can reach more than half of the whole crystal. These sandwich crystals contain only one polymorph as determined by Confocal Raman Microscopy and single crystal X-Ray Diffraction. However, the middle layer material melts at lower temperature than outer layer material. / <p>QC 20130515</p> / investigate nucleation and crystallization of drug-like organic molecules