Χρήση υπερκρίσιμων ρευστών για την κατεργασία βιοαποικοδομήσιμων πολυμερών και φαρμακευτικών ουσιών
Creators: name: Καλογιάννης, Κωνσταντίνος Γ.
Publisher: name: Aristotle University of Thessaloniki
Year: 2006
Subjects: Βιαποικοδομήσιμα πολυμερή
Μικροσωματίδια
Μικροεγκλεισμός
Biodegradable polymers
Microparticles
Microencapsulation

description: Οι διεργασίες με υπερκρίσιμα ρευστά είναι σύγχρονες πολλά υποσχόμενες εναλλακτικές τεχνικές παραγωγής μικροσωματιδίων. Στην παρούσα διατριβή σχεδιάστηκε και αναπτύχθηκε διάταξη παραγωγής μικροσωματιδίων με χρήση υπερκρίσιμου διοξειδίου του άνθρακα (CO2) ως αντιδιαλύτη. Επιλέχθηκε το C02 λόγω του χαμηλού κρίσιμου σημείου του, της ευκολίας παραγωγής του από άλλες βιομηχανικές διεργασίες και της φιλικότητάς του προς το περιβάλλον. Χρησιμοποιώντας CO2 ως αντιδιαλύτη, παρήχθησαν μικροσωματίδια από το βιοποικοδομήσιμο πολυμερές πολυ(γαλακτικό οξύ) (PLLA). Επιπρόσθετα, παρήχθησαν σωματίδια των φαρμακευτικών ουσιών παρακεταμόλης και αμοξικιλίνης. Μελετήθηκε η επίδραση των παραμέτρων της διεργασίας στα μέσα μεγέθη, πλάτη κατανομών και τάσεις συσσωμάτωσης των παραγόμενων σωματιδίων. Οι βασικότερες παράμετροι της διεργασίας που μελετήθηκαν ήταν η πίεση, η θερμοκρασία, η συγκέντρωση των οργανικών διαλυμάτων και η φύση των οργανικών διαλυτών. Για την καλύτερη κατανόηση της αλληλεπίδρασης οργανικού διαλύτη-υπερκρίσιμου C02, μελετήθηκε αρχικά η ισορροπία φάσεων ενός δυαδικού μίγματος και στη συνέχεια τριαδικών μιγμάτων πολυμερούς-οργανικοιύ διαλύτη-C02. Η διάταξη μελέτης τριαδικών μιγμάτων σχεδιάστηκε και αναπτύχθηκε στα πλαίσια της παρούσας διατριβής. Τέλος, επιχειρήθηκε εγκλεισμός αμοξικιλίνης σε PLLA με τη χρήση υπερκρίσμου C02. Μελετήθηκε η επίδραση των παραμέτρων της διεργασίας στο ποσοστό του εγκλειόμενου φαρμάκου και στην απόδοση του εγκλεισμού
description: Many properties of industrial powdered products can be adjusted by changing the particle size and particle size distribution of the powder. This applies in many fields of the industry, from inorganic powders to pharmaceuticals. Micronization for industrial purposes is mostly carried out by two techniques, recrystallization from solution and comminution. However, these two methods have several drawbacks. Wide size distribution, high thermal and mechanical stress, environmental pollution, large quantities of residual organic solvent, multi stage processes are some of them. These drawbacks are the main reasons for the increasing interest in alternative methods of precipitation. Supercritical fluids offer considerable advantages as solvents or antisolvents in crystallization and precipitation processes. This is why their role has been up scaled and their use as solvents and antisolvents is nowadays in the center of attention. In the sensitive area of pharmaceuticals processing, various requirements need to be fulfilled: 1)Use of the smallest possible amounts of organic solvents 2)Molecular control of the process 3)One stage technique that leads to pure product with no residual solvent 4)Control of the properties of the formed microparticles 5)Application on a large field of pharmaceutical compounds. Supercritical fluid processes fulfill all these requirements and moreover present numerous other advantages. One of the most important and popular ones in recent years is the administration of drugs via the pulmonary route. Prerequisites for this type of drug administration are the small size of the particles (~ 2 μm), the narrow size distribution and the absence of organic solvents in the drug. Moreover, production of microparticles of biodegradable polymers is now of major interest. These polymers may be employed as matrices, within which pharmaceuticals can be impregnated. These matrices can control the release of a drug substance in the human body, making the most out of the pharmaceutical. Therefore, a layout was designed for the production of microparticles from organic solutions with the aid of a supercritical antisolvent, namely carbon dioxide. Carbon dioxide was chosen due to its environmentally friendly nature, its low critical point, its non - toxicity and its low price. Microparticles of the biodegradable polymer poly(l-lactic acid) (PLLA), were produced. SEM photographs of the produced microparticles were taken so as to study the morphology and the characteristics of the produced particles. The main parameters and conditions of the experiments were pressure, temperature, concentration and nozzle diameter. Their effects on particle characteristics such as mean size and particle size distribution were studied and identified. In addition, studies of the binary system carbon dioxide - organic solvent and of ternary mixtures of carbon dioxide - organic solvent - polymer, took place. These studies gave an insight into the way carbon dioxide (antisolvent), the organic solvent and the polymer interact. For the study of the ternary mixtures of carbon dioxide - organic solvent - polymer, an experimental layout was designed and developed. The layout was a variation of those found in bibliography. Its main advantage is that it allows for the absolute control of the mixture composition, allowing for good reproducibility of the studied conditions. Moreover, microparticles of drugs were produced. Both, paracetamol and amoxicillin were micronised with the technique of the supercritical antisolvent. The process parameters and the conditions were studied and SEM photographs of the samples were taken to assess the effect of pressure, temperature, concentration and nozzle geometry. The samples were studied with x-ray diffraction and infrared spectroscopy. The crystallinity of the products was determined and infrared spectroscopy showed that there were no residual solvent traces. Thus, the process yielded particles of small mean sizes, with specific properties free from solvent traces. In addition, the effect of the organic solvent was studied in an effort to replace dangerous solvents with environmentally friendlier ones. Microparticles of mean sizes between 1 - 5 μm were produced. Microparticles of such mean sizes may be delivered to the human body via the pulmonary route. Finally, taking into account the observations made for the ternary systems of carbon dioxide - organic solvent - polymer, and the observations concerning the effects of the process parameters on PLLA and amoxicillin micronization, the encapsulation of amoxicillin in PLLA acid was attempted. Firstly, a suspension of amoxicillin microparticles in a solution of PLLA in dichloromethane was made. Employing carbon dioxide as an antisolvent, microencapsulation was attempted in the form of PLLA microparticles precipitating around the suspended microparticles of amoxicillin. These preliminary experiments aimed at determining whether it was possible to encapsulate amoxicillin in PLLA. The above experiments yielded particles of PLLA that contained amoxicillin. The encapsulated percentage of amoxicillin was determined via liquid chromatography (HPLC). Mixtures of amoxicillin and PLLA were created in solutions of the solvents dichloromethane and dimethylsulfoxide. Various external conditions of pressure, temperature, concentration and solvent ratios were investigated. The different encapsulation percentages were correlated with the corresponding conditions of each experiment.