Dokument: Crystal Engineering von γ-Aminobuttersäure und ihren Pharmazeutisch Aktiven Derivaten

Titel:	Crystal Engineering von γ-Aminobuttersäure und ihren Pharmazeutisch Aktiven Derivaten
Weiterer Titel:	Crystal Engineering of γ-Amino Butanoic Acid and its Pharmaceutically Active Derivatives
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=62402
URN (NBN):	urn:nbn:de:hbz:061-20230424-081341-3
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Komisarek, Daniel [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 108,76 MB in 2 Dateien [ZIP-Datei erzeugen] Dateien vom 12.04.2023 / geändert 13.04.2023
Beitragende:	Prof. Dr. Janiak, Christoph [Gutachter] Prof. Dr. Ganter, Christian [Gutachter]
Stichwörter:	Crystal Engineering, GABA, Mechanochemie, Gitterenergie
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 540 Chemie
Beschreibungen:	Crystal Engineering hat sich spätestens seit den neunziger Jahren des vergangenen Jahrhunderts als eigenständige Subdisziplin der supramolekularen Chemie etabliert. Allerdings sind viele Vorgänge, die das supramolekulare Aggregationsverhalten betreffen, auch über dreißig Jahre später noch nicht vollkommen aufgeklärt. Daraus ergeben sich zahlreiche Probleme für das Feld, welche vor Allem die Vorhersagbarkeit von Struktur und Eigenschaften kristalliner Festkörper betreffen. In der Pharmazie gipfelt diese geminderte Kontrollfähigkeit über die Festphase im Phänomen der sogenannten Disappearing Polymorphs. In so bezeichneten Fällen ist es im industriellen Maßstab plötzlich nicht mehr möglich ein zuvor über lange Zeit wohldefiniertes Produkt unter den scheinbar gleichen Bedingungen wie in der Vergangenheit zu erhalten. Ein unerkannter Einfluss begünstigt dabei einen unerwarteten Phasenwechsel des Zielproduktes zu einer anderen polymorphen Modifikation. Dieses Problem ist beispielhaft für die Herausforderungen des modernen Crystal Engineerings: der Komplexität des Kristallisationsvorgangs mit Mitteln Herr zu werden, die kaum die Vielzahl an möglichen Einflüssen auf diesen Prozess erfassen können. In den vorliegenden Arbeiten wurde die Kristallisation der γ-Aminobuttersäure (GABA) und ihren Derivaten Gabapentin, Pregabalin, Phenibut und Baclofen im Vergleich miteinander untersucht. Dabei wurden zahlreiche Kristallstrukturen sowohl von Einzel- als auch Multikomponentenphasen wie Salzen und Co-Kristallen dieser Stoffe mit einer Auswahl an Carbonsäuren aufgeklärt und ihre physikochemischen Eigenschaften bestimmt. Dazu wurden sowohl analytische Methoden wie auch Computer basierte Rechnungsmodelle verwendet. Es konnte gezeigt werden, dass in vielerlei Hinsicht ein ähnliches Verhalten in den Bindungsmodi der supramolekularen Aggregation der untersuchten Substanzen besteht. Solche Gemeinsamkeiten bleiben jedoch oberflächlich. So wurde beispielsweise festgestellt, dass die Bildung von Multikomponentensystemen mit der selben Carbonsäure oftmals mit mehr als einem GABA-Derivat möglich ist. Allerdings unterscheiden sich die erhaltenen Produkte in vielerlei Fällen sowohl strukturell als auch in ihren Eigenschaften. Ein kristallisationsbasiertes Verfahren zur Deracemisierung von Pregabalin ist nicht in gleicher Weise auf Phenibut übertragbar. Die Arbeit zeigt auf, dass sogar zwischen molekular nah verwandten Spezies gravierende Unterschiede im Kristallisationsverhalten bestehen können, denen nicht einfach Herr zu werden ist. Crystal engineering has been established as an independent subdiscipline of supramolecular chemistry since the 1990s of the previous century at the latest. However, many processes affecting supramolecular aggregation behaviour have not been fully elucidated even more than thirty years later. This poses numerous problems for the field, mainly concerning the predictability of structure and properties of crystalline solids. In pharmaceutics, this diminished ability to control the solid phase culminates in the phenomenon known as disappearing polymorphs. In such cases, it is suddenly no longer possible on an industrial scale to obtain a product that has previously been well-defined over a long period of time under what appear to be the same synthesis conditions as in the past. In this case, an unrecognized influence favours an unexpected phase change of the target product to a different polymorphic modification. This problem is exemplary for the challenges of modern crystal engineering: to cope with the complexity of the crystallization process by means that can hardly capture the multitude of possible influences on this process. In the present work, the crystallization of γ-amino butanoic acid (GABA) and its derivatives Gabapentin, Pregabalin, Phenibut, and Baclofen were studied in comparison with each other. Numerous crystal structures of both single and multicomponent phases such as salts and co-crystals of these substances with a selection of carboxylic acids were elucidated and their physicochemical properties were determined. Both analytical and computational models were used for this purpose. It was shown that in many respects there is similar behaviour in the binding modes of supramolecular aggregation of the studied substances. However, such similarities remain superficial. For example, it was found that the formation of multicomponent systems with the same carboxylic acid is often possible with more than one GABA-derivative. However, in many cases the products obtained differ both structurally and in their properties. A crystallization-based procedure for the deracemization of Pregabalin is not equally applicable to Phenibut. The work demonstrates that even between molecularly closely related species there can be serious differences in crystallization behaviour that are not easy to master.
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