Exploring Inclusion Complex Formation of Cyclodextrins with Drug Molecules
Chapter 2. Introduction to Part I
Chapter 2. Introduction to Part I
Introduction 2.1.
Native cyclodextrins (CDs) are cyclic oligosaccharides composed of six or more units of α–
D-glucopyranose linked by α–(1→4) glycosidic bonds (Figure 2.1). Depending on the number of glucopyranose units, native CDs have been classified as α-, β- and γ-CD having 6, 7 and 8 pyranose units, respectively. A CD molecule has a hollow truncated cone-like shape where the primary hydroxy groups sit on the narrow side of the truncated cone and the secondary ones on the wide side (Figure 2.1). The architecture of CDs molecules favours the partition of the structure into an outer surface and an inner cavity, which are hydrophilic and hydrophobic in character, respectively (Figure 2.2).1 α- and γ-CDs have considerably higher water solubility compared to β-CD, with values of 145, 232, and 18.5 g/L, respectively.2 The very low water solubility of β-CD has been ascribed to the formation of intramolecular hydrogen bonds between glucose molecules in solution.3 Chemical modifications, mainly by methylation or hydroxypropylation, have been applied on CDs to improve their water solubility creating so-called CDs derivatives.
Figure 2.1. Chemical diagram of α–D-glucopyranose unit (left) and the general shape of a CD molecule (right)
CDs were extracted for the first time in 1891 by Villiers while studying the bacterial transformation of starch into dextrin by Bacillus amylobacter:4 CDs were thought to be the product of the fermentation of starch, and were named “dextrin precipitate” by Villiers. Twelve years later, Schardinger, while studying thermophilic bacteria producing the same “cellulosine” as a product of degradation of starch, reported that Villiers’ bacterial cultures were not pure, and “cellulosine”
or “crystalline dextrin” was produced by Bacillus macerans.5 This marked the beginning of a pioneering work on “Schardinger sugars” initiated by Schardinger and undertaken later on by several research groups. The first report on inclusion complex formation was a suggestion made by Cramer in the 1940s, which was equally accepted and disapproved by the chemical community.6 Cramer followed his idea and proved by experimental means not only that “Schardinger sugars”
Chapter 2. Introduction to Part I 16
form inclusion complexes, but also that they are enantiomer selective and have catalytic properties.
These findings started a worldwide interest in “cyclodextrins” and especially in inclusion complex formation. Cramer’s work has been well summarised and referenced by Stoddart in 1989.7
In 1957, French reported that a Schardinger-sugar-based diet on rats caused their death within a week.8 This led to a temporary distrust of the scientific community towards cyclodextrins for using them as prominent drug carriers. Fortunately, Anderson et al. counter-published a thorough toxicological study on rats, based on a marked 14C-cyclodextrins diet, showing that native cyclodextrins are safer than initially thought, and that the initial report about lethality was due to insufficient food intake.9 This triggered a particular interest in CD application as drug carrier and pioneering work in this area was undertaken by different groups, notably by Saenger’s in Germany.10
Figure 2.2. Chemical diagram of α-, β- and γ-CD
The advances in biotechnology and genetic engineering of the 1970s facilitated and boosted CD production. Specifically, CD were found to form due to an enzymatic degradation of starch by the family of cyclodextrin glycosyltransferase found in several bacterial species.11 The type of CD formation can be oriented depending on the origin of the enzyme,11 but more commonly through the purification process by either 1) precipitation, 2) chromatography/adsorption techniques, or 3) filtration.11 Purification by precipitation is the easiest process and particularly elective for the production of β-CD taking advantage of its low solubility in water.2 These advances caused a drop in CDs’ prices; as the compounds became more accessible, their properties were explored and exploited by an increasing number of research groups. This translated into a tremendous inflation in the number of CD-based-literature since the 1980s. For further reading, Szejtli summarised nicely the history of cyclodextrins in two of his reviews.3,12
Nowadays, CDs find a broad application and are mostly attractive thanks to their inclusion complex formation property. They are for instance used in a) the pharmaceutical industry to enclose drug molecules and indirectly improve their solubility and bioavailability; b) the food
Chapter 2. Introduction to Part I 17
industry as masks of taste and smell, and as flavour protectors; c) the chemical industry as catalysts and retention agents in chromatography; d) cosmetics as stabiliser. Martin del Valle reported an extensive list of CDs properties and applications.13
In 1976, α- and β-CD were approved as food additives in Japan and within the same year the first CD-based pharmaceutical products, encapsulated prostaglandins14, were commercially available.15 Nowadays, CDs are used worldwide and a non-exhaustive list of CD-based products can be found in the references by Szejtli16 as well as Loftsson and Duchêne.15
The literature reveals, to the best of our knowledge, that structural studies of CDs and CD inclusion complexes have always been carried out using ambient-pressure techniques. High-pressure techniques have been shown to be a suitable method for obtaining novel crystal forms of pharmaceutical compounds, in particular for exploring the phenomenon of polymorphism and solvate formation more thoroughly.17,18 Investigating inclusion complex formation of cyclodextrins would be an interesting extension of the technique: can cyclodextrin complex formation be achieved at high pressure or would individual crystal components crystallise separately, and if so, which ones? In this section, examples of successful in-situ complex formation as well as unexpected results are presented for α- and β-cyclodextrin with active pharmaceutical ingredients using water as crystallisation medium.
Chapter 2. Introduction to Part I 18
(2) French, D.; Levine, M. L.; Pazur, J. H.; Norberg, E. Studies on the Schardinger Dextrins; the Preparation and Solubility Characteristics of Alpha, Beta and Gamma Dextrins. J. Am. Chem.
Soc. 1949, 71 (1), 353–356.
(3) Szejtli, J. Introduction and General Overview of Cyclodextrin Chemistry. Chem. Rev. 1998, 98, 1743–1753.
(4) Villiers, M. A. Sur La Transformation de La Fécule En Dextrin Par Le Ferment Butyrique.
Comptes rendus des séances l’académie des Sci. 1891, 435–437.
(5) Schardinger, F. Über Thermophile Bakterien Aus Verschiedenen Speisen Und Milch, Sowie Über Einige Umsetzungsprodukte Derselben in Kohlenhydrathaltigen Nährlösungen, Darunter Krystallisierte Polysaccharide (Dextrine) Aus Stärke. Zeitschrift für Untersuchung der Nahrungs- und Genußm. 1903, 19, 865–880.
(6) Cramer, F. Cyclodextrin - A Paradigmatic Model. In Proceedings of the First International Symposium on Cyclodextrins; Szejtli, J., Ed.; Springer Science+Business Media: Budapest, Hungary, 1981; pp 3–14.
(7) Stoddart, J. F. A Century of Cyclodextrins. Carbohydr. Res. 1989, 192, xii – xv.
(8) French, D. The Schardinger Dextrins. Adv. Carbohydr. Chem. 1957, 12, 189–260.
(9) Andersen, G. H.; Robbins, F. M.; Domingues, F. J.; Moores, R. G.; Long, C. L. The Utilization of Schardinger Dextrins by the Rat. Toxicol. Appl. Pharmacol. 1963, 5, 257–266.
(10) Saenger, W. Cyclodextrin Inclusion Compounds in Research and Industry. Angew. Chemie Int. Ed. English 1980, 19 (5), 344–362.
(11) Biwer, A.; Antranikian, G.; Heinzle, E. Enzymatic Production of Cyclodextrins. Appl.
Microbiol. Biotechnol. 2002, 59, 609–617.
(12) Szejtli, J. Past, Present and Futute of Cyclodextrin Research. Pure Appl. Chem. 2004, 76 (10), 1825–1845.
(13) Martin Del Valle, E. M. Cyclodextrins and Their Uses: A Review. Process Biochem. 2003, 39 (9), 1033–1046.
(14) Inaba, K.; Wakuda, T.; Uekama, K. Prostaglandins and Their Cyclodextrin Complexes. J.
Incl. Phenom. 1984, 2 (3-4), 467–474.
(15) Loftsson, T.; Duchêne, D. Cyclodextrins and Their Pharmaceutical Applications. Int. J.
Pharm. 2007, 329 (1-2), 1–11.
(16) Szejtli, J. Cyclodextrins: Applications. In Encyclopedia of Supramolecular Chemistry, volume 1;
Atwood, J. L., Steed, J. W., Eds.; CRC Press: New York, 2004; pp 405–413.
(17) Fabbiani, F. P. A.; Pulham, C. R. High-Pressure Studies of Pharmaceutical Compounds and Energetic Materials. Chem. Soc. Rev. 2006, 35 (10), 932–942.
(18) Boldyreva, E. V. High-Pressure Diffraction Studies of Molecular Organic Solids. A Personal View. Acta Crystallogr. A. 2008, 64 (Pt 1), 218–231.
Chapter 3. α-CD∙SA inclusion complex: a novel packing type of α-CD 19