Cyclodextrins in Pharmaceutics, Cosmetics, and Biomedicine

Current and Future Industrial Applications

Erem Bilensoy

• Publisher: Wiley
• Year: 2011
• Print ISBN:
  9780470474228
• eBook ISBN:
  9780470934616
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

Cyclodextrins in Pharmaceutics, Cosmetics, and Biomedicine covers a wide range of knowledge on cyclodextrins, from an overview of molecular and supramolecular aspects of cyclodextrin physicochemistry, to the latest outcomes in cyclodextrin use and future possibilities in the employment of these systems. This book focuses on the derivatives and physicochemical and biological properties of cyclodextrins, and considers drug delivery through topical, mucosal, and oral via cyclodextrin complexes.

Part I

Cyclodextrins: History, Properties, Applications, and Current Status

Chapter 1

Cyclodextrins and Their Inclusion Complexes

Dominique Duchêne

UMR CNRS 8612, Physico-Chimie–Pharmacotechnie–Biopharmacie, Université Paris–Sud, Châtenay, Malabry, France

1. Introduction

Cyclodextrins (CDs) are molecules of natural origin discovered in 1891 by Villiers. Studied by Schardinger at the beginning of the twentieth century, they became the topic of prominent scientific interest only in the late 1970s, early 1980s [1]. The main value of these oligosaccharides resides in their ring structure and their consequent ability to include guest molecules inside their internal cavity. This is at the origin of many applications: modification of the physicochemical properties of the included molecule (i.e., physical state, stability, solubility, and bioavailability), preparation of conjugates, and linking to various polymers. This results in the use of CDs in many industries, such as agro-food, cosmetology, pharmacy, and chemistry. Presently, the annual average number of articles, book chapters, lectures, and scientific contributions is between 1500 and 2000.

Presented briefly in this chapter are the main cyclodextrins available on the market, and their major characteristics, focusing on their ability to yield inclusion complexes. Also described is the manner in which complexes can be obtained and studied.

2. Main CDs and Their Ability to Include Guest Molecules

2.1 Main CDs

2.1.1 Natural CDs

CDs result from starch degradation by cycloglycosyl transferase amylases (CGTases) produced by various bacilli, among them Bacillus macerans and B. circulans [2]. Depending on the exact reaction conditions, three main CDs can be obtained: α-, β-, and γ-cyclodextrin, comprising six, seven, or eight α(1,4)-linked D(+)-glucopyranose units, respectively [3]. CDs are ring molecules, but due to the lack of free rotation at the level of bonds between glucopyranose units, they are not cylindrical but, rather, toroidal or cone shaped [4]. The primary hydroxyl groups are located on the narrow side; the secondary groups, on the wider side (Fig. 1).

Figure 1 Schematic representation of α-CD.

Due to steric factors and tensions in the ring, CDs with fewer than six glucopyranose units cannot exist. On the other hand, although cyclodextrins with 9, 10, 11, 12, or 13 glucopyranose units (δ-, ε-, ζ-, η-, or θ-CD, respectively) have been described, only δ-CD has been well characterized [4]. The largest CDs, those with a helicoidal conformation, are rapidly reduced to smaller products.

The aqueous solubility of CDs is much lower than that of similar acyclic saccharides. This is the consequence of strong binding of CD molecules inside the crystal lattice. Furthermore, for β-CD, with its odd number of glucopyranose units, intramolecular hydrogen bonds appear between hydroxyl groups, preventing hydrogen bond formation with surrounding water molecules and resulting in poor water solubility [4] (Table 1).

Table 1. Main Natural CDs and Their Characteristics.

The central cavity of CDs, which is composed of glucose residues, is hydrophobic when the external part is hydrophilic because of the presence of hydroxyl groups. In aqueous solution, water molecules inside the CD cavity can easily be replaced by apolar molecules or apolar parts of molecules, leading (reversibly) to an inclusion host–guest complex [5] which can be isolated.

When compared with its free molecular state, the included guest molecule has (apparent) new physicochemical properties, among which is higher apparent water solubility. This increase in water solubility depends on the CD water solubility, but this parameter is limited compared with linear oligosaccharides. This is one reason that highly water-soluble CD derivatives have been synthesized.

2.1.2 CD Derivatives

CDs' low aqueous solubility results from hydrogen bonds between hydroxyl groups. Any substitution on the hydroxyl groups, even by hydrophobic moieties, leads to a dramatic increase in water solubility [4]. The different CD derivatives still have the ability to include molecules inside their cavity, but with a different affinity than that of the parent CD. Among the water-soluble CD derivatives most often employed are three classes of modified CDs: methylated, hydroxypropylated (both neutral), and sulfobutylated (negatively charged).

Theoretically, methylation of CDs can occur on either two or three hydroxyl groups per glucopyranose unit. In the first case [dimethyl-cyclodextrins (DM-CDs)] the methylation takes place on all the primary hydroxyl groups (position C₆) and all the secondary hydroxyl groups in position C₂, the secondary hydroxyl groups in position C₃ remaining free. In the second case [trimethyl-cyclodextrins (TM-CDs)] all the hydroxyl groups are substituted, including those in C₃.

Most often, and in the case of β-CD, it is a randomly substituted CD that is used with an average substitution degree (number of substitutions per glucopyranose unit) of 1.8 (e.g., RAMEB, which is an amorphous product). There also exists a very slightly substituted β-CD: Crysmeb, with a substitution degree of 0.5.

Hydroxypropylation occurs in a purely random manner on the primary or secondary hydroxyl groups, leading to an amorphous mixture. Most often, in the case of β-CD, it is 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) that is used; this means that it is a 2-hydroxylpropyl moiety that is linked. Because of different producers, the substitution degree has to be mentioned.

There is only one sulfobutylated CD, the β-derivative, with 6.8 substituents per CD (SBE_7m-β-CD). It has about seven negative charges per CD, which are counterbalanced with sodium ions. Usually, a charged group reduces the CD complexation ability, but in the case of SBE_7m-β-CD, it shows high binding properties, due to the significant separation from the CD cavity of the charged sulfonate moieties [5].

2.2 Formation of Inclusion Compounds

2.2.1 Principle

The CD central cavity, composed of glucose residues, is lipophilic and in aqueous solutions can reversibly entrap suitably sized molecules (or parts of molecules) to form an inclusion complex [4]. Formation of an inclusion complex is the result of equilibrium between the free guest and CD molecules and the supramolecules of inclusion:

Formation and dissociation of an inclusion complex is governed by a constant K, which may have different names: affinity constant (affinity of the guest molecule for the CD cavity), stability constant (stability of the inclusion complex in a nondissociated form), association constant, or binding constant. The higher the K value, the more stable the inclusion, and the less dissociation that occurs. The value of K depends on, among other factors, the size of the CD cavity and that of the guest molecule (or part of the molecule). It also depends on the more-or-less good fitting of the guest molecule inside the CD cavity. As a general rule, the complex is strong when there is size complementarity between the guest and the CD cavity [6]. Depending on their respective size, the guest molecule will enter the CD cavity at the narrow side (primary hydroxyl groups) or at the wide side (secondary hydroxyl groups) (Fig. 2).

Figure 2 Influence of the guest and CD cavity size on the inclusion mechanism.

2.2.2 Driving Force

The driving force for complex formation has been attributed to many factors, among them the extrusion of water from the cavity; hydrophobic, hydrogen bonding, and electrostatic interactions; induction forces; and London dispersion forces [7]. To better understand the inclusion mechanism, it is important to consider the thermodynamic parameters: the standard free-energy change (ΔG), the standard enthalpy change (ΔH), and the standard entropy change (ΔS). Hydrophobic interactions are entropy driven (slightly positive ΔH and large positive ΔS). Van der Waals forces are characterized by negative ΔH and negative ΔS. Compensation (increasing enthalpy related to less negative entropy) is often correlated with water acting as the driving force. In this case, being unable to satisfy their hydrogen-bonding potentials, the enthalpy-rich water molecules from the cyclodextrin cavity are released from the cavity and replaced by guest molecules less polar than water, with a simultaneous decrease in the system energy [4].

2.2.3 Different Types of Complexes

When speaking of inclusion complexes, it is clear that an apolar molecule, or at least an apolar part of a molecule, is inside the CD cavity. But other complexes can be formed which are not inclusion complexes but in which...

Table of contents

• Cover
• Title Page
• Copyright
• Contributors
• Preface
• Part I: Cyclodextrins: History, Properties, Applications, and Current Status
• Part II: Novel and Specialized Applications of Cyclodextrins
• Color Plates
• Index