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Cyclodextrins are a group of structurally related natural products formed during bacterial digestion of cellulose and belongs to a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Because of the chair conformation of the glucopyranose units, the cyclodextrins are shaped like a truncated cone rather than perfect cylinders. Their molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. They are widely used as "molecular cages" in the pharmaceutical industry, as complexing agents to increase the aqueous solubility of poorly soluble drugs and to increase their bioavailability and stability. In addition, cyclodextrins can be used to reduce gastrointestinal and ocular drug irritation, reduce or eliminate unpleasant smells or tastes, convert liquid drugs into microcrystalline or amorphous powder, and prevent drug-drug and drug-excipients interactions etc.
Figure 1: (a) the chemical structure and (b) toroidal or cone shape of the Î²-cyclodextrin molecule
There are three naturally occurring cyclodextrins are Î±, Î² and Î³ types containing 6, 7 and 8 D-glucopyranonsyl units respectively. The natural cyclodextrins, in particular Î²-cyclodextrin, are of limited aqueous solubility meaning that complexes resulting from interaction of lipophiles with these cyclodextrins can be of limited solubility resulting in precipitation of solid cyclodextrin complexes from water and other aqueous systems. Hydrophilic cyclodextrins are considered nontoxic at low to moderate oral dosages.
The natural cyclodextrin and its derivatives are used in topical and oral formulations, but only Î±-cyclodextrin and the hydrophilic derivatives of Î²- and Î³-cyclodextrin can be used in parenteral formulations.
Table 1: Molecular properties of Î± -, Î² - and Î³ -CD
Cavity diameter (nm)
Complex formation and drug solubility of cyclodextrin
Complexation is the association between two or more molecules to form a nonbonded entity with a well defined stoichiometry. In aqueous solutions, CDs are able to form inclusion complexes with many drugs by taking up the drug molecule or some lipophilic moiety of the molecule, into the central cavity. No covalent bonds are formed or broken during complex formation, and the drug molecules in complex are in rapid equilibrium with free molecules in the solution. The driving forces for the complex formation include release of enthalpy-rich water molecules from the cavity, hydrogen bonding, Vander Waals interaction, charge transfer interaction etc. The physicochemical properties of free cyclodextrin molecule differ from those in complex. Many techniques are used to form CD complexes, like co-precipitation, slurry complexation, kneading method, damp mixing, atomization (Spray drying), lyophilisation (Freeze drying), supercritical fluids.
Important effects of Cyclodextrins on drug properties in formulations
CDs play a very important role in formulation of poorly water soluble drugs by improving the apparent drug solubility and dissolution through inclusion complexation or solid dispersion.
CDs enhance the bioavailability of insoluble drugs by increasing its drug solubility, dissolution and drug permeability.
They reduce side effects and local irritation of drugs by preventing their direct contact with biological membranes.
They improve the stability of several labile drugs against dehydration, hydrolysis, oxidation and photodecomposition and thus increase the shelf life of drugs.
Complexation and mechanism of drug release from CD complexes
The internal cavity, hydrophobic in nature, is a key feature of the CDs providing the ability to form complexes, which include a variety of guest molecules. CD inclusion is a stoichiometric molecular phenomenon in which usually only one molecule interacts with the cavity of the CD molecule to become entrapped. Inclusion complex formation can be regarded as 'encapsulation' of the drug molecule, or at least the labile part of the molecule. Complexation of the drug (D) to CD occurs through a non-covalent interaction between the molecule and the CD cavity. No covalent bonds are formed or broken during the drug/cyclodextrin complex formation. The driving forces leading to the inclusion complex formation include release of enthalpy rich water molecules from the cavity, electrostatic interaction, vander Waals interaction, hydrophobic interaction, hydrogen bonding release of conformational strain, and charge-transfer interaction. This is a dynamic process whereby the drug molecule continuously associates and dissociates from the host CD. The most common type of cyclodextrin complexes is the 1:1 drug/cyclodextrin (D/CD) complex where one drug molecule (D) forms a complex with one cyclodextrin molecule (CD). Assuming a 1:1 complexation, the interaction will be as follows:
CD Drug Drug - CD complex
Figure 2: Illustration of equilibrium binding of drug and cyclodextrin to form a 1:1complex.
In a given aqueous complexation medium, saturated with the drug, the concentration of free drug ([D]) is constant and equal to the apparent intrinsic solubility of the drug in the aqueous medium (i.e. drug solubility in absence of cyclodextrin). CDs show a remarkable ability to form inclusion complexes with various molecules that fit partially or entirely inside the cavity. Cyclodextrin encapsulation of a drug will change the drug's physicochemical properties, such as its aqueous solubility and chemical stability. The cyclodextrin molecule forms a hydrophilic shield around applicable lipophilic moiety of the drug molecule. This will, in general, increase the apparent aqueous solubility of the drug. Reduction of drug crystallinity on complexation or solid dispersion with CDs also contributes to the CD increased apparent drug solubility and dissolution rate. CDs can enhance drug dissolution even when there is no complexation. A combined use of different CDs and/or pharmaceutical additives will provide more balanced oral bioavailability with prolonged therapeutic effects.
Study of cyclodextrin complexation
The most widely used approach to study inclusion complexation is the phase solubility method described by Higuchi and Connors, which examines the effect of a solubilizer, ie, CD or ligand, on the drug being solubilized, ie, the substrate. Phase solubility diagrams are categorized into 'A' and 'B' types as shown in Figure 2.
Figure 3: Graphical representations of A and B-type phase-solubility profiles with
applicable subtypes (AP, AL, AN and BS, BI)
'A' type curves indicate the formation of soluble inclusion complexes while 'B' type suggests the formation of inclusion complexes with poor solubility. A BS type response denotes complexes of limited solubility and a BI curve indicates insoluble complexes. A-type curves are subdivided into AL (linear increases of drug solubility as a function of CD concentration), AP (positively deviating isotherms), and AN (negatively deviating isotherms) subtypes. Î²-CD often gives rise to B-type curves due to their poor water solubility whereas the chemically modified CDs like HP-Î²-CD and SBE-Î²-CD usually produce soluble complexes and thus give A-type systems.
Most of the drug-cyclodextrin complexes are thought to be inclusion complexes, but cyclodextrins are also known to form non-inclusion complexes and the complex aggregates are capable of dissolving drugs through micelle-like structures. The phase-solubility profiles only describe how the increasing cyclodextrin concentration influences the drug solubility. In the case of a 1:1 complex, using the following equation one can determine the equilibrium binding or association constant, K, from the slope of the linear portion of the curve.
Where So is the intrinsic solubility of the drug studied under the conditions
Cyclodextrins and the Biopharmaceutics Classification System of Drugs
According to the biopharmaceutics classification system (BCS), aqueous solubility and permeability are the most important parameters affecting drug bioavailability. CDs can enhance the aqueous solubility of lipophilic drugs without changing their intrinsic ability to permeate biological membranes. Thus, through cyclodextrin complexation it is possible to move Class II drugs, and sometimes even Class IV drugs, into Class I.
Table 2: The Biopharmaceutics Classification System (BCS)
In this system a given drug substance is considered "highly soluble" when the highest dose strength is soluble in â‰¤250 ml water over a pH range 1 to 7.5 and "highly permeable" when the extent of absorption in humans is determined to be â‰¥90% of an administered dose (in solution), based on mass balance or related to an intravenous reference dose. For a rapidly dissolving tablet â‰¥85% of the labeled amount of drug substance must dissolve within 30 min. Thus, for rapidly dissolving solid oral dosage forms the dose-to-solubility ratio (D:S) of the drug must be â‰¤250 ml over pH range of 1 to 7.5.
Class II consists of water-insoluble drugs that easily permeate lipophilic biologic membranes once they are in solution, displaying dissolution-limited drug absorption after oral administration (low CAq and high P). Thus, low CS hampers their dissolution. The drug permeation through the aqueous diffusion layer adjacent to the mucosal surface will also be slow as a result of low CS. Water-soluble cyclodextrin complexes of these drugs will increase their apparent CS value, enhance their diffusion to the mucosal surface and increase their CAq value, leading to enhanced oral bioavailability. Hence, Cyclodextrins are ideal for Class II drugs possessing relatively high potency and good complexing capabilities.
Applications of Cyclodextrins in drug delivery
Because of multi-functional characteristics and bioadaptability, cyclodextrin are used in many drug delivery systems such as Oral drug delivery [Immediate release, Delayed release( pH-dependent release), Prolonged release and Modified release, Site-specific release (Colon-targeting)], Sublingual drug delivery, Parenteral drug delivery, Ophthalmic drug delivery, Nasal drug delivery, Transdermal drug delivery, Rectal drug delivery, Pulmonary drug delivery, Peptide and Protein Delivery, Gene and Oligonucleotide Delivery, Site-specific drug delivery: Brain targetting and Novel drug delivery: Liposomes, Microspheres, Microcapsules, Nanoparticles
Pharmaceutical applications of CDs Cyclodextrins can be used in pharmaceutical formulations to achieve the following:
Convert liquids and oils to free-flowing powders
Reduce evaporation and stabilize flavours
Reduce odours and tastes
Prevent admixture incompatibilities
Limitations of CDs
Drug molecule to be complexed with CD should have certain characteristics as given below.
â€¢ More than five atoms (C, P, S, N) which form the skeleton of the drug molecule.
â€¢ Melting point temperature of the substance is below 250 ï‚° C.
â€¢ Solubility in water is less than 10 mg/mL.
â€¢ The guest molecule consists of less than five condensed rings.
â€¢ Molecular weight between 100 and 400.
1.14. Methods for Characterization of Inclusion complexes
The inclusion complexes can be studied and characterized in two ways:
1. In solid state: Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), Differential scanning calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared Spectrometry (FTIR), X-ray diffractometry (XRD).
2. In Solution state: Solubility studies, Dissolution studies, UV-spectral studies, 1H- NMR studies and Thin Layer Chromatography (TLC)