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  1. CYCLODEXTRIN Mr. Sagar Kishor savale [Department of Pharmacy (Pharmaceutics)] Department of Pharmacy (Pharmaceutics) | Sagar savale 23-12-2015 1
  2. Solubility The term ‘Solubility’ is defined as maximum amount of solute that can be dissolved in a given amount of solvent to form a homogenous system at specified temperature. The solubility of a drug is represented through various concentration expressions such as parts, percentage, molarity, molality, volume fraction, mole fraction. • Table 1: USP & BP Solubility criteria Definition Parts of solvent required for one part of solute Very soluble < 1 Freely soluble 1 - 10 Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000 Very slightly soluble 1000 - 10,000 Insoluble > 10,000 23-12-2015 2
  3. Importance of Solubility • Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of drug molecules. • Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. • Currently only 8% of new drug candidates have both high solubility and permeability. • Nearly 40% of the new chemical entities currently being discovered are poorly water soluble. • More than one-third of the drugs listed in the U.S. Pharmacopoeia fall into the poorly water-soluble or water-insoluble categories. • Low aqueous solubility is the major problem encountered with formulation development of new chemical entities. • Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption.23-12-2015 3
  4. Complexation • Complexation is the reversible association between two or more molecules to form a non bonded entity with a well defined stoichiometry . Complexation relies on relatively weak forces such as van-derwaal forces, hydrogen bonding and hydrophobic interactions. • Inclusion Complexation - These are formed by the insertion of the nonpolar molecule or the nonpolar region of one molecule into the cavity of another molecule or group of molecules. The most commonly used host molecules are cyclodextrines. Cyclodextrines are non- reducing, crystalline , water soluble, cyclic, oligosaccharides. Cyclodextrines consist of glucose monomers arranged in a donut shape ring. CYCLODEXTRIN Hydrphobic Hydrophillic The surface of the cyclodextrines molecules makes them water soluble, but the hydrophobic cavity provides a microenvironment for appropriately sized non- polar molecules. Based on the structure and properties of drug molecule it can form 1:1 or 1:2 drug cyclodextrines complex. Three naturally occurring CDs are α Cyclodextrines, β Cyclodextrines, and γ Cyclodextrines. 23-12-2015 4
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  6. History of Cyclodextrines Cyclodextrins, as they are known today, were called “cellulosine” when first described by A. Villiers in 1891. Soon after, F. Schardinger identified the three naturally occurring cyclodextrins - α, -β, and -γ. These compounds were therefore referred to as “Schardinger sugars”. For 25 years, between 1911 and 1935, Pringsheim in Germany was the leading researcher in this area, demonstrating that cyclodextrins formed stable aqueous complexes with many other chemicals. By the mid- 1970s, each of the natural cyclodextrins had been structurally and chemically characterized and many more complexes had been studied. Since the 1970s, extensive work has been conducted by Szejtli and others exploring encapsulation by cyclodextrins and their derivatives for industrial and pharmacologic applications. 23-12-2015 6
  7. Cyclodextrines • It is a Complexaing agent. • Synonym: cavitron, cycloamyloses, cycloglucan, cyclic oligosaccharide • It is a important for increasing the solubility of poorly water soluble drugs. • Cyclodextrines are produced from starch by means of enzymatic conversion. • They are used in food, pharmaceutical, drug delivery, and chemical industries, as well as agriculture and environmental engineering. • Cyclodextrines are composed of 5 or more α-D glucopyranoside units linked 1->4, as in amylose linkage. • Cyclodextrines contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring. • CDs, with lipophilic inner cavities & hydrophilic outer surfaces, are interacting with a guest molecule to form non covalent inclusion complexes. • Today CDs are only synthesized either by fermentation or enzymatically. • Many CGTases from different microorganisms are known, cloned, sequenced, characterized and used for production of CDs. 23-12-2015 7
  8. Types • α (alpha)-cyclodextrin: 6-membered sugar ring molecule. • β (beta)-cyclodextrin: 7-membered sugar ring molecule. • γ (gamma)-cyclodextrin: 8-membered sugar ring molecule. Synthesis The production of cyclodextrins is relatively simple and involves treatment of ordinary starch with a set of easily available enzymes.Commonly cyclodextrin glucosyltransferase (CGTase) is employed along with α-amylase. First starch is liquefied either by heat treatment or using α- amylase, then CGTase is added for the enzymatic conversion. CGTases can synthesize all forms of cyclodextrins, thus the product of the conversion results in a mixture of the three main types of cyclic molecules, in ratios that are strictly dependent on the enzyme used: each CGTase has its own characteristic α:β:γ synthesis ratio. Purification of the three types of cyclodextrins takes advantage of the different water solubility of the molecules: β-CD which is very poorly water-soluble (18.5 g/l or 16.3mM) (at 25C) can be easily retrieved through crystallization while the more soluble α- and γ-CDs (145 and 232 g/l respectively) are usually purified by means of expensive and time consuming chromatography techniques. As an alternative a “complexing agent” can be added during the enzymatic conversion step: such agents (usually organic solvents like toluene, acetone or ethanol) form a complex with the desired cyclodextrin which subsequently precipitates. The complex formation drives the conversion of starch towards the synthesis of the precipitated cyclodextrin, thus enriching its content in the final mixture of products. Wacker Chemie AG uses dedicated enzymes, that can produce alpha-, beta- or gamma-cyclodextrin specifically. This is very valuable especially for the food industry, as only alpha- and gamma-cyclodextrin can be consumed without a daily intake limit. 23-12-2015 8
  9. Manufacture of CDs Cyclodextrins are manufactured by the enzymatic degradation of starch using specialized bacteria. ethylene oxide starch Starch or a starch hydrolysate enzyme cyclodextrin glucosyltransferase organic solvent noncyclic starch solvent is removed by vaccume cyclodextrin carbon treated crystallized from water, dried Hydroxyethyl-β-cyclodextrin propylene oxide β- cyclodextrin23-12-2015 9
  10. • Empirical Formula and Molecular Weight 10 • Chemical Name and CAS Registry Number • FUNCTIONAL CATEGORY 1. Solubilizing agent 2. stabilizing agent 23-12-2015
  11. Characteristics • It is solubilizing agent • It is Complexaing agent • It is a white, practically odorless, fine crystalline powders, having a slightly sweet taste. • cyclodextrin derivatives occur as amorphous powders. • It is Physico-chemically stable. • It is chemically innert. • It is Free from Microbial contamination. • It is Pharmacological active material. 23-12-2015 11
  12. Structure Cyclodextrins are a group of structurally related natural products formed during bacterial digestion of cellulose. These cyclic oligosaccharides consist of (α-1,4)-linked α-D-glucopyranose units and contain a somewhat lipophilic central cavity and a hydrophilic outer surface. Due to the chair conformation of the glucopyranose units, the cyclodextrins are shaped like a truncated cone rather than perfect cylinders. The hydroxyl functions are orientated to the cone exterior with the primary hydroxyl groups of the sugar residues at the narrow edge of the cone and the secondary hydroxyl groups at the wider edge. The central cavity is lined by the skeletal carbons and ethereal oxygens of the glucose residues, which gives it a lipophilic character. The polarity of the cavity has been estimated to be similar to that of an aqueous ethanolic solution. The natural α-, β- and γ-cyclodextrin consist of six, seven, and eight glucopyranose units, respectively. The natural cyclodextrins, in particular β- cyclodextrin, are of limited aqueous solubility meaning that complexes resulting from interaction of lipophiles with these cyclodextrin can be of limited solubility resulting in precipitation of solid cyclodextrin complexes from water and other aqueous systems. In fact, the aqueous solubility of the natural cyclodextrins is much lower than that of comparable acyclic saccharides. This is thought to be due torelatively strong intermolecular hydrogen bonding in the crystal state. Substitution of any of the hydrogen bond forming hydroxyl groups, even by lipophilic methoxy functions, results in dramatic improvement in their aqueous solubility. Cyclodextrin derivatives of pharmaceutical interest include the hydroxypropyl derivatives of β- and γ-cyclodextrin, the randomly methylated β-cyclodextrin, sulfobutylether β-cyclodextrin, and the so-called branched cyclodextrins such as glucosyl-β- cyclodextrin. 23-12-2015 12
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  15. Properties Type of CD cavity Diameter A° Molecular weight Solubility (g/100ml) α-CD 4.7-5.3 972 14.5 β-CD 6.0-6.5 1135 1.85 γ-CD 7.5-8.3 1297 23.2 δ-CD 10.3-11.2 1459 8.19 23-12-2015 15
  16.    Molecular weight 972 1135 1297 Glucose monomers 6 7 8 Internal cavity diameter (angstroms) 4.7-5.3 6.0–6.6 7.5–8.3 Water solubility (g/100mL: 25 deg. C) 14.2 1.85 23.2 Melting range (deg. C) 255-260 255-265 240-245 Water of crystallization 10.2 13-15 8-18 Water molecules in cavity 6 11 17 Cavity volume (ml/mol) 174 262 472 Price (US$/g pharma-grade) 1.0 0.025 0.8 23-12-2015 16
  17. •Stability • β-Cyclodextrin and other Cyclodextrins are stable in the solid state if protected from high humidity. •Storage • Cyclodextrins should be stored in a tightly sealed container, in a cool, dry place. •Incompatibilities • The activity of some antimicrobial preservatives in aqueous solution can be reduced in the presence of hydroxypropyl-β-cyclodextrin. 23-12-2015 17
  18. Derivative Methyl-β-cyclodextrin Both β-cyclodextrin and methyl-β-cyclodextrin (MβCD) remove cholesterol from cultured cells. The methylated form MβCD was found to be more efficient than β-cyclodextrin. The water-soluble MβCD is known to form soluble inclusion complexes with cholesterol, thereby enhancing its solubility in aqueous solution. MβCD is employed for the preparation of cholesterol-free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed. MβCD is also employed in research to disrupt lipid rafts by removing cholesterol from membranes. 23-12-2015 18
  19. Use Cyclodextrins are able to form host-guest complexes with hydrophobic molecules given the unique nature imparted by their structure. As a result, these molecules have found a number of applications in a wide range of fields. Cyclodextrins can solubilize hydrophobic drugs in pharmaceutical applications, and crosslink to form polymers used for drug delivery. One example is Sugammadex, a modified γ-cyclodextrin which reverses neuromuscular blockade by binding the drug rocuronium. Other than the above-mentioned pharmaceutical applications, cyclodextrins can be employed in environmental protection: these molecules can effectively immobilise inside their rings toxic compounds, like trichloroethane or heavy metals, or can form complexes with stable substances, like trichlorfon (an organ phosphorus insecticide) or sewage sludge, enhancing their decomposition. This ability of forming complexes with hydrophobic molecules has led to their usage in supramolecular chemistry. In particular they have been used to synthesize certain mechanically-interlocked molecular architectures, such as rotaxanes and catenanes, by reacting the ends of the threaded guest. The photodimerization of substituted stilbazoles has been demonstrated using g-cyclodextrin as a host. Based on the photodimer obtained, it is established that the halogen-halogen interactions, which play an interesting role in solid state, can be observed in solution. Existence of such interactions in solution has been proved by selective photodimerization of dichloro substituted stiblazoles in Cyclodextrin and Cucurbiturils.The application of cyclodextrin as supramolecular carrier is also possible in organometallic reactions. The mechanism of action probably takes place in the interfacial region. Wipff also demonstrated by computational study that the reaction occurs in the interfacial layer. The application of cyclodextrins as supramolecular carrier is possible in various organometallic catalysis. In 2013, α-cyclodextrin is found to be able to selectively form second-sphere coordination complex with tetrabromoaurate anion ([AuBr4]-) from transition-metal anion mixtures, and thus is used to selectively recover gold from various gold-bearing materials in an environmentally benign Manner.β-cyclodextrins are used to produce HPLC columns allowing chiral enantiomers separation,[and are also the main ingredient in P&G’s product Febreze which claims that the β-cyclodextrins “trap” odor causing compounds, There by reducing the odor.23-12-2015 19
  20. According to drug • It can increases solubility of drug. • It can increases dissolution rate of drug. • It can increases absorption rate of drug. • It can increases Bioavailability of drug. • It can increases Pharmacological and Therapeutic ability. 23-12-2015 20
  21. Rationale • Increase Solubility of Hydrophobic Drugs. • Increase Heat Resistance To Drugs. • Increase Oxidation Resistance To Drugs. • Increase Hydrolysis Resistance To Drugs. • Increase Bioavailability of Drug. • Decrease Gastrointestinal Irritation By Drugs. • Decrease Enzymatic Degradation of Drug. 23-12-2015 21
  22. Applications In Drug Delivery System  Oral drug delivery  Parenteral drug delivery  Nasal drug delivery  Rectal drug delivery  Controlled drug delivery  Peptide & protein delivery  Dermal & transdermal delivery  Liposomes  Microcapsules  Nanoparticles 23-12-2015 22
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  25. Reference 1. Brewster ME, Loftsson T. 1999. Complexation: Use of cyclodextrins to improve pharmaceutical properties of intramuscular formulations. In: Gupta PK, Brazeau GA, editors. Injectable drug development: Techniques to reduce pain and irritation. Denver: Interpharm Press, pp 307–336. 2. Tomasik P, Schilling CH. 1998. Complexes of starch with inorganic guests. In: Horton D, editor. Advances in carbohydrate chemistry and biochemistry. San Diego: Academic Press, pp 263–343. 3. Tomasik P, Schilling CH. 1998. Complexes of starch with organic guests. In: Horton D, editor. Advances in carbohydrate chemistry and biochemistry. San Diego: Academic Press, pp 345–426. 4. Aoyama Y, Otsuki J, Nagai Y, Kobayashi K, Toi H. 1992. Host-guest complexation of oligosaccharides: Interaction of maltodextrins with hydrophobic fluorescence probes in water. Tetrahedron Lett 33:3775–3778. 5. Kano K, Minami K, Horiguchi K, Ishimura T, Kodera M. 1995. Ability of noncyclic oligosaccharides to form molecular complexes and its use for chiral separation by capillary zone electrophoresis. J Chromatogr A 694:307–313. 6. Gabelica V, Galic N, De Pauw E. 2002. On the specificity of cyclodextrin complexes detected by electrospray mass spectrometry. J Am Soc Mass Spectrom 13:946–953. 23-12-2015 25
  26. 7. International journal of pharma professional’s research review article solubility enhancement techniques with special emphasis o n hydrotrophy - volume 1, issue 1, July 2010 8. Solubility enhancement techniques - volume 5, issue 1, November – December 2010; article-007 9. Journal of global pharma technology techniques to enhance solubility of poorly soluble drugs: a review available at www.Jgpt.Co.In 10. Pharmacie globale -international journal of comprehensive pharmacy- review on solubility enhancement techniques for hydrophobic drugs 11. D. M. Brahmankar, sunit b. Jaiswal, Biopharmaceutics and pharmacokinetics a treatise page no.282-283. 12. M.E.Aulton .Pharmaceutics, The science of dosage form design, 2nd edition, Churchill Livingstone, London, 2002¡113 – 252. 23-12-2015 26
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