Inclusion compounds & Cyclodextrins

Presented by: Kunal goyal Pt.B.D. sharma univ. Health sci. rohtak

INCUSION COMPUNDS
A complex in which one component (the host) forms a cavity or, in the case of a crystal, a crystal lattice containing spaces in the shape of long tunnels or channels in which molecular entities of a second chemical species (the guest) are located. There is no covalent bonding between guest and host, the attraction being generally due to van der Waals forces.

 Requirements for inclusion compounds formation:

The host molecule should be able to form void spaces of a certain molecular dimension The guest molecule has to fit or atleast partially fit into these void spaces The stereochemical structure and polarity of guest and host molecule may be important
Although guest is not chemically modified by inclusion its physiochemically properties are dominated by host after complex.

Also called as:

o o o o o Clathrates to clathratus Inclusion complex Occlusion complex Intercalation compound packing complex

Classifications:
Polymolecular inclusion compounds -channel like spaces -cage like spaces Monomolecular inclusion compounds Macromolecular inclusion compounds Product of blue iodine reaction

Polymolecular inclusion compounds:

Channel like space: This group of host characterized by the fact that they form channel In which guest molecules fits.e.g urea, thiourea and selenurea. In The presence of hydrocarbon(st. chain) urea form hollow channel like structure in Which guest molecule fit .thiourea form same structure but with Increased diameter(cyclic and branched hydrocaron).so can be used For sepration of hydrocarbon mixtures.

Urea and thiourea can be used to stabalized oxidized substance by Protecting the guest from oxygen. Example lipoic acid, poly unsaturat Fatty acid and vitamin A Cholic acid also act as a host in this type of class. Eg 4,4dinitrobiphenyl,perhydrotriphenylene,trianthranilides

Cage like space:

In this kind the guest molecule is completely surrounded by the host molecules. Example Gas hydrates in which water crystal trap a number of gases and liquid(like ice). depending Upon the size of guest molecule water forms the void spaces. the guest water stoichiometry Varies from 1:5.75 to1:17. no valance bond form between guest and water molecules only due To repulsion forces they are unable to escape from void space.typical example is clathrates of Warferin sodium with isopropyl alcohol and water. Eg Hydroquinon, phenol, dianin`s compound, trimesic acid,

Monomolecular inclusion compounds

These are the substance s in which every guest molecule is included by one host molecule The host molecule in this have relatively large as they contain void spaces of molecular Dimension.e.g cyclodextrin

Crown ethers: these macromonocyclic polyether show complexing properties towards

Metal cations,primary alkylaluminium salt and other neutral organic guest. Some noncyclic Crown ether consisting of several oxygen atoms connected by ethylene group are able to Complex guest molecule. They are useful for solubility enhancer ina polar solvent and Permeability enhacer in lipid membrane for metal cations.

Crypates: are macropolycyclic diazopolyether which show simillar inclusion behaviour as

As crown ether bt having large stability. Same used as crown ether and also be used for Lead poisioning(excrete the large amount of lead through urine) Eg calixrenes,cyclotriveratrylene bearing polyoxy ethylene chain.

Products of blue iodine reaction

Iodine is known to form long linear inclusion compounds with many molecules having blue black colour. The iodine atom is polymerized into a linear template around which host moleculeordered and stabalized by electron donor capacity of host. Eg host like amylose, amylopectin ,Inulin, flavone ,barbituric acid made these type of complexs. These idophore are used for the Skin disinfection for human and vetnary use due in disinfecting property of iodine

Macromolecular inclusion compounds

Host molecules are of macromolecular size Zeolites are the hydrated aluminium silicate that may contain sodium ,potassium, calcium or Barium. It cane be imagined as a precisely arranged number of cavities interconnected by channels. Depending on the size of channels and cavities a avriety of molecule can be included in cavities. Normally water is present in these spaces bt othe ions can ve filled when they are of size they can fit in them. These can be used for the ion excahnger and urea adsorption on several mineral was tested.

Cyclodextrin
Cyclodextrins are a group of structurally related natural products and also known as cycloamylosis and as Schardinger dextrins. The CDs are water soluble, non reducing macrocyclic polymers containing glucose molecules joined by a- 1, 4- linkages. The most common of these compounds are the a, and g CDs formed by 6, 7 and 8 glucose units respectively

The CDs are produced by the degradation and cyclization of Starch by an Enzyme produced Bacillus macerans. Molecules of a suitable size and shape can be held within the cavity of a particular CDs by van der Waals forces [18]. The ability to form inclusion compounds in aqueous solution is due to the typical arrangement of the glucose units. The interior of the cavity is relatively hydrophobic because of the CH2 groups. Where as, the cavity entrances are hydrophilic owing to the presence of primary and secondary hydroxyl groups. Molecules of appropriate size and stereochemistry can be included in the CD cavity by hydrophobic interaction. Complexation does not ordinarily involve in the formation of covalent bond. CDs are studies as solubilizing and stabilizing agents in pharmaceutical dosage forms

S.no. 1. 2. 3. 4. 5. 6. 7. 8.

Characteristics Glucose unit (Numbers) Molecular weight Cavity diameter (Ao) Height of torus (Ao) Diameter of outer Periphery (Ao) Approximate vol of cavity (Ao3) Crystals forms (from water)

Alpha CD 6 972 4.7-5.3 7.9 01 14.6 0.4 174 Hexagonal plates 10.2 3.443 12.332 14.5 275 33

Beta CD 7 1135 6.0-6.5 7.9-01 15.4 0.4 262 Monoclinic parallelogrm 13.2-14.5 3.224 12.202 1.85 280 29

Gamma CD 8 1297 7.5-8.3 7.9 01 17.5 0.4 427 Quadratic prism 8.13-17.7 3.000 12.081 23.2 275 15

9. 10. 11.
12. 13. 14.

Crystal water (%w/w) Diffusion constant(at 40oC) Pka (by potentiometry) (at 25o C) Solubility in water at 25 o C (g/ 100 ml) Melting point o C
t of ring opening (h)

Cyclodextrin Derivatives Methylated beta-CDs Dimethyl beta-CD Trimethyl beta-CD Randomly methylated beta -CD Hydroxy-alkylayed beta CDs 2-hydroxy-ethyl 2-hydroxy-propyl 3-hydroxy-propyl 2,3-dihydroxy-propyl Sulfo butyl ether beta CD

Characteristics Water soluble

Routs of Application Oral Ocular Nasal

Amorphous mixture with different degree of substitution, highly water soluble, less toxic Soluble in water

Oral Ocular Rectal intravenous

Oral Ocular Parentral Pulmonry

There are four favorable interactions between cyclodextrin and active drug , which shift the equilibrium towards complex formation . 1. The displacement of polar water molecules from the a polar cyclodextrin cavity, 2. the increased number of hydrogen bonds formed as the displaced water returns to the larger pool, 3. A reduction of repulsive interaction between the hydrophobic active drug and the aqueous environment, and 4. An increase in hydrophobic interaction as the active drug inserts itself into the polar cyclodextrin cavity.

Complexation Techniques Complexes can be formed by a variety of techniques that depends on the properties of the active drug, equilibrium kinetic, other formulation ingredients, processes, end object and the final dosage form desired. S.no Techniques 1. Physical blending/Milling/Co-grinding/ Solid phase complexation Kneading Approachs The cyclodextrin and active drug are physically blended, milled or co-grinded using a high level of mechanical energy. The cyclodextrin is converted into a paste by the addition of water or hydro Alcoholic solution and then drug is added & kneaded with the above paste for a sufficient time. The kneaded mixture is then driedand passed through a suitable size sieve.

2.

S.no 3

Techniques Co-precipitation

Approachs The cyclodextrin and active drug are added to wateror a short chain alcohol (eg. Ethanol or Isopropanol) at 40C60C to form a saturated solution. Upon cooling, the complex precipitate is formed which isfurther isolated by filtration or centrifugation. In thismethod, Complexation time may vary from 24 to 48hours. The active drug is dissolved in alkaline solution and mixed with aqueous solution of cyclodextrin. The resultant clear solution is then neutralized under stirring using hydrochloric acid solution till equivalence point. At equivalence point, a white precipitate is formed. Confirming the formation of inclusion complex. The cyclodextrin and active drug are dissolved separately in a two different miscible solvents and mixing of both solutions to get molecular dispersion of drug and complexing agent. The solvent is evaporated finally under vacuum to obtain a solid powdered inclusion compound.

Neutrilization precipitation

5.

Solvent evaporation

S.no. 6.

Techniques Spray drying/ Automization

Approachs The cyclodextrin is either dissolved or suspended in water(1:10) at room temperature and solution stirred vigorously. The active drug is slowly added to water cyclodextrin solution or suspension. The active drug can either be added as in or dissolved in a solvent. The complex is isolated by spray during solution. The cyclodextrin and active drug are dissolved in water or in water-cosolvent mixture. The complex is isolated by freeze drying the solution. The CD and active drug are dissolved in a mixture of water and organic solvent. The mixture is reacted for short time of about one or two minute at 60C in the microwave oven. After completion of reaction , adequate amount of solvent mixture is added to above reaction mixture to remove the residual Uncomplexed free drug and cyclodextrin. The precipitate obtain is filtered and dried in vaccum oven.

7.

Freeze drying

8.

Microwave irradiation

The complex formation and the characterisation of the complex in solutions and solid state can be done with following Techniques:

For solids:
Thermo analytical methods
DTA DSC SEM XRD Dissolution test TLC IR Solubility

For Solution
Electrochemistry: -Polarography, conductivity, polarimetry Solubility Spectroscopy- NMR, ESR, UV, Flourometry, CD pH- Potentiometric titrations

Advantages of Cyclodextrins:
Aqueous solubility, Low toxicity, No or poor pharmacological activity, Resistant to decomposes by hot alkali, Thermal Stability up to 300C, Protect the drug for their biodegradation, Non-irritating or Non-allergenic, Therapeutically inert, Ease in complex formation, Improvement in shelf life of product, and Regulatory Compliance.

Entrapment of different molecular size drugs due to different cavity diameter,

Drug delivery
Oral hydrophillic cyclodextrin are used for the solubility enhancement and bioavalibilty Of poorly soluble drugs and the hydrophobic cyclodextrion used for the prolong or modify Release. Sublingual complex not only improve the absorption also mask th ebitter taste of the drug. Ocular Cyclodextrin solubilisation of drug will increase the amount of dissolved drug at the Lipophillic membrane surface but the excess cyclodextrin will decrease the drug partiiton To lipophillic barier Nasal : in nasal formulaton cyclodextrins are used to inc aq. Solubility of lipophillic drugs. However lipophillic cyclodextrin can also interact with the biological membranes and act As a permeation enhancer. Pulmonary it increase the solubility stability and disolution of water insoluble and unstable drugs . Decrease clearence ,inc absorption and faster onset of action. Complex convert liquid Drug to solid form Some drug show increase in aq solubility with cyclodextrins: cardiac glycoside,barbiturats Sex hormone, vitamins Corticosteroids Benzidiazapenes

Role in novel drug delivery

S.No Novel drug delievery Advantages

1
2.

Liposomal
Microspheres

Improve the stability of liposome Improve drug loading efficiency

Improve drug loading efficiency. As a stabilizing agent for lysozyme & bovine serum albumin preparation. As a crosslinking agent Provide hydrolytic or photolytic stability of drug As a solubilizer As a solubilizer As a solubilizer Improve chemical and enzymatic stability Improve absorption

3. 4. 5.

Nanoparticles Osmotic delivery Peptide and protein delivery

Trade name

Dosage form

CD

API

Company

Pansporin T Stadatravel
lonmiel Glymesason Indocid

Tablet Chewable tablet

Capsule Ointment Eye drop

Alpha Alpha Beta

Beta Beta

Cefotiam hexetil HCl Alprostadil Diphenhydramine and chlortheophylline

Benexate HCl Dexamethasone

Takeda Pfizer Stada

Shionogi Fujinaga chauvin

Caverjext Dual IV sol.

2Indomethacin hydroxypro pyl beta CD

Aerodiol

Nasal spray

Methylated 17 beta estradiol Beta CD

servier

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