Inclusion compounds & Cyclodextrins

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

INCUSION COMPUNDSA 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 dimensionThe 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 Clathrates to clathratuso Inclusion complexo Occlusion complexo Intercalation compoundo packing complex

Classifications:Polymolecular inclusion compounds -channel like spaces -cage like spacesMonomolecular inclusion compoundsMacromolecular inclusion compoundsProduct 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 unsaturated 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. ExampleGas 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 stoichiometryVaries from 1:5.75 to1:17. no valance bond form between guest and water molecules only dueTo repulsion forces they are unable to escape from void space.typical example is clathrates of Warferin sodium with isopropyl alcohol and water. EgHydroquinon, phenol, dianin`s compound, trimesic acid,

Monomolecular inclusion compoundsThese are the substance s in which every guest molecule is included by one host moleculeThe 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 sizeZeolites are the hydrated aluminium silicate that may contain sodium ,potassium, calcium orBarium. 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 CD’s are water soluble, non reducingmacrocyclic polymers containing glucose molecules joined by a- 1, 4- linkages. The mostcommon of these compounds are the a, and g CD’s formed by 6, 7 and 8 glucose unitsrespectively

The CD’s are produced by the degradation and cyclization of Starch by an Enzymeproduced Bacillus macerans. Molecules of a suitable size and shape can be held within thecavity of a particular CD’s by van der Waals forces [18]. The ability to form inclusioncompounds 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. Whereas, the cavity entrances are hydrophilic owing to the presence of primary and secondaryhydroxyl groups.

Molecules of appropriate size and stereochemistry can be included in theCD cavity by hydrophobic interaction. Complexation does not ordinarily involve in theformation of covalent bond. CD’s are studies as solubilizing and stabilizing agents inpharmaceutical dosage forms

S.no. Characteristics Alpha CD Beta CD Gamma CD

1.2.3.4.5.6.7.

8.

9.10.11.

12.

13.

14.

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

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

t ½ of ring opening (h)

69724.7-5.37.9 ± 0114.6 ± 0.4

174

Hexagonalplates10.23.44312.332

14.5

275

33

711356.0-6.57.9-0115.4 ± 0.4

262

Monoclinicparallelogrm13.2-14.53.22412.202

1.85

280

29

812977.5-8.37.9 ± 0117.5 ± 0.4

427

Quadratic prism8.13-17.73.00012.081

23.2

275

15

Cyclodextrin Derivatives

Characteristics Routs of Application

Methylated beta-CD’s Dimethyl beta-CD Trimethyl beta-CD Randomly methylated beta -CD

Water soluble • Oral• Ocular• Nasal

Hydroxy-alkylayed –beta CD’s• 2-hydroxy-ethyl• 2-hydroxy-propyl• 3-hydroxy-propyl• 2,3-dihydroxy-propyl

Amorphous mixturewith different degreeof substitution, highlywater soluble, lesstoxic

• Oral• Ocular• Rectal• intravenous

Sulfo butyl ether beta CD Soluble in water • Oral• Ocular• Parentral• Pulmonry

There are four favorable interactions between cyclodextrin and active drug , whichshift 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, and4. An increase in hydrophobic interaction as the active drug inserts itself into the polar cyclodextrin cavity.

Complexation TechniquesComplexes can be formed by a variety of techniques that depends on the propertiesof the active drug, equilibrium kinetic, other formulation ingredients, processes, end objectand the final dosage form desired.S.no

Techniques Approachs

1. Physical blending/Milling/Co-grinding/Solid phase complexation

The cyclodextrin and active drug are physically blended, milled or co-grinded using a high level of mechanical energy.

2. Kneading 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.

S.no Techniques Approachs

3 Co-precipitation The cyclodextrin and active drug are added to wateror a short chain alcohol (eg. Ethanol or Isopropanol) at 40°C-60°C 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.

4 Neutrilization precipitation

The active drug is dissolved in alkaline solution andmixed with aqueous solution of cyclodextrin. Theresultant clear solution is then neutralized understirring using hydrochloric acid solution till equivalence point. At equivalence point, a white precipitate is formed. Confirming the formation ofinclusion complex.

5. Solvent evaporation

The cyclodextrin and active drug are dissolvedseparately in a two different miscible solvents andmixing of both solutions to get molecular dispersionof drug and complexing agent. The solvent is evaporated finally under vacuum to obtain a solid powdered inclusion compound.

S.no. Techniques Approachs

6. Spray drying/ Automization

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.

7. Freeze drying The cyclodextrin and active drug are dissolved in water or in water-cosolvent mixture. The complex is isolated by freeze drying the solution.

8. Microwave irradiation

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.

The complex formation and the characterisation of the complex in solutions and solid statecan 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:· Entrapment of different molecular size drugs due to different cavity diameter,· Aqueous solubility,· Low toxicity,· No or poor pharmacological activity,· Resistant to decomposes by hot alkali,· Thermal Stability up to 300°C,· 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.

Drug deliveryOral 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 theLipophillic membrane surface but the excess cyclodextrin will decrease the drug partiiton To lipophillic barierNasal : 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 deliveryS.No

Novel drug delievery

Advantages

1 Liposomal Improve the stability of liposome Improve drug loading efficiency

2. Microspheres Improve drug loading efficiency. As a stabilizing agent for lysozyme & bovine serum albumin preparation. As a crosslinking agent

3. Nanoparticles Provide hydrolytic or photolytic stability of drug As a solubilizer

4. Osmotic delivery As a solubilizer

5. Peptide and protein delivery

As a solubilizer Improve chemical and enzymatic stability Improve absorption

Trade name

Dosage form

CD API Company

Pansporin T Tablet Alpha Cefotiam hexetil HCl

Takeda

Caverjext Dual

IV sol. Alpha Alprostadil Pfizer

Stadatravel Chewable tablet

Beta Diphenhydramine and chlortheophylline

Stada

lonmiel Capsule Beta Benexate HCl Shionogi

Glymesason

Ointment Beta Dexamethasone Fujinaga

Indocid Eye drop 2-hydroxypropyl beta CD

Indomethacin chauvin

Aerodiol Nasal spray MethylatedBeta CD

17 beta estradiol servier

THANKYOU