Application of complexation 01

Application of Complexation Phenomenon in Pharmacy. Presented by:-Mona S. Gupta. Guided by: Mrs. J.B. Taksande (M.Pharm, Pharmaceutics).:

Application of Complexation Phenomenon in Pharmacy. Presented by:-Mona S. Gupta. Guided by: Mrs. J.B. Taksande (M.Pharm, Pharmaceutics). S.K.B. College of Pharmacy, New Kamptee, Nagpur. Department of Pharmacy. 1

Complexation::

Complexation: Species formed by the association of two or more simple species capable of independent existance OR Complex can be formed between species A & B when there are A species and or closer to B species than random distribution of A’s & B’s would bring about. Rational behind complexation: Complex formation has been used to alter the physicochemical & biopharmaceutical properties of drug. Complex drug may have altered stability, solubility, molecular size, partition coefficient & diffusion coefficient. 2

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4. In various types of poisonings, 5. In drug absorption & bioavailability from various dosage form. 3 3. Complexation is used in solubilisation & stabilizations of product.

Therapeutic agents administered as complexes::

Therapeutic agents administered as complexes: Two well known exaples under this category are: Other ex. are: 1 .Complex with iron(Haematinic): Iron complex with simple salt like, Ferrous sulphate & carbonate. e.g.Insulin complex with Zn & Vitamin-B12 complex with Co.

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Rational: 1.Reduce the GIT irritation, 2. Increase the absorption, after oral administration. 3.Less irritation at the site of injection.

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2.Use of ion exchange principle: Cholestyramine resin (quaternary ammonium anion exchange resin). Used to relief pruritis, the resin exchange chloride ion from bile this result in increased elimination of bile through faeces.

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3. In diagnosis: Technetium 90 (a radionuclide) is prepared in the form of citrate complex this complex is used in diagnosis of kidney function & GFR. Squibb (complex of a dye Azure A with carbacrylic cation exchange resin): used for detection of achlorhydria due to condition such as carcinoma, pernicious anaemia.

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Test: This involve administration of complex orally Subsequent collection of urine In presence of HCl blue dye is displaced from resin by H+ ion & urine will be colored, Intensity of color depend on acidity.

Complexation as a therapeutic tool::

Complexation as a therapeutic tool: Complexing agent are suggested for variety of uses , many of are related to chelation of metal ion. One of the imp. use is Preservation of blood, both EDTA & CITRATES are employed for in-vitro to prevent clotting. -Anticoagulant acid citrate dextrose solution & -Anticoagulant sodium citrate solution.

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Citrates Act by chelating calcium ion in blood as it depletes body calcium arrhythmias & skeletal muscle tetany In vitro In vivo Are not much in use

Complex formation in treatment of poisoning::

Complex formation in treatment of poisoning: Therapeutic procedure involve complexation which minimizes; a. Absorption of toxicants from GIT through the use of complexing & adsorbing agent. b. Inactivation of toxic material systemically and enhanced elimination of toxic substance through use of dialysis. 1.Heavy metal poisoning : basic step involve in detoxification are:

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Inactivate metal present in body Through chelation (metal chelates) Water soluble constitute Readily eliminated from body via KIDNEY

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A. Arsenic and mercury poisoning: Most effective agent is BAL i.e.Dimercaprol which was originally c/as British antilewisite. The arsenical dimercaprol is shown as: CH2 S CH S As-R CH2OH

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Mechanism : two sulphahydryl gr. Chelate with metal & free OH gr. Promote water solubility BAL is effective in t/t of poisoning from gold, bismuth, cadmium & polonium.

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B. Lead poisoning: t/t of choice for acute/chronic lead poisoning is i/v administration of calcium, disodium complex of EDTA. This complex will chelate ions which exhibit a higher affinity of EDTA than do the calcium. Route of administration of complex is imp. it is only given by slow i/v drip in solution of isotonic NaCl / Sterile 5% dextrose. Oral administration promote absorption of LEAD from G.I.T & increase body levels of lead .

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C. Radioactive materials : Poisoning with these material particularly with long biological half-lives present two problems: a. metal itself has toxic effect , b. body may suffer from radiation damage . Uranium & Plutonium exposure have been successfully treated with CaNaEDTA Plutonium get deposited and chelate in bone so, prompt t/t is necessary t/t with CaNaDTPA has been suggested experimentally. ( DTPA: Diethylenetriamine pentaacetic acid )

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METAL CHELATING AGENT USEFUL IN MAN 1.ANTIMONY BAL 2.ARSENIC BAL 3.LEAD CaNaEDTA 4.MERCURY BAL 5.PLUTONIUM CaNaEDTA & CaEDTA 6.GOLD BAL

Dialysis and complexation in t/t of poisoning::

Dialysis and complexation in t/t of poisoning: Removal of poisons from systemic circulation has been successfully promoted by the use of DIALYSIS. This can be done by either using A. Artificial kidney B. By peritoneal dialysis.

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Liters of dialysing fluid are injected into peritoneal cavity fluid may be continually circulated into and out of the cavity toxic material diffuse through the wall of the blood vessel into the the fluid present in the cavity.

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To improve the efficiency of this procedure the principle of complexation has been employed. If the toxicant in the dialysing fluid is complexed with some high mole.wt., non-diffusible component, then the rate of dialysis of the toxicant will be increased and complexed toxicant will be prevented from returning into the circulation. SERUM ALBUMIN has been studied to the greatest extent in this respect. It is useful in humans as well as in lab. animals in t/t of intoxication due to salicylates and barbiturates .

Influence of complex formation on drug distribution & drug bioavailability::

Influence of complex formation on drug distribution & drug bioavailability: D D + C C Kd Kc DC DC Kdc Ks membrane This fig depicts transfer of Drug(D), Complex(DC), & complexing agent © across biological membrane. With subsequent dissociation of complex after transfer.So, in this case

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The rate of transfer of total drug on the right side of the membrane will be a function of rate of transport of drug in its free & complex form. So, in above case, If transport rate of complex is more than drug the diffusion will be aided by complex formation If complexing agent is not diffusible Rate of appearance of drug will be a function of transfer of free uncomplexed drug.

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In 2 nd case, where the complex is not transported diffusion will be retarded by complexation. The mechanism by which complex formation can affect the passage compound include alteration of O/W partition coefficient, apparent solubility, effective size of drug, change in the charge of the drug & alteration in diffusion of drug.

Decreased drug absorption due to complexation::

Decreased drug absorption due to complexation: One of the best ex. In this class is the interferance of calcium ions with the intestinal absorption of TETRACYCLINE. Initially, some tetracycline preparation were made with calcium diphosphate as ingredient & recommended that gastric irritation could be minimized by taking preparation with milk. Later, it become clear that poor absorption was related to the formation of relative insoluble complex of tetracycline & calcium.

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Other ex’s include: Impairment of antibiotic absorption after oral administration involve formation of complex between NEOMYSIN/KANAMYSIN & Bile salt. Some of the complexing agent such as EDTA depress the absorption of strychnine alcohol & sulfanilamide in lab. animals. EDTA is thought to be related to their interaction with metal ion in the G.I.T.

Enhanced drug absorption through complex formation::

Enhanced drug absorption through complex formation: NO. of experimental reports suggested that complex formation may prove to be an effective means of enhancing the absorption of poorly absorbed drug. Ex.1.Improvement of intestinal absorption of tetracycline's and enhanced blood levels are obtained with the addition of citric actd, glucosamine or sodium hexametaphosphate or use of tetracycline phosphate complex. 2.Heparin,an ionized drug of rather high molecular weight is not absorbed from G.I.T. However, in the presence of EDTA or surfactant such as SLS or dioctyl sodium sulfosuccinate, intestinal absorption of heparin is increased.

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3.EDTA has also been shown to be effective in enhancing the intestinal absorption of various Quaternary ammonium compounds, organic acids & some neutral molecules such as mannitol & inulin. * INFLUENCE OF COMPLEXATION ON PRESERVATIVE ACTION: Various studies have indicated that many of the commonly used preservative can strongly interact with materials such as suspending & emulsifying agents & with various excipients present in a dosage form.

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Such interaction may reduce the conc. of unbound preservative to such a level thatit is no longer an effective antimicrobial agent. Anionic, cationic& nonionic preservative are capable of interacting with ionic & nonionic compounds. Knowledge of extent of interaction should permit a rational selection of app. quantities of preservative to use. For ex.

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If we calculate concentration of total methyl paraben to free methyl paraben present in a system in presence of various concentration of Tween 80 then it is observed that at a tween 80 concentration of 2% about 58% of paraben present in the system will be bound by the tween 80. The use of complexation enhance activity of preservative. EDTA can increase the effectiveness of Benzalkonium chloride solution against Pseudomonas aeruginosa . EDTA alter the permeability of cell wall by chelation of divalent metal ions within the membrane.

Complexation & p’ceutical formulation::

Complexation & p’ceutical formulation: Complexation is applied extensively during p’ceutical formulation to solubilize & stabilize. Solubilization through complexation: One of the problem which the formulator come across is the limited solubility of one or more active ingredients of the preparation. Several approaches may be employed like change in the solvent, change in the pH etc. However, in some instances princilple of complexation is used.

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Use of soluble complexes: Ex:1.Adrenochrome monosemicarbazone is complexed with sodium salicylate. Adrenochrome (active) was found to be unstable in solution & semicarbazone has only limited solubility at the pH at which it stable.However, the stable product can be prepared by the addition of sodium salicylate which complexes with adrenochrome, & increases appearent solubility by 10 folds.

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2.The injectable product caffeine & sodium benzoate is used as stimulant & diuretic . The complexation of caffeine by sodium benzoate increases solubility of caffiene. B. Stabilization through complexation: The problem of stabilization of the ingradient present in the preparation against hydrolysis, oxidation etc.is another instance where coplexation formation has been used. Molecular complexes: The interaction of labile functional gr. of a drug with complexing agent may shield the drug by the attack of other species.

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OR the interaction may alter the usual electronic properties of the drug& result either increase or decrease stability. Ex: Local anesthetic esters has been stabilised against hydrolysis by complexation with caffiene. The half life for procaine in the solution has been observed to increase from 26 Hrs in the absence of caffiene to about 46Hrs in the presence of 2% caffiene & to about 71 Hrs in the presence of 5% caffiene.

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2. Inclusion complexes: The stabilization of certain compounda can be done by incorporation within the crystal lattice of a solid or with in the voids formed by the arrangement of large polymeric molecules in solution.

Classification:

Classification Metal ion complexes. Organic compounds. Inclusion compounds. Application of complex formation: 1.Metal chelate complex: a)Chelates : A substance containing two or more donor group may combine with metal to form a special type complex. e.g.Teracycline with Ca ++ . 2.Therapeutic agents administered as complex: e.g.Insulin complex with Zn & Vitamin-B12 complex with Co. 35

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Picric acid complexes: e.g.Butesin picrate 2:1 complex of butyl p-amino benzoate and picric acid. 2 Butyl p-amino benzoate + Picric acid (Topical anaesthetic) + (Antiseptic) This complex reduces the carcinogenic activity. 36

3.Complex with iron(Haematinic):

3.Complex with iron(Haematinic) Iron complex with simple salt iike,Ferrous sulphate & carbonate. Rational: 1.Reduce the GIT irritation, 2.increase the absorption, 3.increase the oral administration, 4.less irritation at the site of injection. 4.Complexes of diagnostic agents: e.g. a)Technetium 99m : Determination of Kidney function & GFR. b)Diagnex blue : Determination of achlorhydria. 37

Complexation as a therapeutic tool:

Complexation as a therapeutic tool Preservation of blood : e.g.EDTA & citrate complex (Role as an Anticoagulant invitro ). Two official citrate solutions: 1.Acid citrate dextrose solution (USP). 2.Sodium citrate solution (USP). MOA: By citrate & Ca chelation which is present into the blood. Not to use ( Invivo ) : Because loss of Ca & development of Skeletal muscle tetany & generation of cardiac arrythmias. 38

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Treatment of Wilsons disease Or Hepatolenticular degeneration: Cause: Absense of Cu or protein binding. Result: Amount of free Cu gets deposited into the lung & brain,as a result degeneration of it occurs. Remedy: Formation of complex between Cu & D-penicillamine. 39

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Treatment of poisoning: By forming complex include, 1.minimizing absorption of toxicants from GIT, 2.adsorbing agents, 3.systematic inactivation & 4.enhanced elimination. a) In heavy metal poisoning: By using Chelating agent. MOA: Chelating agent + metal=Soluble compound Elimination from the kidney. 40

References:

References J.P.Greenstein,”Biochemistry of Cancer”,Academic press,New York,Page no.151. A.Martin”Physical Pharmacy”Third Edition,Page no.320. D.M Bramhankar & S.B.Jaiswal”Biopharmaceutics & Pharmacokinetics A Treatise”,Ist edition,Page no.45,61,298. K.D Tripathi,”Essentials of Medical Pharmacology”5 th edition,Page no.240-241. U.Satyanarayana,”Biochemistry’2 nd edition,Page no.155-160. Remington’s,”the Science & Practise of Pharmacy”Volume-Ist,21 st edition,Page no.1037. 41

Thank you.:

Thank you. 42