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1 INCREASE SOLUBILITY OF POORLY WATER SOLUBLE DRUGS COMPLEXATION OF DRUG WITH POLYMER

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Page 1: 1. CONTENTS Introduction. Techniques of solubility enhancement. Polymer-drug complex. -Polymer and it’s classification. Formulation of polymer drug complex

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INCREASE SOLUBILITY OF POORLY WATER SOLUBLE DRUGS

COMPLEXATION OF DRUG WITH POLYMER

Page 2: 1. CONTENTS Introduction. Techniques of solubility enhancement. Polymer-drug complex. -Polymer and it’s classification. Formulation of polymer drug complex

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CONTENTS• Introduction.

• Techniques of solubility enhancement.

• Polymer-drug complex. -Polymer and it’s classification.

• Formulation of polymer drug complex. -Methods of complexation.

• Advantages of Polymer – Drug complex

• References.

Page 3: 1. CONTENTS Introduction. Techniques of solubility enhancement. Polymer-drug complex. -Polymer and it’s classification. Formulation of polymer drug complex

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INTRODUCTION

Many of the drug or compounds are reported to be poorly water

soluble.

‘‘ Drug that don’t dissolve will not heal you.’’

Thus by increasing the solubility of such drug candidate are

becoming more and more importance to the pharmaceutical

industry.

A number of methodologies can be adapted to improve

solubilization of poor water soluble drug and further to improve

its bioavailability.

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TECHNIQUES OF SOLUBILITY ENHANCEMENT1) PHYSICAL MODIFICATIONS Particle size reduction Micronization Nanosuspension Sonocrystalisation Supercritical fluid process Modification of the crystal habit Polymorphs Pseudopolymorphs Drug dispersion in carriers Eutectic mixtures Solid dispersions Solid solutions

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Complexation

Use of complexing agents

Solubilization by surfactants:

Microemulsions

Self microemulsifying drug delivery systems2) CHEMICAL MODIFICATIONS

3) OTHER METHODS

Cocrystalisation

Cosolvency

Hydrotrophy

Solvent deposition

Selective adsorption on insoluble carrier

Use of soluble prodrug

Functional polymer technology

Porous microparticle technology

Nanotechnology approaches

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DRUG – POLYMER COMPLEX

Page 7: 1. CONTENTS Introduction. Techniques of solubility enhancement. Polymer-drug complex. -Polymer and it’s classification. Formulation of polymer drug complex

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WHAT IS POLYMER ?

“Polymer” word is derived from Greek roots “Poly” meaning many and “Meros” meaning parts.

Definition :

Polymers are long chain organic molecules assembled from many smaller molecules called as monomers.

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NATURAL VS. SYNTHETIC POLYMERS

I ) Natural polymers (e.g. celluloses, collagen, chitosan, polylactic acid)

- Polymers of vegetarian origin.

- Polymers of animal origin .

- Biocompatible, expensive to produce and refine, batch-to-batch variability.

II) Synthetic polymers (e.g. PVP, PVA, polymethacrylates)

- Polymers are widely and commonly applied in various controlled drug release systems.

- Clear advantages over natural polymers.

- Toxicological issues should be taken into account.

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POLYMER- DRUD COMPLEX

Polymer drug complex is composed of a drug that is

covalently bound to a polymer,which may be either hydrophilic

or hydrophobic.

The linkage of a drug to a macromolecular carrier will alter its

pharmacokinetics properties of drug, enhances the

bioavailability, specificity and duration of action.

Applications :

1) Increases the solubility of poorly soluble drugs

Example: Cisplatin comlexes with Dextran

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COMPLEXATION

Complexes are formed by the insertion of the nonpolar molecule

or the nonpolar region of one molecule (known as guest) into the

cavity of another molecule or group of molecules (known as host).

The major structural requirement for complexation is a snug fit

of the guest into the cavity of host molecule.

The cavity of host must be large enough to accommodate the

guest.

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FORMULATION OF COMPLEX OF DRUG WITH POLYMER

Physical blending method.

Kneading method.

Co-precipitation technique.

Solution/solvent evaporation method.

Neutralization precipitation method.

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CONT……

Milling/Co-grinding technique.

Atomization/Spray drying method.

Lyophilization/ Freeze drying technique.

Microwave irradiation method.

Supercritical antisolvent technique.

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PHYSICAL BLENDING METHOD

A solid physical mixture of drug and polymer is prepared

simply by mechanical trituration. In laboratory scale polymer

and drug are mixed together thoroughly by trituration in a

mortar and passes through appropriate sieve to get the desired

particle size in the final product.

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KNEADING METHOD:

This method is based on impregnating the polymer with

little amount of water or hydro alcoholic solutions to

converted into a paste.

The drug is then added to the above paste and kneaded

for a specified time.

The kneaded mixture is then dried and passed through

sieve if required.

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CO- PRECIPITATION TECHNIQUE

This method involves the co-precipitation of drug and

polymer in a complex.

In this method, required amount of drug is added to the

solution of polymer.

The system is kept under magnetic agitation with controlled

process parameters.

The formed precipitate is separated by vacuum filtration and

dried at room temperature.

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SOLUTION / SOLVENT EVAPORATION METHOD

This method involves dissolving of the drug and polymer

separately in to two mutually miscible solvents.

Generally, the aqueous solution of polymer is simply added to the

alcoholic solution of drugs.

The resulting mixture is stirred for 24 hours and evaporated under

vacuum at 45 °C.

The dried mass was pulverized and passed through a 60-mesh

sieve.

This method is quite simple and economic.

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NEUTRALIZATION PRECIPITATION METHOD

Technique consists of dissolving the drug in alkaline solutions

like sodium/ammonium hydroxide and mixing with an aqueous

solution of polymer.

The resultant clear solution is then neutralized under agitation

using HCl solution till reaching the equivalence point.

A white precipitate is being formed at this moment,corresponding

to the formation of the complex.

This precipitate is filtered and dried.

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MILLING / CO-GRINDING TECHNIQUE

Drug and polymer are mixed intimately and the physical mixture

is introduced in an oscillatory mill and grinded for suitable time.

This technique is superior to other approaches from economic as

well as environmental stand point.

This methods does not require any toxic organic solvents.

This method differs from the physical mixture method where

simple blending is sufficient and in co-grinding it requires to

achieve extensive combined attrition and impact effect on

powder blend.

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ATOMIZATION / SPRAY DRYING TECHNIQUE

This method represents one of the most employed methods to

produce the polymer complex starting from a solution.

The mixture pass to a fast elimination system propitiate solvent

and shows a high efficiency in forming complex.

Besides, the product obtained by this method yield the particles

in the controlled manner which in turn improves the dissolution

rate of drug in complex form.

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LYOPHILIZATION/ FREEZE DRYING TECHNIQUE

In this technique, the solvent system from the solution is

eliminated through a primary freezing and subsequent drying of

the solution containing both drug & polymer at reduced pressure.

Thermolabile substances can be successfully made into complex

form by this method.

The limitations of this technique are long time process and yield

poor flowing powdered product.

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MICROWAVE IRRADIATION METHOD

This technique involves the microwave irradiation reaction between

drug and complexing agent using a microwave oven.

The drug and polymer are dissolved in a mixture of water and organic

solvent in a specified proportion into a round bottom flask.

The mixture is reacted for short time of about 1 - 2 minutes at 60°C in

the microwave oven. After the reaction completes, adequate amount of

solvent mixture is added to the above reaction mixture to remove the

residual, uncomplexed free drug and polymer.

The precipitate so obtained is separated using whatman filter paper,

and dried in vaccum oven at 40°C for 48 hrs.

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SUPERCRITICAL / ANTISOLVENT TECHNIQUE

In this technique, carbon dioxide is used.

The use of supercritical carbon dioxide is advantageous as its low

critical temperature and pressure makes it attractive for processing

heat-labile pharmaceuticals.

It is also non-toxic, nonflammable, inexpensive and is much easier

to remove from the polymeric materials when the process is

complete, even through small amount of carbon dioxide remains

trapped inside the polymer, it possesses no danger to the

consumer.

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FUNCTIONAL POLYMER TECHNOLOGY

These polymers are ion exchange materials which contain basic or

acidic groups that interact with the ionizable molecules of the

surrounding medium.

The resultant complex, known as, “Resinate”.

The resins are insoluble and not absorbed into the body and the drug is

released from the resinate on exposure to the physiological fluids.

In other word, the dissolution rate of poorly soluble, ionizable drug like

cationic, anionic and amphoteric actives can be enhanced by this

technology.

This can also be heat applicable to heat sensitive materials .

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ADVANTAGES OF DRUG – POLYMER COMPLEX

Improve therapeutic properties of peptides, proteins, small

molecules or oligonucleotides.

Exhibit prolonged half-life.

Higher stability.

Water solubility.

Specific targeting to tissues or cells.

Ease of drug adminitration.

Improved Patient Compliance.

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EXAMPLE :-Dissolution Enhancement Of Poorly Soluble Aceclofenac By

Complexation With β-Cyclodextrin

Aceclofenac is a NSAID with good analgesic and anti-pyretic

properties.

Aceclofenac is partially insoluble in water and aqueous fluid and

as such it exhibits poor variable oral bioavailability.

The inclusive complex of Aceclofenac with β-Cyclodextrin was

prepared for improvement of dissolution rate and bioavailability of

the drug

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FORMULATION OF COMPLEX OF ACECLOFENAC WITH Β-CYCLODEXTRIN

Method of preparation:

Physical mixture:

Aceclofenac with β-Cyclodextrin in different molar

ratios (i.e. 1:1M, 1:2M & 1:3M) were mixed in a mortar

for about one hour with constant trituration, passed

through sieve No. 80

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CO-PRECIPITATE METHOD:

Aceclofenac was dissolved in ethanol at room temperature and β-

Cyclodextrin was dissolved in distilled water. Different molar

ratios of Aceclofenac and β-Cyclodextrin (1:1M, 1:2 M &1:3M)

were taken.

The mixture was stirred at room temperature, for one hour and

then slowly evaporated on a boiling water bath.

The complex precipitated as a crystalline powder was pulverized

and passed through sieve No. 80 and stored in a desiccator till free

from any traces of the organic solvent.

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KNEADING METHOD :-

Aceclofenac with β-Cyclodextrin in different molar ratios (i.e.

1:1M, 1:2M) were taken.

First β-Cyclodextrin is added to the mortar, small quantity of

50% ethanol is added while triturating to get slurry like

consistency.

Then slowly drug is incorporated into the slurry and trituration

is further continued for one hour.

Slurry is then air dried at 25°C for 24 hours, pulverized and

passed through sieve No. 80

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SOLVENT EVAPORATION TECHNIQUE:

In this method the drug and polymer are used in different

ratios (1:1, 1:2 & 1:3).

The respective amount of polymer was dissolved in methanol

and Aceclofenac was added in parts with continuous stirring

the solvent was then removed by evaporation.

The prepared dispersion were pulverized and sifted through

sieve 100#.

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CONCLUSION

‘‘ Drug that don’t dissolve will not heal you.’’

The solubility of the drug is the factor that controls the

formulation of the drug as well as therapeutic efficacy of the

drug, hence the most critical factor in the formulation and

development.

Solubility can be enhanced by many techniques and number of

folds increase in solubility

It is now possible that to increase the solubility of poorly soluble

drugs with the help of various techniques as mentioned above.

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REFERENCES :-

World Journal of Pharmaceutical Research Volume 1, Issue 2,273-287

Journal of Advanced Pharmacy Education & Research 2 (1) 32-67 (2012) ISSN 2249-3379.

International Journal of Comprehensive Pharmacy -Enhancement Of Solubility & Dissolution Rate.

Journal of Drug Delivery & Therapeutics; 2013,3(2) 2011-

( www.jddtonline.info)

www.jddtonline.info

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