1. contents introduction. techniques of solubility enhancement. polymer-drug complex. -polymer and...
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INCREASE SOLUBILITY OF POORLY WATER SOLUBLE DRUGS
COMPLEXATION OF DRUG WITH POLYMER
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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.
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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
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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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