solubulization 2012

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SOLUBILISATION

TECHNIQUES

BY H.S.V.S.GUPTHA.P

Under the Guidance of: Dr.K.Suria Prabha



SOLUBILITY IS THE MAXIMUM

QUANTITY OF SOLUTE THAT CAN

DISSOLVE IN A CERTAIN QUANTITY OF

SOLVENT AT A SPECIFIC

CONDITIONS(LIKE TEMP)

OR

SOLUBILITY IS DEFINED AS THE

NUMBER OF MILLILITERS OF SOLVENT

IN WHICH 1 GM OF SOLUTE WILL DISSOLVE.

I

NT

R

O

DU

C

T

IO

N



DESCRIPTIVE TERMSRELATIVE AMOUNTS OFSOLVENTS TO

DISSOLVE 1 PART OF

SOLUTE

Very soluble Less than 1

Freely soluble From 1-10

Soluble From 10-30

Sparingly soluble From 30-100

Slightly soluble From 100-1000

Very slightly soluble From 1000-10,000

Insoluble or practically insoluble More than 10,000



TECHNIQUES FOR

IMPROVEMENT IN

DRUG

SOLUBILIZATION



1.COMPLEXATION

TECHNIQUES

2.CLATHRATES

3.ALTERATION IN THE PH OF

THE SOLVENT

4.SALT FORMATION

5.HYDROTROPICSOLUBILIZATION



6. MICELLAR

SOLUBILIZATION BY

SURFACTANTS

7. MICRONIZATION

8. SOLID SOLUTION

9. SOLID DISPERSION



10. FREEZE DRYING

11. COSOLVENCY

12. POLYMORPHISM

13. LIPID BASED DRUG

DELIVERY SYSTEM



14. MOLECULAR

ENCAPSULATION

15. SELECTIVE ADSOPTION

16. SUPERSATURATED DRUG

DELIVERY SYSTEM

17. PRODRUG



COMPLEXATION



COM PLEXATI ON COM PLEXATI ON is the a ssociat ion between two or mor e mol ecul e s is the a ssociat ion between two or mor e mol ecul e s t o f or m a no bond ed ent ity with a well t o f or m a no bond ed ent ity with a well--d ef ined St oichiomet r y.d ef ined St oichiomet r y.

Two type s:Two type s:

stacking stacking inclusioninclusion



THE MATHEMATICAL DESCRIPTION FOR THE EQUILIBRIUMTHE MATHEMATICAL DESCRIPTION FOR THE EQUILIBRIUM

CONSTANTCONSTANT

OF A 1:1 COMPLEX, K1:1 IS DEFINED BYOF A 1:1 COMPLEX, K1:1 IS DEFINED BY

K 1:1 = [SL] / [S] [L]K 1:1 = [SL] / [S] [L]

WHER E WHER E

S IS THE CONCE NTRATION OF THE FR EE SOLUTE,S IS THE CONCE NTRATION OF THE FR EE SOLUTE,

L IS THE CONCE NTRATION OF THE FR EE LIGAND, &L IS THE CONCE NTRATION OF THE FR EE LIGAND, &

[SL] IS THE CONCE NTRATION OF THE [SL] IS THE CONCE NTRATION OF THE

SOLUTE/LIGANDSOLUTE/LIGAND COMPLEX.COMPLEX.



CLATHERATESCLATHERATES

An inclusion compound is a unique f or m o f chemical compl ex in which one An inclusion compound is a unique f or m o f chemical compl ex in which one

mol ecul e is enclosed within another mol ecul e or st ruct ur e o f mol ecul e s.mol ecul e is enclosed within another mol ecul e or st ruct ur e o f mol ecul e s.



THIS COMBINATION IS CHARACTERIZED BYTHIS COMBINATION IS CHARACTERIZED BY

THEABSE NCE OF ORDINARY CHEMICALTHEABSE NCE OF ORDINARY CHEMICALBONDS ;THE ESSE NTIAL CRITERION IS SIMPLYBONDS ;THE ESSE NTIAL CRITERION IS SIMPLY

THAT THE E NCLOSED MOLECULE OR GUEST THAT THE E NCLOSED MOLECULE OR GUEST

BE OF A SUITABLE SIZEAND SHAPE, TO FIT BE OF A SUITABLE SIZEAND SHAPE, TO FIT

INTO A CAVITY WITHIN A SOLID STR UCTUR E INTO A CAVITY WITHIN A SOLID STR UCTUR E

FORMED BYHOST MOLECULES. THE HOLLOWFORMED BYHOST MOLECULES. THE HOLLOW

SPACE FORMED BY THE HOST MAY BE IN THE SPACE FORMED BY THE HOST MAY BE IN THE

FORM OF A CHANNEL, CAGE OR LAYER .FORM OF A CHANNEL, CAGE OR LAYER .



OTHER TERMS THAT HAVE BEE N USED TO DESCRIBE OTHER TERMS THAT HAVE BEE N USED TO DESCRIBE

THESE COMPLEXES AR E OCCLUSIONTHESE COMPLEXES AR E OCCLUSIONCOMPOU NDS, ADDUCTS ANDCOMPOU NDS, ADDUCTS AND CLATHERATESCLATHERATES..

CLATHERATESCLATHERATES::

THE INDIVIDUAL HOST MOLECULESTHE INDIVIDUAL HOST MOLECULES

LINK TOGETHER TO FORM A CAGE OR A CUPLINK TOGETHER TO FORM A CAGE OR A CUP± ± SHAPED STR UCTUR E, THE OPE N E ND OF WHICH SHAPED STR UCTUR E, THE OPE N E ND OF WHICH

JOINS WITH THE OPE N E ND OF A SECOND SIMILAR JOINS WITH THE OPE N E ND OF A SECOND SIMILAR

STR UCTUR E TO FORM THE CAGE.STR UCTUR E TO FORM THE CAGE.



ALTERATION IN THE PHALTERATION IN THE PH

OF SOLVENTOF SOLVENT F or ionizabl e drugs, the aqueous solubility is st rongl y in f luenced by the pH o f F or ionizabl e drugs, the aqueous solubility is st rongl y in f luenced by the pH o f

the solvent.the solvent.

The pH adjustment may be the most simpl e , economic and effect ive way o f The pH adjustment may be the most simpl e , economic and effect ive way o f

incr ea sing the aq. solubility o f the drug .incr ea sing the aq. solubility o f the drug .



FOR WEAK LY ACIDIC DRUGS /SALTFOR WEAK LY ACIDIC DRUGS /SALT,,

LOWER PH U NIONIZED FORM INSOLUBLE/ LOWER PH U NIONIZED FORM INSOLUBLE/

PR ECIPITATIONPR ECIPITATION

HIGHER PH IONIZED FORM MOR E SOLUBILITYHIGHER PH IONIZED FORM MOR E SOLUBILITY

FOR WEAK LY BASIC DRUGS / SALT,FOR WEAK LY BASIC DRUGS / SALT,

LOWER PH IONIZED FORM MOR E SOLUBILITYLOWER PH IONIZED FORM MOR E SOLUBILITY

HIGHER PH U NIONIZED FORM INSOLUBLE/ HIGHER PH U NIONIZED FORM INSOLUBLE/

PR ECIPITATIONPR ECIPITATION



MODIFIED HENDERSONMODIFIED HENDERSON

HASSLBALCHHASSLBALCH EQUATIONEQUATION

F or weakly acidic drugs F or weakly acidic drugs , , pH = pH = pKa pKa + log S + log S --S oS o

S oS o F or weakly basic drugs F or weakly basic drugs pH = pH = pKa pKa + log S o+ log S o

S S --S oS oS = over all solubility o f a drug at a given pH S = over all solubility o f a drug at a given pH

S o = int rinsic solubility o f unionized f or mS o = int rinsic solubility o f unionized f or m



SALT FORMATIONSALT FORMATION

Sal t f or mat ion is f r equent l y per f or med on weak acidic or ba sic drugs becauseSal t f or mat ion is f r equent l y per f or med on weak acidic or ba sic drugs because

it is a r el at ivel y simpl e chemical mani pul at ion, which may al ter theit is a r el at ivel y simpl e chemical mani pul at ion, which may al ter the

phy sicochemical, f or mul at ion, bio phar maceut ical, and ther apeut ic pro per t ie s phy sicochemical, f or mul at ion, bio phar maceut ical, and ther apeut ic pro per t ie s

o f a drug without modi fying the ba sic chemical st ruct ur e.o f a drug without modi fying the ba sic chemical st ruct ur e.



HYDROTROPIC SOLUBILIZATIONHYDROTROPIC SOLUBILIZATION

Hydrot ro pic effect , the meaning is tak en a s the incr ea se in sat ur at ion solubility Hydrot ro pic effect , the meaning is tak en a s the incr ea se in sat ur at ion solubility

o f a sub stance in water by the addit ion o f org anic sal t s or also nono f a sub stance in water by the addit ion o f org anic sal t s or also non--

el ect rol yte s, which o f course must be phy siologicall y compat ibl e f or el ect rol yte s, which o f course must be phy siologicall y compat ibl e f or

phar maceut ical applicat ion. phar maceut ical applicat ion.



The mode of action of the hydrotropic substances

is thought to be due to either an associateformation, in low concentrations to a formation o

molecular complexes or in higher concentrations

to the water structure being influenced. Thesehydrotropic substances are able to increase the

number of hydrogen bridges in the water clusters.

This makes the water more hydrophobic & thus iis a better solvent for non-polar drug.



MICELLER SOLUBILIZATION BY

SURFACTANTS

S ur factant s ar e compounds that have mol ecul ar st ruct ur e s with two dist inct

r e gions:

A pol ar (hydro philic ) head grou p and a N on pol ar (hydro phobic tail ).



TRADITIONAL SURFACTANTS:

ANIONIC SURFACTANT ANIONIC SURFACTANT :

Hydro philic grou p carrie s a ne g at ive charg e.

e. g .:- SLS , P ota ssium Laur ate

CATIONIC SURFACTANT CATIONIC SURFACTANT :

Hydro philic grou p carrie s a posit ive charg e.

e. g . :- Cet rimid e , Benzalkonium Chlorid e

AMPHOLYTIC SURFACTANT (ZWITTERIONIC AMPHOLYTIC SURFACTANT (ZWITTERIONIC

SURFACTANT) :SURFACTANT) : M ol ecul e carrie s both ne g at ive and posit ive charg e.

e. g .:- N -dod ec yl- N , N -dimethyl betaine



NON TRADITIONAL

SURFACTANTS NONIONIC SURFACTANT NONIONIC SURFACTANT :

Hydro phil e carrie s no charg e but d erive s it s water solubility f rom hig hl y pol ar

grou p s such a s hydro xyl or pol yo xyethyl ene grou p s.e. g . :- Cet omacrogol (pol yo xyethyl ated gl ycol monoethers )

Spans and Tweens ( S or bitan e sters )



In the water, as the concentration of

surfactant increases above a critical value,its molecule self associate into structures

called Micelles and the concentration at

which they begin to form is called Critical

Micellar Concentration (CMC) .

CMC



In micellar structure , the hydrophobic tail gathers

in the core and is surrounded by mantle of

hydrophobic heads which are in contact with water

.

Therefore a hydrophobic (nonpolar) drug which is

squeezed from the water

locates in the micelle core .

Since micelle is soluble in water , any drug

incorporated into the micelle is

also soluble in water



Micellar Solubilisation is defined as:

The spontaneous passage of solute

molecules of a substance insoluble

in water into an aqueous solution of a surfactant in which a

thermodynamically stable solution is

formed



SOLUBILISATION BY MICELLESSOLUBILISATION BY MICELLES



THE TOTAL SOLUBILITY ST OF A SOLUTE THE TOTAL SOLUBILITY ST OF A SOLUTE

IN A SURFACTANT SYSTEM IS :IN A SURFACTANT SYSTEM IS :

ST = SW + K (ST = SW + K ( CSURFCSURF -- CMC )CMC )

WHER E ,WHER E ,

K = SOLUBILISING CAPACITYK = SOLUBILISING CAPACITYCSURFCSURF ± ± CMC = MICELLE CMC = MICELLE

CONCE NTRATIONCONCE NTRATION



TYPES OF MICELLES:TYPES OF MICELLES:

SPHERICALSPHERICAL



LAMELLAR MICELLES (L) ANDLAMELLAR MICELLES (L) AND SPHER ULITESPHER ULITE MICELLES (M) :MICELLES (M) :



R EVERSEMICELLES OR INVER TED MICELLESR EVERSEMICELLES OR INVER TED MICELLES



BILAYER STR UCTUR E :BILAYER STR UCTUR E :



HLB VALUESHLB VALUES



MICRONIZATION M icronizat ion is r educt ion o f par t icl e size u p t o micron l evel . An y probl em

r el ated with the bioavaibility o f drug may be r el ated with dissolut ion o f

drug and solubility o f drug is affect ing dissolut ion o f drug .

I n ord er t o g et better dissolut ion need t o incr ea se solubility and

micronizat ion is used a s one o f the solubilizing t ool t o incr ea se solubility



By micronization we get uniform and narrow

particle size distributionwhich is essential for developing uniform dosage

form.

As micronization occurs surface area increases

with decreasing particle size and solubility

increases and observed solubility increased withdecreasing particle size.

LIPID BASED DR UG DELIVERY

SYSTEM: Useful for highly non polar drugs

Non polar drugs higher solubility in oils,



SOLID SOLUTION

Definition A solid solution is a binary system comprising of a solid

solute

molecularly dispersed in a solid solvent. Since the 2 components

crystallize

together in a homogenous one phase system, solid solutions are alsocalled as

molecular dispersions or mixed crystals OR M ELTS



It is defined as a dispersion of one or more ingredients in an inert

carrier or matrix in solid state prepared by the melting (fusion)

method, solvent method or melting-solvent method The solid

dispersion may also called as solid state dispersions



CLASSIFICATION OF SOLID DISPERSION

1)S impl e eutect ic mi xt ur e.

2)S olid solut ion.

3)Gl a ss solut ion and gl a ss sus pension.

4) Amor phous pr eci pitat ions in a cr y stalline carrier .

5) C ompound or C ompl ex f or mat ion.

6)C ombinat ions o f pr evious f ive type s



COSOLVE NCYThe addit ion o f a water-miscibl e or par t iall ay miscibl e

org anic solvent ( i.e.cosolvent t o water ) is a common and

effect ive way by which t o incr ea se solubility o f a non pol ar

drug . The technique is known a s cosolvenc y

(ak a solvent bl ending )



POLYMORPH

ISM A prodrug is a chemicall y modi f ied iner t drug pr ecursor

which u pon biot r ans f or mat ion liber ate s the

phar macologicall y act ive par ent compound .



PRODR UG A prodrug is a chemicall y modi f ied iner t drug pr ecursor

which u pon biot r ans f or mat ion liber ate s the

phar macologicall y act ive par ent compound .



HYDROTROPHY Hydrot ro py is a solubilizat ion phenomenon wher eby addit ion o f l arg e amount

o f a second solute r e sul t s in an incr ea se in the aqueous solubility o f another

solute. C oncent r ated aqueous hydrot ro pic solut ions o f sodium benzoate ,

sodium salic yl ate , ur ea , nicot inamid e , sodium cit r ate and sodium acetate have

been ob served t o enhance the aqueous solubilit ie s o f man y poorl y water-

solubl e drugs.



SELECTIVE ADSOPTION H ig hl y act ive adsor bent inorg anic cl ay lik e bent onite enhance dissolut ion r ate

o f poorl y water solubl e drugs lik e griseo f ulvin

Rapid r el ea se due t o

Weak phy sical bonding between adsor bent -ad sor bate

Hydr at ion Swelling o f cl ay in the aqueous media



R EFER E NCE1)http:// www.ij ppronline.com /ind ex.php?o pt ion=com_ content&view=ar t icl e&id =185&Itemid =155 ISSN (Online): 0976 - 6723

ISSN (P rint) : 2249 - 3948

2) S olubility and r el ated pro per t ie s by Kenneth c.Jame s. P g ± : 253 ±271.

3) Reming t on: the science and pr act ice o f phar mac y vol .1 p g:-169-202.

4) Pµ ceut ical Dosa g e f or m and Drug Deliver y Sy stem by H oward C. Ansel

S olubility & r el ated pro per t ie s By Jame s K.C. pa g e s ± 251-260

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