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8/3/2019 solubulization 2012
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SOLUBILISATION
TECHNIQUES
BY H.S.V.S.GUPTHA.P
Under the Guidance of: Dr.K.Suria Prabha
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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
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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
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TECHNIQUES FOR
IMPROVEMENT IN
DRUG
SOLUBILIZATION
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1.COMPLEXATION
TECHNIQUES
2.CLATHRATES
3.ALTERATION IN THE PH OF
THE SOLVENT
4.SALT FORMATION
5.HYDROTROPICSOLUBILIZATION
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6. MICELLAR
SOLUBILIZATION BY
SURFACTANTS
7. MICRONIZATION
8. SOLID SOLUTION
9. SOLID DISPERSION
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10. FREEZE DRYING
11. COSOLVENCY
12. POLYMORPHISM
13. LIPID BASED DRUG
DELIVERY SYSTEM
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14. MOLECULAR
ENCAPSULATION
15. SELECTIVE ADSOPTION
16. SUPERSATURATED DRUG
DELIVERY SYSTEM
17. PRODRUG
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COMPLEXATION
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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
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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.
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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.
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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 .
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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.
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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 .
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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
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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
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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.
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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.
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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.
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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 ).
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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
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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 )
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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
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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
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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
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SOLUBILISATION BY MICELLESSOLUBILISATION BY MICELLES
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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
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TYPES OF MICELLES:TYPES OF MICELLES:
SPHERICALSPHERICAL
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LAMELLAR MICELLES (L) ANDLAMELLAR MICELLES (L) AND SPHER ULITESPHER ULITE MICELLES (M) :MICELLES (M) :
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R EVERSEMICELLES OR INVER TED MICELLESR EVERSEMICELLES OR INVER TED MICELLES
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BILAYER STR UCTUR E :BILAYER STR UCTUR E :
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HLB VALUESHLB VALUES
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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
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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,
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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
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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
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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
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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 )
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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 .
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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 .
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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.
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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
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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