BY SOLUTE – SOLVENT
SOLUTE – SOLVENT
• The association process
• Phase solubility diagram
• The complexation constant
• Methods of determining equilibrium
THE ASSOCIATION PROCESS
•Association of solute and solvent
•Observation of Hilderbrand and Jenks.
(a) In violet colored solution of IODINE regular
family of curves because of molecular dispersion.
(b) Some were red , since iodine solvated in red.
• Based on Donor – acceptor mechanism.
• Donor --- : Lewis base
• Acceptor ----: Lewis acid
I2 + CH3 -O- CH3 (CH3-O-CH3)
CARBON HAVING HYDROGEN AND
ELE. WITHDRAWING GROUP
• Hydrogen is ele. Acceptor , forming h –
bond with ele. Donor.
• This is special type of donor –acceptor
• Ele. Transfer complex of those not
involving H – bond.
(a) Solute + Inert solvent + solute
Increase or decrease solubility
(b) Solute +Inert solvent + solvent
(complex. agent )
• nS + mL k SnLm
S = substrate
L = complexing agent
n = no. of moles of substrates
m = no. of moles of complex. Agents
k = stability constant
k α Degree of complexation
RELATIVITY WITH IDEAL SOLUTION
• [ Liquid –liquid ] complex
Soluble in all proportion but not the ideal .
eg : chloroform – diethyl ether show negative
deviation from Rault’s law.
• [ solid solute + liquid ] complex
limit of solute conc. Above which the mixture
ceases to be a homogenous liquid.
REPRESENTATION BY PHASE
• Addition of ,
(a) solute in excess of its solubility.
(b) various conc. Of complex. Agents
(c) Inert solvent
Mixture brought to equilibrium at required temp.
Analyze the sat. solution for total conc.
Plot graph of total molar conc. Of solute
against molar conc. Of complexing
Type A Type B
Three Used when complex.
types Agent is not solvent
• nS + mL SnLm
(Apply law of mass action and rearrange
[SnLm] = k [ s ] n [ L ] m
Complexation produce with
decreases in entropy.
• G = -RT Ln K
• High K = low Gibb's free energy of complexation.
lowering of enthalpy of complexation.
Solute-solvent cohesive energy density
positive function of the complexation constant.
METHODES OF DETERMINE
• Electronic absorption
• Infrared absorption
• Correlate the color of solution with the
degree of complexation
• All aromatic solvent give intense band at
300 nm. eg. ( iodine –aromatic complex.
• Exception : - Benztrifloride having electro
• Based on the nature of bond joining the group
to the parent molecule.
• Association lead change
1. Stretching vibrational frequency
2. Peak broadening
3. Increases or decreases in absorption
4. Appearance of new peak
• MECHANISM OF SOLID SOLUTION
• TYPES IF SOLID SOLUTION
(A) Based on miscibility
(B) Based on molecular size
• Aging process of solid solution.
• Consisting of just one phase.
• Poorly water soluble drug dissolved in a
carrier with good aqueous solubility for
improving Bio – availability.
• Drug particle size reduced to absolute
minimum – molecular dimension.
• Judicious selection of carrier for better
dissolution rate .
MECHANISM OF SOLID
• As carrier dissolves ,having solublization
effect on the drug.
• Carrier material may also enhancing
wettability or dispersibility of drug.
• Formation of metastable form having a
TYPE OF SOLID SOULTION
• Based on miscibility :-----
• Two components are miscible in the solid
state in all proportion.
• Solid solution exist at extremes of
Based on molecular size
• The solute molecule substitute for the
solvents molecule in crystal lattice.
• Molecular size not differ by more than
(1) p-dibromobenzene - Para
(2) Anthracene – acenaphthene
(3) Ammonia – potacium thiocyanate
INTERSTITIAL SOLID SOLUTION
• Solute molecule occupies the interstitial space.
• Diameter should be less than 0.59 that of
• Having large molecule size polymer favors the
formation of interstitial solid solution.
Example : -
• Solid solution of digitoxin, methyl
testosterone, prednisolone acetate &
hydrocortisone acetate in matrix of
PEG -6000 .
AGING EFFECT OF SOILD
• Precipitation (Decomposition ,Demixing)
• Precipitation from super saturated solution
along with changes of physical – chemical
THEORY OF PRECIPITATION : --
• Occurs when conc. Of solute exceed its
• At high temp. quenching from melt to ambient
temp. and meta stable form is obtained.
• Extra solute bound to precipitate and reduce
• RELATIONSHIP WITH SOLUBILITY
• METHODS FOR MICRONISATION.
• RECENT WORKS ON MICRONISATION.
• Process of converting coarse particle into
less than 5 micron.
• All technique apply force on particle in the
form of collision.
• Force act against imperfections in the
crystal lattices initiating crack propagation
though the particle.
RELATION WITH SOLUBILITY
• Enhancement of solubility by increasing surface
• Presentation by Kelvin Eqn.
• ln (a/ao) = 2γ v / RTr
• a/ao = ratio of the activity increase on
decreasing a large crystal to a radius r.
• γ = Average surface free energy of crystal
• V = molar volume
• R = Gas constant
• T = Absolute temp.
METHODS FOR MICRONISATION
1. Conventional trituration and grinding.
2. Ball milling.
3. Fluid energy Micronisation .
4. Controlled precipitation by change of solvent
5. Spray drying
6. By ultrasonic waves
7. In vivo Micronisation
8. By super critical fluid technique. (RESS)
9. By controlled crystallization (GAS)
SUPER CRITICAL FLUID
• Every solvent have critical temp. (Tc) and
critical pressure (Pc) ,beyond which no
pressure can force solvent into its liq.
• SCF :-- Temp. and pressure higher than
Tc and Pc.
• In critical region normal gas behave liq.
• Unique and Innovative method for particle
• Micro precipitation / Micro crystallization.
Just like salting out effect
• GAS equipment
IN VIVO MICRONISATION
♠ Liquid solution using non aqueous solvent
Diluted with GIT fluid ,very fine particle.
♠ Water soluble salts of poorly soluble drug
parent drug precipitate in ultra fine form in
RECENT WORKS ON
Micronized purified flavonoid fraction for chronic
venous insufficiency , venous ulcer and
Improvement of dissolution rate of
ARTEMISININ by supercritical fluid tech. and
Enhancement of dissolution rate of poorly water
soluble particle by spray freezing into liq. With
atmospheric freeze – drying.
• In situ micronization of Disodium
chromoglycate for pulmonary delivery.
• Nanocrystals for stability and dissolution
rate improvement of NIFEDIPINE.
• Griseofulvin and Ampicillin Micronisation
by SCF with atomization.
• Micronisation of Insulin from halogenated
alcohol using super critical carbon dioxide.
Micronisation of anti –inflammatory drugs for
pulmonary delivery by controlled
Micronized hydrophobic drugs.
Respirable fraction increase compare to
Avoiding drug deposition side effect in
Homogenous particle size distribution.
Critical effect by milling are avoided.
Describe the association process of solute- solvent
Discuss thermodynamic of solute – solvent
Discuss methods of determining equilibrium
What is solid solution ? Discuss different types of
What is micronization ? And its relationship with
Encyclopedia of pharmaceutical technology, vol. -18 , page
-: 219 – 233.
Encyclopedia of pharmaceutical technology, vol. -3, page -:
Solubility and related properties by kenneth c.James. Pg – :
253 – 271.
Remington: the science and practice of pharmacy vol.1 pg:-
J.pharma. sci. 92 :35-44
J.pharma. sci. 91 :258-262
J.pharma. sci. 94 :56-68