SOLUBILITY ENHANCEMENT

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SOLUBILITY ENHANCEMENT Powered By Docstoc
					       Seminar on

SOLUBILITY ENHANCEMENT
 BY SOLUTE – SOLVENT
 COMPLEXATION, SOLID
    SOLUTION AND
    MICRONISATION
          SOLUTE – SOLVENT
           COMPLEXATION
•   The association process
•   Phase solubility diagram
•   The complexation constant
•   Methods of determining equilibrium
    parameter
 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.
          MECHANISM OF
           ASSOCIATION

• Based on Donor – acceptor mechanism.
• Donor --- : Lewis base
• Acceptor ----: Lewis acid


                                 I
I2 + CH3 -O- CH3        (CH3-O-CH3)
                                 I
 CARBON HAVING HYDROGEN AND
   ELE. WITHDRAWING GROUP
• Hydrogen is ele. Acceptor , forming h –
  bond with ele. Donor.
• This is special type of donor –acceptor
  complex.
• Ele. Transfer complex of those not
  involving H – bond.
      COMPLEXATION PROCESS
(a)    Solute + Inert solvent + solute
                           (complex. Agent)

      Increase or decrease solubility

(b)   Solute +Inert solvent + solvent
                            (complex. agent )

           Increase solubility
             EXPRESSION

• 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
      SOLUBILITY DIAGRAM.
• 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.
              Of solute



Plot graph of total molar conc. Of solute
   against molar conc. Of complexing
                  agent.
         Phase diagram




Type A              Type B

Three               Used when complex.
types               Agent is not solvent
          THE COMPLEXATION
              CONSTANT
• nS + mL              SnLm

 (Apply law of mass action and rearrange
 the Eqn.)

 [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.
          decreases entropy.
          lowering of enthalpy of complexation.

Solute-solvent cohesive energy density

   positive function of the complexation constant.
  METHODES OF DETERMINE
  EQUILIBRIUM PARAMETER

• Electronic absorption

• Infrared absorption

• Solubility
 ELECTRONIC 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
  withdrawing effect.
    INFRARED ABSORPTION
•   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
   intensity
4. Appearance of new peak
        SOLID SOLUTION
• INTRODUCTION
• MECHANISM OF SOLID SOLUTION
• TYPES IF SOLID SOLUTION
 (A) Based on miscibility
 (B) Based on molecular size
• Aging process of solid solution.
         INTRODUCTION
• 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
         SOLUTION
• Micronisation
• As carrier dissolves ,having solublization
  effect on the drug.
e.g.: acetaminophane,chlorpropamide,urea.
• Carrier material may also enhancing
  wettability or dispersibility of drug.
• Formation of metastable form having a
  greater solubility.
   TYPE OF SOLID SOULTION

• Based on miscibility :-----



   Continuous solution



                  Discontinuous solution
   CONTINUOUS SOLUTION
• Two components are miscible in the solid
  state in all proportion.
DISCONTINUOUS SOLUTION
• Solid solution exist at extremes of
  composition.
      Based on molecular size




Substitutional
                       Interstitial
SUBSTITUTIONAL SOLUTION
• The solute molecule substitute for the
  solvents molecule in crystal lattice.
• Molecular size not differ by more than
  15%.
            EXAMPLES

    (1) p-dibromobenzene - Para
chlorobromobenzene
   (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
  solvent molecules.
• 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
           SOLUTION
• Precipitation (Decomposition ,Demixing)
• Precipitation from super saturated solution
  along with changes of physical – chemical
  properties.

THEORY OF PRECIPITATION : --
• Occurs when conc. Of solute exceed its
  equilibrium solubility.
• At high temp. quenching from melt to ambient
  temp. and meta stable form is obtained.
• Extra solute bound to precipitate and reduce
  total energy.
       MICRONISATION
• INTRODUCTION
• RELATIONSHIP WITH SOLUBILITY
  ENHANCEMENT
• METHODS FOR MICRONISATION.
• RECENT WORKS ON MICRONISATION.
          INTRODUCTION
• 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
• Enhancement of solubility by increasing surface
  area.
• 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
     temp.
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
          TECHNOLOGY
• Every solvent have critical temp. (Tc) and
  critical pressure (Pc) ,beyond which no
  pressure can force solvent into its liq.
  Phase.
• SCF :-- Temp. and pressure higher than
  Tc and Pc.
• In critical region normal gas behave liq.
  Like density.
     RAPID EXPANTIONOF
   SUPERCRITICAL SOLUTIN
            (RESS)

• Unique and Innovative method for particle
  Micronisation.
           GAS ANTISOLVENT
           RECRYSTALLITION

• 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

   GIT fluid.
          RECENT WORKS ON
           MICRONISATION
Micronized purified flavonoid fraction for chronic
 venous insufficiency , venous ulcer and
 haerrorrhoids.
Improvement of dissolution rate of
 ARTEMISININ by supercritical fluid tech. and
 solid dispersion.
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
                crystallization.

Micronized hydrophobic drugs.
Respirable fraction increase compare to
 jet milling.
Avoiding drug deposition side effect in
 throat.
Homogenous particle size distribution.
Critical effect by milling are avoided.
           QUESTION BANK
 Describe the association process of solute- solvent
  complexation.
 Discuss thermodynamic of solute – solvent
  complexation.
 Discuss methods of determining equilibrium
  parameter.
 What is solid solution ? Discuss different types of
  solid solution.
 What is micronization ? And its relationship with
  solubility enhancement.
                    REFRENCES
   Encyclopedia of pharmaceutical technology, vol. -18 , page
    -: 219 – 233.
   Encyclopedia of pharmaceutical technology, vol. -3, page -:
    337-344.
   Solubility and related properties by kenneth c.James. Pg – :
    253 – 271.
   Remington: the science and practice of pharmacy vol.1 pg:-
    201.
 J.pharma. sci. 92 :35-44
 J.pharma. sci. 91 :258-262
 J.pharma. sci. 94 :56-68
Thank you…

				
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