Dissolution

							         Dissolution

        Dr. Sakina Sultana
 Ph.D (King’s College London. UK
   M.S (U-SA, South Australia)
          M.Pharm (DU)
       B.Pharm (Hons.) (DU)

               Proessor
      Department of Pharmacy
     Jahangirnagar University
             Savar, Dhaka
E mail : sultana_s2003@yahoo.co.uk
                            Dissolution
    Definition :
    Dissolution is a mass transfer phenomenon that involves transfer of
    a solid mass in a liquid media.This is similar to ‘solution’. But not
    the same.
-   While solution is a general term. It may be a mass transfer
    phenomenon occurring between solid and liquid or between solid
    and vapors. But it is not so in other cases. For example sucrose
    syrup is a solution and making sucrose syrup involves mass transfer
    phenomenon. But if it is ‘air’ it does not involve mass transfer
    phenomenon. Because air is simply a homogenous mixture of
    gases.
-   Solution when is made with solid and liquid then it could be similar
    to dissolution; but it is made with gases it is not so.
-   thus for dissolution there should a solid in the system and it is
    compulsory.
                               Characteristics
* In dissolution the system comprises of a solid solute and a bulk liquid
   medium. So in this phenomenon there is an interface (separating boundary)
   between the two phases and hence the phenomenon involves an interfacial
   reaction.
   * In this reaction solid molecules are liberated first from the (solid) surface.
   * Then these molecules are transferred away against concentration gradient
   in to the bulk.
   * Thus concentration gradient is the driving force for the process to occur.
   * Such transfer of solute molecules does not require any energy and is
   passive in nature similar to diffusion.

   * Thus dissolution is a mass transfer process that occurs in two consecutive
   stages namely ‘interfacial reaction stage’ and the ‘diffusion stage’.

   (Note : concentration gradient is developed at the sides of the interface
   where concentration is high near the solid surface and it is low in the bulk)
     Justification of study in Pharmacy
 or Importance of the process in pharmacy
For drug action knowledge about dissolution is very important when
drug is given a solid dosage form.
Explanation : In general for drug action the drug must be available at the
site of action. Blood carries the drug to the site of action. So drug has to
be absorbed to enter into the circulation. Drug absorption occurs if drug is
in a solution form. In liquid dosage forms drug is already in solution form.
So drug is easily absorbed and drug enters into circulation and it goes to
the site of action through circulation. So drug response (i.e. drug action)
results. For solid dosage forms like tablets, capsules the situation differs.
Here a step called ‘disintegration; is a pre-requisite for the process. In
disintegration process the solid first breaks up into pieces and then goes
into solution following absorption. For solid dosage forms if disintegration
does not occur then it won’t go into solution readily and drug won’t be
available for absorption and hence a rapid drug action won’t result.. Here
if drug is not absorbed drug won’t be in the blood and drug action won’t
result. This is ‘bio-availability’ meaning in-vivo availability of drug at the
site of action. When a drug is bio-available drug action i.e. drug response
then is possible. The sequence of events is like this :
                           Tablet
  Disintegration

                           Gastro intestinal fluid   Dissolution and
                                                     absorption
                           +




                                                            Blood vessel
                          Site of action
Response




            So it is important to know about ‘dissolution’ process in
            details
  Dissolution process and its mathematical expression

Dissolution is a quantifiable process and can be
                                                      Thus the equation becomes
expressed by an equation as developed earlier
                                                      Dc / dt = K S (Cs –C) / h
by two collaborators. The equation is termed as
                                                      Where Dc / dt = rate of dissolution
‘Noyes-Whitney’ equation and it has been              i.e. change in concentration (dc) with a change
named after them.                                     in time (dt)
The equation is basically a law and has been          S = surface area of the solid
                                                      Cs – C = concentration gradient
derived   over     a   number    of   experimental
                                                      Cs = concentration of the solid in
observations. The law states that      the rate of
                                                      the thin saturated liquid layer
dissolution is proportional to the surface area of    (boundary later) adjacent to the
the   solid     (s),   is   proportional   to   the   solid surface
concentration gradient developed between the          C = concentration of the solid in
solid surface (Cs) and bulk of the liquid (C) at      the surrounding bulk medium.
                                                      K = proportionality constant and is
that time and is inversely proportional to the
                                                      called dissolution rate constant.
thickness of diffusion layer surrounding the
                                                      h = thickness of diffusion layer
particles (h)
                                                      surrounding the particles. This may be the thickness of
                                                      interfacial layer.
                       Modification of the law
 The law was developed on the basis of                                     K1 A (Cs – C)
some      in-vitro studies   But    in-vivo   dm / dt =
phenomenon are not exactly the same as                                    h
happens with in-vitro. So considering the
process when is occurring through a static
diffusion layer (as found with biological           Where
membrane) the law is modified. Here                 dm / dt = rate of transfer meaning change in mass
membrane is the main concern. Because bio           with time
membrane has many variables like nature             A = area of migration
(polarity or non polarity), number of               h = thickness of the boundary layer
pores present, surface area, and                    Cs – C = concentration gradient across the boundary
thickness. Each variable has an affect on           In this new form dissolution is said to occur
the process which involves the membrane.
Considering the effects of bio- membrane            under the sink condition which is similar to the fact
                                                    that as soon as tablet releases from the surface inside
the law therefore need modification and it          gastro intestinal fluid that fraction is taken up and is
becomes with the replacement of terms               distributed then and there in the bulk liquid. So drug
S→A                                                 concentration is less than in the media. If Cs>> Co
                                                    (where Cs presents drug concentration at the surface
K → K1                                              and Co presents drug concentration in the bulk Now
                                                    when volume of dissolution media is very high then C
                                                    becomes low and when the value is < 10% of Cs )
                                                    then Co will be insignificant. Thus equation is reduced
                                                    to the form
                                                    dm / dt = D A Cs / h

                                                    Here K1, diffusion coefficient takes a new form D
                Factors

It is found that several factors affects
dissolution. Some factors are similar to
those as found with diffusion and solution
phenomenon. These factors are :
a. Experimental / environmental
b. Physico chemical
c. Biological or physiological (in case of
solid dosage forms taken internally)
d. Formulation
          Experimental factors of dissolution
Temperature :

La Chatelier’s principle is applicable to this process i.e. for solids
showing absorption of heat during making a solution (endothermic
meaning heat of reaction is +ve, Tutorial Pharmacy – Coper and
Gunn, pp 9) there a rise in temperature increases the rate. So application of
heat speeds up the process e.g. KNO3 and upon cooling rate becomes
slow. Conversely for solids with –ve heat of solution like paraldehyde there
a decrease in temperature increases the rate. In formulations a variety of
macromolecules and association colloids like starch, gelatin, PEG and PVP
are used. Each of them shows particular solubility behaviour. For e.g. some
makes solution upon heating or in hot water; while others shows solution in
cool water. So before use their behaviour towards temperature should be
known.
pH :
Drug may be a weak acid (e.g aspirin) or a weak base (procaine). If
aspirin is taken in water and if pH of the aqueous media is made
alkaline then dissolution rate will increase. But if pH is made more
acidic (due to the addition of a strong acid) then dissolution will
decrease. At alkaline pH drug turns into a salt and salt is more
soluble in water. So net result is an increase in dissolution. In more
acidic environment a weakly acidic drug drug loses its solubility and
precipitates out. Same is true for a weak basic drug when pH of the
media is increased due to the addition of strong alkali. Here
solubility decreases.
Agitation :
Agitation of the media containing the solid increases dissolution.
Here agitation changes the used solvent layer by a fresh layer. So
rate is increased. During agitation conc. grad increases as every
time new solvent front comes and speeds up the process. However
timing and positioning are two other important factors. But these are
not discussed here.
Common ion effect :
For a sparingly soluble electrolyte presence of a common ion decreases the rate. Say an aq.
solution has a sparingly soluble electrolyte (AB). Say a 2nd electrolyte (BC) is added to the
solution. So in the system B is the common ion. Here because of presence of B the actual
solubility of AB will be low. This is common ion effect.
Say the total solubility of AB is [AB]s. At equilibrium
[AB]s               [AB] + A + + B+
According to law of mass action at equilibrium
Rate of formation of product = Rate of breakdown of products
but rate of formation (Rf) that is rate of forward reaction is proportional to the [reactant]
and rate of breakdown (Rb) that is rate of backward reaction is proportional to the [product]
or Rf = K1 [reactant] and Rb = K2 [product]
As at equillibrium state Rate of formation of product = Rate of breakdown of products
So K1 [reactant] = K2 [product]
i.e. K1 [AB]s = K2 [A +] [B+]
As [AB] represents un-dissolved fraction
Therefore K = K1 / K2 = [A +] [B+] / [AB]s But as it is sparingly soluble
   so [AB]s is a const.
Therefore K = [A +] [B+] = constant
Now if [A +] [B+] > K then [AB]s will be precipitated out and this is
   possible if either [A +] or [B +] is increased due to the addition of
   another substance that contains either [A +] or [B +] i.e AY or BY. To
   restore the equillibrium state then K shifts to the left. This is common
   ion effect.

   Effect of non electrolyte on solubility of electrolyte :
   Presence of a water miscible non electrolyte in an aq. electrolyte
   solution decreases the rate. Here the non electrolyte lowers
   dielectric constant value of water and hence the solvent power. So
   water can not dissociate and hence can not dissolve the electrolyte.
   So rate is decreased. Here water miscible non electrolyte lowers the
   solvency power of water.
Effect of electrolyte on solubility of a non electrolyte :
A non electrolyte can not be dissociated in water and
can’t form ions. They form dissolved individual
molecules. In this phenomenon they form hydrogen
bonds with water molecule and so it is soluble in water.
Now if there is any electrolyte then presence of it will
cause precipitation of the non electrolyte as the latter
can no longer in hydrogen bonding with water. The
bonds are broken by the electrolyte. This occurs as the
electrolyte shows more attraction for water and
competes for bonding. So non electrolytes undergo
precipitation. Thus poteins are prepitates out due to the
addition of NH4SO4 in the solution.
                       Physico-chemical

These factors are related to the drug.
 Nature of drug and drug solubility :
For hydrophoebic drug rate of dissolution in aqueous media is less.
Dissolution in gastric fluid is a prerequisite to drug delivery to the
systemic circulation following oral administration. Dissolution at this
point depends on solubility of drug substance in the surrounding
medium. Usually polar drug in water exhibits higher solubility than in
the organic solvent medium and vice versa. Alternately an ionised
species shows higher solubility in water than un-ionised species.
In fact total solubility of an acidic species or a base in water is
dependent on pH of the media. Usually drug with high aqueous
solubility shows higher rate of absorption (provided absorption is
passive diffusion mediated).
Particle size and surface area :
Smaller drug molecules show rapid rate of dissolution than bigger
ones.
Size reduction of drug increases rate as surface area of the exposed
solid surface increases. The relation between particle size and
surface area is S = 6m / d ρ where S = surface area, m = mass, d =
effective diameter, ρ = density of drug. If m and ρ = 1, then s = 6/d
thus 1 time reduction in size increases surface area by 6.
For example griseofulvin is a drug of low water solubility (15
microgram /ml) though drug is a neutral molecule.For this drug
absorption is size dependent. When micronised surface area
increases. So is the absorption. It is seen that this drug when is
further reduced to powders and takes a fine solid dispersion in PEG
absorption rate becomes doubled.
However for hydrophobic drugs (e.g Aspirin, phenobarb) extreme
size reduction opposes the effect.
Porosity of solid :
For a porous solid rate is slow as diffusion path is increased
State of solid :
Solid may be polymorphic (state is more than one). Some forms are stable some are
not. Unstable forms are meta stable meaning they change properties (solubility is one
of them) with a change in temperature. So dissolution changes.Again polymorphs
have different intermolecular forces. Polymorphs with weak attractive force of
attraction lie in a high energy state and as such shows greater solubility than that with
strong attractive force of attraction.Naproxen as free acid is less dissolved but sodium
salt of it dissolution is rapid.
Chloramphenicol is a basic drug. But hydrochloride form of this drug is a strong acid.
Again drug may be in an anhydrous state or may be in a hudrous form. Usually rate
of dissolution of an anhydrous drug is rapid than the respective hydrous form
(note : Ketconazole is an anti fungal drug. It is a weak base. In stomach dissolution
increases).
                          Biological factors
Presence of food :
This slows down the process as presence of food increases viscosity of fluid
 Presence of bile salts and bio-surfactants:
Rate is increased as wetting of the drug increases
Intestinal motility :
This increases rate.
(see Aulton pp 236 for better understanding)
Formulation factors
Presence of surfactants :
Rate is increased
Viscosity :
An increase in viscosity of the medium containing the drug rate of dissolution
decreases.
Co solvency :
Presence of co solvent increases dissolution of some drugs as solubility increases.
Salt formation :
A drug in a salt form increases dissolution in aqueous media.
Complexation :
 Complexation usually increases the rate. Due to
the addition of a second solute the first solute
may undergo an enhancement in solubility in
water because an inter molecular complex is
formed. For e.g 3 amino benzoic acid and a di
carboxylic acid (e.g glycolic acid) forms a
complex. So apparent solubility of amino
benzoic acid increases. Mercuric iodide is
insoluble in water. But in presence of KI its
solubility increases. It happens due to the
formation of a complex like K2(Hg I4)
Intrinsic dissolution and tests
  This is dissolution without the influence of
  factor(s). This represents dissolution of the
  drug itself where no other factor or influence
  works.
  Tests :
  Beaker method
  Paddle method
  Rotary basket method
               Rotary basket method
Simulated gastric fluid (900ml) is kept in the bucket which has a
small container made up of wire mesh for holding the drug. The
container is attached to a metallic shaft. The shaft is attached to a
motor and can be rotated at different rpm. The bucket has got a lid
with openings. Through them syringes are passed through. Machine
is rotated and tablet starts to dissolute. After definite time period a
definite drug sample is taken out and is analysed for the
concentration. The amount taken out is replaced with fresh water or
buffer solution and is assayed by titrametric / potentiometric /
conductivity method. By assay percentage of drug released is
calculated out and is plotted against time. Usually the process is
continued until the whole tablet is dissoluted. Time taken from the
start to the finish is called the dissolution time.
At last results are compared with any official pharmacopoea.
References :
Tutorial pharmacy – Cooper and Gunn, pp : 8-13
Dosage form design – Aulton. Pp 20-21, 236
Industrial pharmacy-Lachmann pp221
British pharmacopoea. Dissolution test for tablets and
capsules