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‫الكليـــــــــــــة‬ ‫رؤيــــــــــــة‬
‫الكليــــــــــــة‬ ‫رســـــــــــــــالة‬
‫الريادة‬
ً
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ً
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ً
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‫والبحوث‬
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.
‫توفير‬
‫أفضل‬
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‫في‬
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‫في‬
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‫للنهوض‬
‫بالصحة‬

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Upon successful completion of this course the student
should be able to;
 Describe the physicochemical and physiological factors that
influence the absorption of drugs from extra and intravascular
routs of administration, their distribution within the body, and
the irroutes and mechanisms of elimination.

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The pH - partition theory explains the influence of GI
pH and drug pKa on the extent of drug absorption.
A. pH - Partition Theory
As most drugs are weak electrolytes, the unionized
form of weakly acidic or basic drugs (i.e. the lipid-
soluble form) will pass across the gastrointestinal
epithelia, whereas the gastrointestinal epithelia is
impermeable to the ionized (i.e. poorly lipid-soluble)
form of such drugs.

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According to the pH-partition hypothesis, the
absorption of a weak electrolyte will be determined
chiefly by the extent to which the drug exists in its
unionized form at the site of absorption.

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The extent to which a weakly acidic or basic drug ionizes
in solution in the gastrointestinal fluid is determined by:
its pKa & the pH at the absorption site and may be
calculated using the appropriate form of the Henderson-
Hasselbach equation

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What is acid?
acid is a substance that liberates hydrogen ions [H+] in
solution.
What is a base?
A base is a substance that can bind H+ and remove them
from solution.
pH = - log [H+]
Strong acids, strong bases, as well as strong electrolytes
are essentially completely ionized in aqueous solution.
Weak acids and weak bases are only partially ionized in
aqueous solution and yield a mixture of the
undissociated compound and ions.

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HA H+ + A-
Ka =
[H+] [A-]
[HA]
In solutions of weak acids
equilibria exist between
undissociated molecules and
their ions.
The ionization constant Ka of a
weak acid can be obtained by
applying the Law of Mass Action:

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pKa = pH - log
[A-]
[HA]
log
[A-]
[HA]
= pH - pKa
Henderson - Hasselbalch
Equation
pKa = the negative logarithm
of Ka
From the pKa, one can
calculate the proportions of
drug in the charged and
uncharged forms at any pH:
For acidic drugs, the lower
the pKa the stronger the acid

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Some Typical pKa Values for Weak Acids at 25 °C
pKa
Weak Acid
4.76
Acetic
3.49
Acetylsalicyclic
9.24
Boric
2.73
Penicillin V
8.1
Phenytoin
2.97
Salicyclic
7.12
Sulfathiazole

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In solutions of weak bases equilibria
exist between undissociated
molecules and their ions.
The ionization constant Ka of a
protonated weak base can be
obtained by applying the Law of
Mass Action:
B + H+ BH+
Ka =
[H+] [B]
[BH+]

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pKa = the negative logarithm of Ka
From the pKa, one can
calculate the proportions of
drug in the charged and
uncharged forms at any pH:
pKa = pH - log
[B]
[BH+]
Henderson - Hasselbalch
Equation
log
[B]
[BH+]
= pH - pKa
For basic drugs, the higher the
pKa the stronger the base

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Therefore, according to these equations:
a weakly acidic drug, pKa 3.0, will be:
predominantly unionized in gastric fluid at pH 1.2
(98.4%) and almost totally ionized in intestinal fluid at
pH 6.8 (99.98%),
a weakly basic drug, pKa 5, will be:
almost entirely ionized (99.98%) at gastric pH of 1.2
and predominantly unionized at intestinal pH of 6.8
(98.4%).

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This means that, according to the pH-partition
hypothesis, a weakly acidic drug is more likely to be
absorbed from the stomach where it is unionized,
and a weakly basic drug from the intestine where it is
predominantly unionized.
However, in practice, other factors need to be taken into
consideration.

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Lipid solubility :weak acids and weak bases
HA <==> H+ + A- B + HCl <==> BH+ + Cl-
[ UI ] [ I ] [ UI ] [ I ]
pKa=pH + log (HA/A-) pKa= pH + log(BH+/B)
ASPIRIN pKa = 4.5 (weak acid)
100mg orally
99.9 = [ UI ] [ UI ]
Stomach
pH = 2
Blood
pH = 7.4
0.1 = [ I ]
Aspirin is reasonably absorbed Strychnine not absorbed until
from stomach (fast action) enters duodenum
0.1 = [ UI ] [ UI ]
Blood
pH = 7.4
99.9 = [ I ]
STRYCHNINE pKa = 9.5 (weak base)
100mg orally
Stomach
pH = 2

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Limitations of the pH-partition hypothesis
 Weak acids are also absorbed from the small intestine
due to:
 The significantly larger surface area that is
available for absorption in the small intestine in
contrast to stomach
 The longer small intestinal residence time
 The microclimate pH, that exists at the surface
of the intestinal mucosa and is lower than that
of the luminal pH of the small intestine

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 The pH -partition hypothesis cannot explain the fact
that certain drugs (e.g. tetracyclines) are readily
absorbed despite being ionized over the entire pH
range of the gastrointestinal tract. One suggestion for
this is that such drugs interact with endogenous
organic ions of opposite charge to form an absorbable
neutral species - an ion pair - which is capable of
partitioning into the lipoidal GIT barrier and be
absorbed via passive diffusion.

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Barbitone and thiopentone, have similar dissociation
constants - pKa 7.8 and 7.6, respectively - and
therefore similar degrees of ionization at intestinal pH.
However, thiopentone is absorbed much better than
barbitone. WHY? the absorption of drugs is also
affected by the lipid solubility of the drug.
Thiopentone, being more lipid soluble than barbitone,
exhibits a greater affinity for the gastrointestinal
membrane and is thus far better absorbed.
B. Lipid Solubility of Drugs

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An indication of the lipid solubility of a drug, and (its
absorption) is given by its ability to partition between a
lipid-like solvent (usually octanol) and water.
This is known as the drug's partition coefficient, and is a
measure of its lipophilicity.
How can we measure lipid solubility??

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The partition coefficient P is the ratio of the drug
concentration in the organic phase to its concentration
in the aqueous phase
Partition coefficient (p) = [ L] conc / [W] conc
[ L] conc is the concentration of the drug in lipid phase,
[W] conc is the concentration of the drug in aqueous
phase.
The higher p value, the more absorption is observed.
Polar molecules, i.e. those that are poorly lipid soluble
and relatively large, such as heparin are poorly
absorbed after oral administration and therefore have
to be given by injection.

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A prodrug is a chemical modification,
frequently an ester of an existing drug.
The ester linkage increases the
lipophilicity of the compound thus
enhances the absorption.
A prodrug has no pharmocological activity
itself but it converts back to the parent
compound as a result of metabolism by
the body. (e.g. Rivampicillin a prodrug for
ampicillin)
The drug is too hydrophilic, what can be done??
Prodrug is one of the options that can be used to
enhance p value and absorption as sequence.

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So far we have looked at the transfer of drugs in
solution in the G-I tract, through a membrane, into
solution in the blood.
However, many drugs are given in solid dosage forms
and therefore must dissolve before absorption can take
place.
C. Drug Dissolution

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The rate of solution may be explained using Fick’s First
Low of Diffusion: It is the rate at which a dissolved
solute particle diffuses through the stagnant layer to the
bulk solution
If absorption is slow relative to dissolution then all we
are concerned with is absorption. However, if dissolution
is the slow, rate determining step (the step controlling
the overall rate) then factors affecting dissolution will
control the overall process.

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Fick's first law
By Fick's first law of diffusion:
D diffusion coefficient,
A surface area,
Cs solubility of the drug,
Cb concentration of drug in the bulk solution,
h thickness of the stagnant layer.
As Cb is much smaller than Cs
the equation reduces to :
Solid
Stagnant
Layer
Cs Cb
h
Bulk Solution

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There are a number of factors which affect drug dissolution:
Surface area, A
The surface area per gram (or per dose) of a solid drug
can be changed by altering the particle size.
e.g. a cube 3 cm on each side has a surface area of 54
cm2. If this cube is broken into cubes with sides of 1 cm,
the total surface area is 162 cm2.

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Generally as A increases the dissolution rate will also
increase. Improved bioavailability has been observed
with griseofulvin, digoxin, etc.
Methods of particle size reduction include mortar and
pestle, mechanical grinders, fluid energy mills, solid
dispersions in readily soluble materials (PEG's).

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Diffusion layer thickness, h
This thickness is affected by the agitation in the bulk
solution.
In vivo we usually have very little control over this
parameter.
It is important though when we perform in vitro
dissolution studies because we have to control the
agitation rate so that we get similar results in vitro as
we would in vivo.

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Diffusion coefficient, D
The value of D depends on the size of the molecule and
the viscosity of the dissolution medium.
Increasing the viscosity will decrease the diffusion
coefficient and thus the dissolution rate.
This could be used to produce a sustained release
effect by including a larger proportion of something
like sucrose or acacia in a tablet formulation.

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Drug solubility, Cs
Solubility is another determinant of dissolution rate.
As Cs increases so does the dissolution rate.
We can look at ways of changing the solubility of a drug:

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base, therefore if the drug
can be given as a salt the
solubility can be increased
and we should have
improved dissolution. One
example is Penicillin V.
D. (1) Salt Form
If we look at the dissolution profile of various salts.
Salts of weak acids and weak bases generally have
much higher aqueous solubility than the free acid or

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Some drugs exist in a number of crystal forms or
polymorphs.
These different forms may well have different solubility
properties and thus different dissolution characteristics.
Chloramphenicol palmitate is one example which exists
in at least two polymorphs.
E. (2) Crystal Form

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Plot of Cp versus Time for
Three Formulations of
Chloramphenicol Palmitate
The B form is apparently more bioavailable. This is
attributed to the more rapid in vivo rate of dissolution.
The recommendation
might be that
manufacturers should
use polymorph B for
maximum solubility and
absorption.

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In addition to different polymorphic crystalline forms, a
drug may exist in an amorphous form.
Because the amorphous form usually dissolves more
rapidly than the corresponding crystalline forms there
will be significant differences in the bioavailabilities.
e.g. antibiotic novobiocin. The more soluble and rapidly
dissolving amorphous form of novobiocin was readily
absorbed.
However, the less soluble and slower-dissolving
crystalline form of novobiocin was not absorbed to any
significant extent thus therapeutically ineffective.

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Acid and enzymatic hydrolysis of drugs in GIT is one of
the reasons for poor bioavailability.
Penicillin G (half life of degradation = 1 min at pH= 1)
Rapid dissolution leads to poor bioavailability WHY? (due
to release large portion of the drug in the stomach, pH =
1.2)
How to protect the drug from the gastric juice?
1. Enteric coating the tablet containing the drug.
2. Prodrug that exhibits limited solubility in gastric fluid
but liberates the parent drug in intestine to be absorbed.
F. Drug Stability and Hydrolysis in GIT

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G. Adsorption
Certain insoluble substances may adsorb
co-administrated drugs leading to poor
absorption.
Charcoal (antidote in drug intoxication).

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Complexation of a drug in the GIT fluids may alter rate
and extent of drug absorption.
1. GIT component- drug interaction:
Intestinal mucosa + Streptomycin = poorly absorbed
complex
2. Food-drug interaction:
Calcium + Tetracycline = poorly absorbed complex
3. Tablet additive – drug interaction:
Carboxyl methylcellulose (CMC) + Amphetamine =
poorly absorbed complex
H. Complexation

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4. Complexing agent + polar drugs:
Dialkylamides + prednisone = well-absorbed lipid
soluble complex
5. Lipid soluble drug + water soluble complexing agent
Miconazole + cyclodextrine = water soluble complex

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