physiochemical factors

Question 1

what are the physiochemical properties that influence bioavailability

Answer 1

– Dissolution rate
– pKa
– Lipid solubility
– Chemical stability
– Complexation potential.

Question 2

once again what is the noyes-whitney equation

Answer 2

dissolution rate = D.A/h . (Cs-Cb)

Question 3

what are the Physiological factors affecting the dissolution rate of drugs

Answer 3

1– The environment of the gastrointestinal tract can
affect the parameters of the Noyes-Whitney
equation  and hence the dissolution rate of a
drug.
– For example  the diffusion coefficient (D) of the
drug in the gastrointestinal fluids may be
decreased by the presence of substances that
increase the viscosity of the fluids.
• Food will ↑ viscosity ↓ the rate of diffusion of
the drug molecules away from the diffusion
layer surrounding each undissolved drug
particle  ↓ dissolution rate of a drug.

2- Surfactants in gastric juice and bile salts will ↑ the
wettability of the drug ↑ the effective surface area
(A) exposed to gastrointestinal fluids  ↑ dissolution
rate of a drug.
• Surfactants in gastric juice and bile salts will ↑ the
solubility of the drug in the gastrointestinal fluids via
micellization  ↑ dissolution rate of a drug.

3-The thickness of the diffusion layer (h) will be
influenced by the degree of agitation experienced by
each drug particle in the gastrointestinal tract
– ↑ gastric and/or intestinal motility ↓ the
thickness of the diffusion layer around each drug
particle ↑ the dissolution rate of a sparingly
soluble drug

4-The concentration (C) of drug in solution in the bulk
of the gastrointestinal fluids will be influenced by
– The rate of removal of dissolved drug by
absorption through the gastrointestinal-blood
barrier
– The volume of fluid available for dissolution 
which will be dependent on:
–The position of the drug in the
gastrointestinal tract
–The timing with respect to meal intake.

Question 4

what Drug factors affecting dissolution rate

Answer 4

1–The particle size (surface area)
2–The wettability
3–The solubility
4–The form of the drug
»Salt or free form
»Crystalline or amorphous

Question 5

how does the surface area effects the dissolution rate

Answer 5

noyes-whitney—– the higher the surface area the higher the dissolution rate
meaning—the smaller the particle—- the higher the surface area and dissolution rate —- the higher the bioavailability

One of the classic examples of particle size effects on
the bioavailability of poorly soluble compounds is that
of griseofulvin:
– A reduction of particle size from about 10
m
(specific surface area = 0.4 m
2
/g) to 2.7 m
(specific surface area = 1.5 m
2
/g)  produced
approximately double the amount of drug absorbed
in humans
• The relative bioavailability of danazol has been
increased 400% by administering particles in the
nano- rather than the micrometer size range
• Such improvements in bioavailability can result in an
increased incidence of side-effects 
– For certain drugs, it is important that the particle
size is well controlled, and many Pharmacopoeia
state the requirements of particle size

Question 6

when does aggregation increase

Answer 6

Particle size  ↑ aggregation ( ↓ physical stability).
– For hydrophobic drugs, micronization and other dry
particle size-reduction techniques can result in
aggregation of the material
– Aggregation will reduce the effective surface area
exposed to the gastrointestinal fluids ↓ dissolution
rate and bioavailability.
– Example: Aspirin, phenacetin and phenobarbitone
• How to solve this problem? How to prevent
aggregation of the particles?
– One approach is to micronize or nanosize the drug
with a wetting agent or hydrophilic carrier  these
are called stabilizers.

Question 7

how can we increase the surface area of hydrophobic drugs

Answer 7

by the addition of a wetting agent to the
formulation.
– The presence of polysorbate-80 in a fine suspension
of phenacetin (particle size less than 75 um) ↑ the
rate and extent of absorption of the phenacetin in
human volunteers compared to the same-size
suspension without a wetting agent.
– Why this improvement? Polysorbate-80 helps by
– increasing the wetting of the particles
– Increasing solvent penetration of the particles
– Minimizing aggregation of suspended particles

Question 8

If an increase in the effective surface area of a drug
does not increase its absorption rate 
– It is likely that the dissolution process is not rate
limiting for absorption.
give an example

Answer 8

For drugs such as penicillin G and erythromycin 
they are unstable in gastric fluids  their chemical
degradation will be minimized if they remain in the
solid state.
– For these drugs ↓ particle size  ↑ their
dissolution rate  ↑ chemical degradation  ↓ the
amount of intact drug available for absorption.

Question 9

the aqueous solubility is dependent on what

Answer 9

– The interactions between molecules within the
crystal lattice
– Intermolecular interactions with the solvent in
which it is dissolving
– The entropy changes associated with fusion and
dissolution.

Question 10

what does the solubility of weak electrolytes depends on?

Answer 10

on their pH

• For an orally administered solid dosage form
containing a weak electrolyte drug
– The dissolution rate of the drug will be influenced by
its solubility
– It is solubility will be influenced by the pH in the
diffusion layer surrounding each dissolving drug
particle.
– The pH in the diffusion layer will be affected by the
pKa and solubility of the dissolving drug and the pH
of the bulk gastrointestinal fluids.
– The pH of the bulk gastrointestinal fluids is different
in different regions of the gastrointestinal tract

Question 11

how does the solubility of weak acids and bases increases

Answer 11

• The solubility of weakly acidic drugs increases
with pH  the solubility ↑ as a drug moves down
the gastrointestinal tract from the stomach to the
intestine

• Conversely, the solubility of weak bases
decreases with increasing pH  the solubility ↓
as a drug moves down the gastrointestinal tract
from the stomach to the intestine
– It is important therefore for poorly soluble
weak bases to dissolve rapidly in the stomach

Question 12

give examples on weak electrolytes drugs

Answer 12

• Example 1: the antifungal drug ketoconazole
– It is a weak base
– It is particularly sensitive to gastric pH
– Dosing ketoconazole 2 hours after the
administration of the H2 blocker cimetidine 
cimetidine ↓ gastric acid secretion  ↑ pH of the
stomach  significantly ↓ rate and extent of
absorption.
• Example 2: the antiplatelet dipyrimidole (also a weak
base)
– Pretreatment with the H2 blocker famotidine 
reduces the peak plasma concentration by a
factor of up to 10

Question 13

how can we increase the solubility of a weak acidic drug in the stomach

Answer 13

The pH of the diffusion layer would be increased
if the chemical nature of the weakly acidic drug
were changed from that of the free acid to a
basic salt
– For example, the sodium or potassium form of
the free acid.

Question 14

The pH of the diffusion layer surrounding each particle
of the salt form would be higher (e.g. 5-6) than the low
bulk pH (1-3.5) of the gastric fluids …why?

Answer 14

When dissolved drug diffuses out of the diffusion
layer into the bulk of the gastric fluid 
– The bulk pH is lower than that in the diffusion
layer
– The free acid form of the drug in solution will be in
excess of its solubility at the bulk pH of gastric
fluid
– Precipitation of the free acid form will occur
– This will leave behind a saturated (or near
saturated) solution of free acid in gastric fluid
Often this precipitated free acid will be in the form of
very fine, non-ionized wetted particles  it would
exhibit a very large total effective surface area in
contact with gastric fluids  this will facilitate rapid
redissolution of the precipitated particles of free acid
when additional gastric fluid becomes available as a
consequence of
– Dissolved drug being absorbed
– Additional fluid accumulating in the stomach
– The fine precipitated particles being emptied from
the stomach to the intestine.
• This rapid redissolution will ensure that the
concentration of free acid in solution in the bulk of the
gastric fluids will be at or near to saturation.

Question 15

– The oral administration of a solid dosage form
containing a strong basic salt of a weakly acidic
drug would be expected to:
–Give a more rapid rate of drug dissolution
–In the case of drugs exhibiting dissolution
rate limited absorption  a more rapid rate
of drug absorption than the free acid form of
the drug

Question 16

how can we increase the solubility of a basic drug?

Answer 16

Strongly acidic salt forms of weakly basic drugs
dissolve more rapidly in gastric and intestinal fluids
than do the free bases.
– The pH in the diffusion layer around each drug
particle is lower than the bulk pH in either the
gastric or the intestinal fluid.
– This lower pH will increase the solubility of the drug
Cs
in the diffusion layer.
– The oral administration of a salt form of a weakly
basic drug in a solid oral dosage form generally
ensures that dissolution occurs in the gastric fluid
before the drug passes into small intestine (where
pH conditions are unfavourable).
– Thus, the drug should be delivered to the major
absorption site, the small intestine, in solution.
• If absorption is fast enough  precipitation of the
dissolved drug (in the intestine) is unlikely to
significantly affect bioavailability.
• It is important to be aware that hydrochloride salts may
experience a common ion effect  drug precipitation
– For example: the in vitro dissolution of a sulphate
salt of an HIV protease inhibitor analogue is
significantly greater in 0.1 N HCl than that of the
hydrochloride salt.
– The bioavailability of the sulphate salt is more than
three times greater than that of the hydrochloride
salt.
– These observations are attributed to the common
ion effect of the hydrochloride

Question 17

give examples on salts

Answer 17

The sodium salts of acidic drugs and the hydrochloride
salts of basic drugs are by far the most common.
• However, many other salt forms are increasingly being
employed.
• Some salts have a lower solubility and dissolution rate
than the free form… For example
• Aluminum salts of weak acids and
• Palmitate salts of weak bases.
• In these cases, insoluble films of either aluminium
hydroxide or palmitic acid are found to coat the
dissolving solids when the salts are exposed to a basic
or an acidic environment, respectively.
• Such poorly soluble salts delay absorption and may
therefore be used to sustain the release of the drug.
• A poorly soluble salt form is generally employed for
suspension dosage forms.

Question 18

what is polymorphism

Answer 18

– Many drugs can exist in more than one crystalline
form
– Each crystalline form is known as a polymorph
– A metastable polymorph usually exhibits a greater
dissolution rate than the corresponding stable
polymorph.
– Consequently, the metastable polymorphic form of a
poorly soluble drug may exhibit an increased
bioavailability compared to the stable polymorphic
form.

Question 19

give an example on a metastable drug

Answer 19

chloramphenicol
palmitate.
– It exists in three crystalline forms designated A, B and
C.
– At normal temperature and pressure
• Polymorph A is the stable polymorph
• Polymorph B is the metastable polymorph: it is
sufficiently stable to be included in a dosage form.
• Polymorph C is the unstable polymorph: it is too
unstable to be included in a dosage form,

As the proportion of the polymorphic form B  in the
suspension  the extent of absorption of chloramphenicol
. … why?
– Chloramphenicol palmitate is a prodrug of
chloramphenicol.
– The metastable polymorphic form B of chloramphenicol
palmitate has a more rapid in vivo rate of dissolution.
– Following dissolution  chloramphenicol palmitate is
hydrolysed to give free chloramphenicol in solution
which is then absorbed.
– On the other hand  The stable polymorphic form A of
chloramphenicol palmitate dissolves so slowly  it is
hydrolysed so slowly to chloramphenicol  this
polymorph is virtually ineffective in vivo.

The united state pharmacopoeia states
that:
• Limit of polymorph A: not more than 10%

Question 20

what is an amorphus

Answer 20

The amorphous form dissolves more rapidly than the
corresponding crystalline form

Disadvantage: highly unstable (physically) 
adequate precautions should be taken to ensure that
it does not convert to the more thermodynamically
stable crystalline form

Question 21

what are solvates?

Answer 21

Another variation in the crystalline form of a drug can
occur if the drug is able to associate with solvent
molecules  it will produce crystalline forms known
as solvates.
– When water is the solvent  the solvate formed is
called a hydrate.
– Generally, the greater the solvation of the crystal 
the lower are the solubility and dissolution rate in a
solvent identical to the solvation molecules.
– Anhydrous form is more soluble that the
hydrate
– Non-aqueous solvates are more soluble than
the anhydrous form

Question 22

what are thw Factors affecting the concentration
of drug in solution in the GIT fluids

Answer 22

– Complexation - Micellar solubilization
– Adsorption - Chemical stability

Question 23

what is complexation

Answer 23

May occur within the dosage form and/or in the
gastrointestinal fluids
– It can be beneficial or detrimental to absorption.

– Example 1: complexation with mucin
• The antibiotic streptomycin binds to mucin
• This cause reduction of the available concentration
of streptomycin for absorption.
• It is thought that this may contribute to its poor
bioavailability.

– Example 2: complexation between drugs and dietary
components
• As in the case of the tetracyclines which complex
with Calcium
• This will result in a poorly soluble complex
– For the same reason, the diluent dicalcium
phosphate should not be used in the dosage forms
of tetracycline.

Example 3: complexation between drugs and
excipients present in the dosage form:
– The bioavailability of some drugs can be reduced
because of such complexation.
– As in the case of amphetamine and sodium
carboxymethylcellulose, between phenobarbitone
and polyethylene glycol 4000. (PEG 4000)
– This type of complexation between drugs and
excipients occurs more in liquid dosage forms

Question 24

what is the effects\ use of complexation

Answer 24

Complexation is sometimes used to increase drug
solubility  particularly of poorly water-soluble drugs.
• One class of complexing agents that is increasingly
being employed is the cyclodextrin family.
• Normally, one drug molecule will associate with one
cyclodextrin molecule to form reversible complexes.

• Examples:
– The antifungal miconazole shows poor oral
bioavailability owing to its poor solubility
– However, in the presence of cyclodextrin  the
solubility is 55 times higher, and the dissolution rate
is 255 times higher.
– This enhancement of dissolution rate resulted in a
more than doubling of the oral bioavailability in a
study in rats.

Question 25

Micellar solubization
– It can also increase the solubility of drugs in the
gastrointestinal tract.

Question 26

what is adosrption

Answer 26

– The concurrent administration of drugs and
medicines containing solid adsorbents (such as
kaolin or charcoal):
• The drug will be adsorbed on such solid
adsorbent.
• This may reduce its rate and/or extent of
absorption  owing to a decrease in the
effective concentration of the drug in solution
available for absorption

Question 27

give an example on adsorbtion

Answer 27

• Examples of drug-adsorbent interactions that give
reduced extents of absorption are
– Promazine-charcoal
– Linomycin-kaopectate.
• The adsorbent properties of charcoal have been
exploited as an antidote in drug intoxification.
• Care also needs to be taken when insoluble excipients
are included in dosage forms to check that the drug
will not adsorb to them.
– Talc (included in tablets as a glidant) is claimed to
interfere with the absorption of cyanocobalamin by
virtue of its ability to adsorb this vitamin

Question 28

Instability in gastrointestinal fluids is usually caused by

Answer 28

– Acidic hydrolysis or
– Enzymatic hydrolysis: peptides and proteins

Question 29

How to solve drug instability

Answer 29

– In case of acidic hydrolysis  only the dissolved drug
will be hydrolyzed.
– If we make the drug exhibit low dissolution in gastric
fluid (but still rapid dissolution in intestinal fluid) 
less drug is dissolved  less drug is hydrolyzed 
its bioavailability will be improved.

There are two methods to do that, and they both
were employed for improving the bioavailability of
erythromycin in the gastrointestinal tract by making
either
1. Enteric coated tablets: containing the free base
erythromycin.
2. The administration of chemical derivatives of the
parent drug (prodrug or salt)
– Erythromycin stearate  after passing
through the stomach undissolved  it
dissolves and dissociates in the intestinal
fluid  yielding the free base erythromycin
that is absorbe