Biopharmaceutics

Biopharmaceutics:
It is the science that considers the interrelationship of the physicochemical properties of
the drug, the dosage form in which the drug is given, and the route of administration on the
rate and extent of drug absorption.
Course Objective:
To develop the pharmacy students with good practical knowledge and understanding of
biopharmaceutics through the use of lecture material and practical examples. A key aim is
to develop the ability to logically apply the interrelationship of the physicochemical
properties of the drug, the dosage form in which the drug is given, and the route of
administration on the rate and extent of drug absorption. After completing the absorption
section each student should:-
be able to describe membrane structure and how it might effect drug transport
be able to describe the differences between different transporter mechanisms
be able to describe the relationship between GI physiology and drug absorption
be able to correlate between physical-chemical properties of the drug and
absorption
be able to describe the relationship between dosage forms and drug absorption

Absorption

!iopharmaceutics-Absorption class note

"iagram #epresenting
Absorption, "istribution,
$etabolism and %xcretion
Main factors affecting oral absorption:
&' (hysiological factors
&)' (hysical-chemical factors
&*' +ormulation factors
1. Phsiological factors affecting oral absorption !outline"
A. $embrane physiology
!. (assage of drugs across membranes
i. Active transport
ii. +acilitated diffusion
iii. (assive diffusion
iv. (inocytosis
v. (ore transport
vi. Ion pair formation
,. Gastrointestinal physiology
i. ,haracteristics of GIT physiology and drug absorption
ii. Gastric emptying time and motility
iii. %ffect of food on drug absorption
iv. "ouble peak phenomena
v. $alabsorption
A. Membrane phsiolog
Membrane structure
In -.. /verton performed some simple but classic experiments related to cell
membrane structure. !y measuring the permeability of various types of compounds across
the membranes of a frog muscle he found that lipid molecules could readily cross this
membrane, larger lipid insoluble molecules couldn0t and small polar compounds could
slowly cross the membrane. 1e suggested that membranes were similar to lipids and that
certain molecules 2lipids3 moved across membranes by dissolving in the membrane.
)
!iopharmaceutics-Absorption class note
These results suggest that the biologic membrane is mainly lipid in nature but contains
small a4ueous channels or pores.
#ipid Bilaer
/ther experiments involving surface tension measurements have suggested that there is
also a layer of protein on the membrane. These results and others have been incorporated
into a general model for the biological membrane. This is the "avson-"anielli model
2-*53.
$he %avson-%anielli Model
6ater work 2"anielli, -753 suggested the presence of 8active patches8 and protein
lining to pores in the membrane.
Modified %avson-%anielli Model
9ork during the -7.s and -:.s suggested the model proposed by ;inger and
<icolson -7) called the fluid mosaic model. 9ith this model the lipid bilayer is retained
*
!iopharmaceutics-Absorption class note
but the protein drifts between the lipid rather than forming another layer on either side of
the lipid bilayer.
$he &luid Mosaic Model
The membrane then acts as a lipid barrier with protein formed pores. The protein within
the membrane can act transport enhancers in either direction depending on the protein.
The barriers between various organs, tissues and fluids areas will consist of cells of
different structure and membranes characteristics. In some cases the cells are loosely
attached with extracellular fluid freely moving between the cells. "rugs and other
compounds, lipid or not, may freely move across this barrier. In other cases there may be
tight =unctions between the cells which will prevent non lipid movement.
#oosel Attached Cell Barrier
Cell Barrier 'ith $ight (unctions
These are general structures of the cellular layer. 6ayers in different parts of the body
have somewhat different characteristics which influence drug action and distribution. In
particular, membrane protein form and function, intracellular pore si>e and distribution is
not uniform between different parts of the body.
?
!iopharmaceutics-Absorption class note
)*amples of some barrier tpes:
Blood-brain barrier: The cellular barrier between the blood and brain have very tight
=unctions effectively eliminating transfer between the cells. Additionally there are specific
transport mechanisms, such as (-glycoproteins which actively causes the removal of drugs
and other compounds from the brain. This will prevent many polar 2often toxic materials3
materials from entering the brain. 1owever, smaller lipid materials or lipid soluble
materials, such as diethyl ether, halothane, can easily enter the brain across the cellular
membrane. These compounds are used as general anesthetics.
+enal tubules: In the kidney there are a number of regions important for drug elimination.
In the tubules drugs may be reabsorbed. 1owever, because the membranes are relatively
non-porous, only lipid compounds or non-ioni>ed species 2dependent of p1 and p@a3 are
reabsorbed.
,epatic blood vessels: The capillaries are lined with a basement membrane broken in part
by sinusoids and fenestrations interspersed with cells held together with tight =unctions.
The result is a barrier that allows considerable transfer between the blood and hepatocytes.
Blood capillaries and renal glomerular membranes: These membranes are 4uite porous
allowing non-polar and polar molecules 2up to a fairly large si>e, =ust below that of
albumin, $.9t A-,...3 to pass through. This is especially useful in the kidney since it
allows excretion of polar 2drug and waste compounds3 substances.
B. Passage of drugs across membranes
1. Active transport or carrier mediated transport:
5
!iopharmaceutics-Absorption class note
Carrier-Mediated $ransport Process
The body has a number of speciali>ed mechanisms for transporting particular
compoundsB for example, glucose and amino acids. ;ometimes drugs can participate in this
processB e.g. 5-fluorouracil. Active transport re4uires a carrier molecule and a form of
energy.
the process can be saturated
transport can proceed against a concentration gradient
competitive inhibition is possible
-. &acilitated diffusion
A drug carrier is re4uired but no energy is necessary. e.g. vitamin !) transport.
saturable if not enough carrier
no transport against a concentration gradient only downhill but faster
P-glcoprotein
(-glycoprotein transporters 2(G(, $"#-3 are present throughout the body including
liver, brain, kidney and the intestinal tract epithelia. They appear to be an important
component of drug absorption acting as reverse pumps generally inhibiting absorption. This
is an active, AT(-dependent process which can have a significant effect on drug
bioavailability. (-glycoprotein works against a range of drugs 2)5. - :5. "alton3 such as
cyclosporin A, digoxin, C-blockers, antibiotics and others. This process has been described
as multi-drug resistance 2$"#3. Additionally (-glycoprotein has many substrates in
common with cytochrome (?5. *A? 2,D( *A?3 thus it appears that this system not only
transports drug into the lumen but causes the metabolism of substantial amounts of the drug
as well 2e.g. cyclosporin3.
A
!iopharmaceutics-Absorption class note
,linically significant substrates of (G( include digoxin, cyclosporine, fexofenadine,
paclitaxel, tracrolimus, nortriptyline and phenytoin. A number of compounds can act as
(G( inhibitors including atorvastatin 2digoxin AE, increased3, cyclosporine 2increased
paclitaxel absorption3, grapefruit =uice 2increased paclitaxel absorption3 and verapamil.
#ifampin and ;t. Fohn0s wort have been reported to induce (G( expression.
The distribution of (G( polymorphism varies by race. The 0normal0 *?*5, allele is
found in AG African American and )AG in %uropean American. The clinically important
*?*5T polymorph is found in *G of African American and A)G of %uropean American.
The *?*5T allele has been associated with reduced (G( expression 2concentration3 and
conse4uently higher absorption. "igoxin levels were higher in healthy sub=ects with the
*?*5T allele compared with results in sub=ects with the *?*5, allele.
.. Passive diffusion:
%iagram of Passive $ransport 'ith a Concentration /radient
$ost 2many3 drugs cross biologic membranes by passive diffusion. "iffusion occurs
when the drug concentration on one side of the membrane is higher than that on the other
side. "rug diffuses across the membrane in an attempt to e4uali>e the drug concentration
on both sides of the membrane.
If the drug partitions into the lipid membrane a concentration gradient can be
established. The rate of transport of drug across the membrane can be described by +ick0s
first law of diffusionH-
7
!iopharmaceutics-Absorption class note
&ic01s &irst #a'2 +ate of %iffusion
The parameters of this e4uation areH-
%: diffusion coefficient. This parameter is related to the si>e and lipid solubility of the drug
and the viscosity of the diffusion medium, the membrane. As lipid solubility increases or
molecular si>e decreases then " increases and thus d$Idt also increases.
A: surface area. As the surface area increases the rate of diffusion also increase. The
surface of the intestinal lining 2with villae and microvillae3 is much larger than the
stomach. This is one reason absorption is generally faster from the intestine compared with
absorption from the stomach.
*: membrane thickness. The smaller the membrane thickness the 4uicker the diffusion
process. As one example, the membrane in the lung is 4uite thin thus inhalation absorption
can be 4uite rapid.
!Ch -Cl": concentration difference. ;ince J, the apparent volume of distribution, is at least
four liters and often much higher the drug concentration in blood or plasma will be 4uite
low compared with the concentration in the GI tract. It is this concentration gradient which
allows the rapid complete absorption of many drug substances.
<ormally ,l KK ,h thenH-
Thus the absorption of many drugs from the G-I tract can often appear to be first-order.
:
!iopharmaceutics-Absorption class note
3. Pinoctosis 4 Phagoctosis4 5esicular transport:
6arger particles are not able to move through membranes or interstitial spaces so
other processes must be available. These processes involve the entrapment of larger
particles by the cell membrane and incorporation into the cell, cytosis. A spontaneous
incorporation of a small amount of extracellular fluid with solutes is called pinocytosis.
(hagocytosis is a similar process involving the incorporation of larger particles. %xamples
include Jitamin A, ", %, and @, peptides in newborn.
6. Pore transport:
Jery small molecules 2such as water, urea and sugar3 are able to rapidly cross cell
membrane as if the membrane contained pores or channels Although, such pores have
never been seen by microscope, this model of transportation is used to explain renal
excretion of drugs and uptake of drugs into the liver.
;mall drug molecules move through this channel by diffusion more Lrapidly than at
other parts of the membrane. A certain type of protein called transport protein may form an
open channel across the lipid membrane of cell.
7. 8on pair formation:
;trong electrolyte drugs are highly ioni>ed 2such as 4uaternary nitrogen compounds3
with extreme p@a values, and maintain their charge at physiological p1.
These drugs penetrate membranes poorly. 9hen linked up with an oppositely charged
ion, an ion pair is formed in which the overall charge of the pair is neutral. The neutral
complex diffuses more easily across the membrane. An example of this in case of
propranolol, a basic drugs that forms an ion pair with oleic acid.
8llustration of %ifferent $ransport Mechanisms
-
!iopharmaceutics-Absorption class note
C. /astrointestinal !/8" Phsiolog
8. Characteristics of /8 phsiolog and %rug Absorption
Organs p, Membrane Blood
9uppl
9urface
Area
$ransit $ime B-pass
liver
Buccal approx A thin Good, fast
absorption
with low
dose
small ;hort unless
controlled
yes
)sophagus A-7 Jery thick
no absorption
- small short, typically
a few seconds,
except for
some coated
tablets
-
9tomach .7-?.5
decomposition,
weak acid
unioni>ed
normal good small *. min 2li4uid3
- ). min
2solid food3,
delayed
stomach
emptying can
reduce
intestinal
absorption
no
%uodenum 5 - 7
bile duct,
surfactant
properties
normal good very large very short 2A8
long3, window
effect
no
9mall
8ntestine
A -7 normal good very large
. - ? ft,
:. cm
)
Icm
about * hours no
#arge
8ntestine
A.: - 7 - good not very
large ? - 5
ft
long, up to )?
hr
lower
colon,
rectum
yes
.
!iopharmaceutics-Absorption class note
88. /astric empting and motilit
Generally drugs are better absorbed in
the small intestine 2because of the larger
surface area3 than in the stomach, therefore
4uicker stomach emptying will increase
drug absorption. +or example, a good correlation has been found between stomach
emptying time and peak plasma concentration for acetaminophen. The 4uicker the
stomach emptying 2shorter stomach emptying time3 the higher the plasma concentration.
Also slower stomach emptying can cause increased degradation of drugs in the stomach0s
lower p1B e.g. 6-dopa.
&actors Affecting /astric )mpting
5olume of
8ngested Material
As volume increases initially an increase then a decrease. !ulky
material tends to empty more slowly than li4uids
$pe of Meal +atty food "ecrease
,arbohydrate "ecrease
$emperature of
&ood
Increase in temperature, increase in emptying rate
Bod Position 6ying on the left side decreases emptying rate. ;tanding versus lying
2delayed3
%rugs
Anticholinergics 2e.g. atropine3, <arcotic 2e.g.
morphine, alfentanil3, Analgesic 2e.g. aspirin3
"ecrease
$etoclopramide, "omperidone, %rythromycin,
!ethanchol 2see Gastroparesis ref below3
Increase
888. )ffect of &ood
"ependence of peak acetaminophen
plasma concentration as a function of
stomach emptying half-life

!iopharmaceutics-Absorption class note

+ood can effect the rate of gastric emptying. +or example fatty food can slow gastric
emptying and retard drug absorption. Generally the extent of absorption is not greatly
reduced. /ccasionally absorption may be improved , fore example, Griseofulvin
absorption is improved by the presence of fatty food. Apparently the poorly soluble
griseofulvin is dissolved in the fat and then more readily absorbed.
(ropranolol plasma concentrations are larger after food than in fasted sub=ects. This
may be an interaction with components of the food.
9ome items to consider
The larger surface area of the small intestine means that many drugs are much better
absorbed from this region of the GI tract compared with from the stomach. +or some
drugs the rate of absorption from the stomach is so low that stomach emptying time or
rate controls the rate of absorption of the drug. +or acetaminophen 2paracetamol3 the rate
if absorption from the stomach is so slow relative to the absorption from the intestine that
time of peak absorption or peak concentration after oral administration can be used to
determine stomach emptying rate.
85. %ouble pea0 phenomena
;ome drugs such as cimetidine and rantidine, after oral administration produce a
blood concentration curve consisting of two peaks. The presence of duple peaks has been
attributed to variability in stomach emptying, variable intestinal motility, presence of
food, enterohepatic cycle or failure of a tablet dosage form.
)ffect of &asting versus &ed on
Propranolol Concentrations
)
!iopharmaceutics-Absorption class note
5. Malabsorption
$alabsorption is any disorder with impaired absorption of fat, carbohydrate,
proteins and vitamins. "rug induced malabsorption has been observed after
administration of neomycine, phenytoine and anticancer agents.
+actor $echanism #esult on Absortion
Alcoholism 6eaky gut Increase permeability
Anticancer agent
"amage mucosa that serve as
barrier to large molecules
%nhance absorption
;urgical resection of small
intestine
#educe area of absorption #educe bioavailability
"isease in bowl "ifferent $ay reduce or enhance
Phsical-Chemical &actors Affecting Oral Absorption
Outline of Phsical-chemical factors affecting oral absorption:
*
!iopharmaceutics-Absorption class note
A. p1-partition theory
!. 6ipid solubility of drugs
,. "issolution and p1
". ;alts
%. ,rystal form
+. "rug stability and hydrolysis in GIT
G. ,omplexation
1. Adsorption
A. p, - Partition $heor
+or a drug to cross a membrane barrier it must normally be soluble in the lipid
material of the membrane to get into membrane and it has to be soluble in the a4ueous
phase as well to get out of the membrane. $any drugs have polar and non-polar
characteristics or are weak acids or bases. +or drugs which are weak acids or bases the
p@a of the drug, the p1 of the GI tract fluid and the p1 of the blood stream will control
the solubility of the drug and thereby the rate of absorption through the membranes lining
the GI tract.
!rodie et al. 2;hore, et al. -573 proposed the p1 - partition theory to explain the
influence of GI p1 and drug p@a on the extent of drug transfer or drug absorption.
!rodie reasoned that when a drug is ioni>ed it will not be able to get through the lipid
membrane, but only when it is non-ioni>ed and therefore has a higher lipid solubility.
!rodie tested this theory by perfusing the stomach or intestine of rate, in situ, and
in=ected the drug intravenously. 1e varied the concentration of drug in the GI tract until
there was no net transfer of drug across the lining of the GI tract. 1e could then
determined the ratio, " asH
or
Brodie1s % 5alue
?
!iopharmaceutics-Absorption class note
These values were determined experimentally, but we should be able to calculate a
theoretical value if we assume that only non-ioni>ed drug crosses the membrane and that
net transfer stops when &E'b M &E'g . !rodie found an excellent correlation between the
calculated " value and the experimentally determined values.
+evie' of 8onic ):uilibrium
The ratio &E'I&I' is a function of the p1 of the solution and the p@a of the drug, as
described by the 1enderson - 1asselbach e4uation
;ea0 acids
where 1A is the weak acid and A
-
is the salt or con=ugate base
Brodie1s % 5alue in Another &orm
%iagram 9ho'ing $ransfer
Across Membrane
5
!iopharmaceutics-Absorption class note
%issociation Constant e:uation - ;ea0 Acids
taking the negative log of both sides
and rearranging gives the following e4uation where p@a M -log @a and p1 M -log&1
N
'
,enderson - ,asselbach ):uation - ;ea0 Acids
;ea0 Bases
where ! is the weak base and 1!
N
is the salt or con=ugate acid
%issociation Constant e:uation - ;ea0 Acids
taking the negative log of both sides
and rearranging gives the following e4uation where p@a M -log @a and p1 M -log&1
N
'
,enderson - ,asselbach ):uation - ;ea0 Bases
or alternately
A
!iopharmaceutics-Absorption class note
%issociation Constant e:uation - ;ea0 Base
taking the negative log of both sides
<ote that @a O @b M &1*/
N
' O &/1
-
' M @w which is approximately .
-?
, thus p@b - p/1 M
p1 - p@a and the e4uation above can be changed into %4uation ).).A.
;ea0 Acid p<a
Acetic ?.7A
Acetylsalicyclic *.?-
Ascorbic ?.*, .:
!oric -.)?
(enicillin J ).7*
(henytoin :.
;alicyclic ).-7
9ome $pical p<a 5alues for ;ea0
Acids at -6 =C
7
!iopharmaceutics-Absorption class note
;ulfathia>ole 7.)
Tetracycline *.*, 7.A:, -.A-
;ea0 Base p<b
Ammonia ?.7A
Atropine ?.*5
,affeine ..?, *.?
,odeine 5.:
%rythromycin 5.)
$orphine A.*
(ilocarpine 7.), ).7
:.7Puinine A.., -.:-
Tolbutamide
% 5alues and %rug Absorption
%ven though the " values refer to an e4uilibrium state a large " value will mean
that more drug will move from the GI tract to the blood side of the membrane. The larger
the " value, the larger the effective concentration gradient, and thus the faster the
expected transfer or absorption rate.
9ome $pical p<a 5alues for
;ea0 Bases at -6 =C
:
!iopharmaceutics-Absorption class note
,ompare " for a weak acid 2p@a M 5.?3 from the stomach 2p1 *.?3 or intestine 2p1 A.?3,
with blood p1 M 7.?
9tomach
;ea0 Acid from 9tomach
Blood
;ea0 Acid from Blood
%iagram illustrating %rug
%istribution bet'een 9tomach and
Blood
-
!iopharmaceutics-Absorption class note
Therefore the calculated " value would be
Brodie % 5alue - ;ea0 Acid !9tomach"
%iagram illustrating drug distribution bet'een intestine and blood
!y comparison in the intestine, p1 M A.? ,
The calculated " value is 2..N3I2.N3 M -.)
+rom this example we could expect significant absorption of weak acids from the
stomach compared with from the intestine. #emember however that the surface area of
).
!iopharmaceutics-Absorption class note
the intestine is much larger than the stomach. 1owever, this approach can be used to
compare a series of similar compounds with different p@a values.
It has been applied the p1 - partition theory to drug absorption, later this theory it will be
used to describe drug re-absorption in the kidney.
Plot of 0a versus fu
9ith this theory it should be possible to predict that by changing the p1 of the G-I tract
that we would change the fraction non ioni>ed 2fu3 and therefore the rate of absorption.
Thus ka observed M ku O fu assuming that the ioni>ed species is not absorbed.
)
!iopharmaceutics-Absorption class note
Plot of 0a !apparent" versus fu for 9ulfaethidole from +at 9tomach
+or some drugs it has been found that the intercept is not >ero in the above plot,
suggesting that the ionic form is also absorbed. +or example, results for sulfaethidole.
$aybe the ions are transported by a carrier which blocks the charge, a facilitated
transport process 2 this is called the deviation from p1-(artition theory .
B. #ipid solubilit of drugs
;ome drugs are poorly absorbed after oral administration even though they are non-
ioni>ed in small intestine. 6ow lipid solubility of them may be the reason. The best
parameter to correlate between water and lipid solubility is partition coefficient.
(artition coefficient 2p3 M & 6'conc I &9'conc , where & 6'conc is the concentration of the
drug in lipid phase, &9'conc is the concentration of the drug in a4ueous phase. The higher
p value, the more absorption is observed. (rodrug is one of the option that can be used to
enhance p value and absorption as se4uence.
It should be noted that extreme hydrophobicity has negative effect on absorption,
thus, sometime enhance water solubility also increase bioavailability. This may be due to
the unstirred layer 2mucosa layer3 which is important in drug penetration.
C. %rug %issolution
;o far we have looked at the transfer of drugs in solution in the G-I tract, through a
membrane, into solution in the blood. 1owever, many drugs are given in solid dosage
forms and therefore must dissolve before absorption can take place.
))
!iopharmaceutics-Absorption class note
%issolution and Absorption
If absorption is slow relative to dissolution then all we are concerned with is
absorption. 1owever, if dissolution is the slow, rate determining step 2the step controlling
the overall rate3 then factors affecting dissolution will control the overall process. This is
a more common problem with drugs which have a low solubility 2below gI.. ml3 or
which are given at a high dose, e.g. griseofulvin.
There are a number of factors which affect drug dissolution. /ne model that is
commonly used is to consider this process to be diffusion controlled through a stagnant
layer surrounding each solid particle.

+irst we need to consider that each particle of drug formulation is surrounded by a
stagnant layer of solution. After an initial period we will have a steady state where drug is
steadily dissolved at the solid-li4uid interface and diffuses through the stagnant layer. If
diffusion is the rate determining step we can use +ick0s first law of diffusion to describe
the overall process.
%iagram +epresenting %iffusion
$hrough the 9tagnant #aer
)*
!iopharmaceutics-Absorption class note
Plot of Concentration /radient
If we could measure drug concentration at various distances from the surface of the
solid we would see that a concentration gradient is developed. If we assume steady state
we can used +ick0s first law to describe drug dissolution.
&ic01s first la'
!y +ick0s first law of diffusionH
&ic01s first #a' of %iffusion applied to %issolution
where " is the diffusion coefficient, A the surface area, ,s the solubility of the drug,
,b the concentration of drug in the bulk solution, and h the thickness of the stagnant
layer. If ,b is much smaller than ,s then we have so-called 8;ink ,onditions8 and the
e4uation reduces to
&ic01s &irst #a' - 9in0 Conditions
with each term in this e4uation contributing to the dissolution process.
)?
!iopharmaceutics-Absorption class note
9urface area2 A
The surface area per gram 2or per dose3 of a solid drug can be changed by altering
the particle si>e. +or example, a cube * cm on each side has a surface area of 5? cm
)
. If
this cube is broken into cubes with sides of cm, the total surface area is A) cm
)
.
Actually if we break up the particles by grinding we will have irregular shapes and even
larger surface areas. Generally as A increases the dissolution rate will also increase.
Improved bioavailability has been observed with griseofulvin, digoxin, etc.
Particle 9i>e 8ncreases 9urface Area
$ethods of particle si>e reduction include mortar and pestle, mechanical grinders,
fluid energy mills, solid dispersions in readily soluble materials 2(%G0s3.
%iffusion laer thic0ness2 h
This thickness is determined 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.
)5
!iopharmaceutics-Absorption class note
Plot of Concentration versus %istance for %issolution into a +eactive Medium
The apparent thickness of the stagnant layer can be reduced when the drug dissolves
into a reactive medium. +or example, with a weakly basic drug in an acidic medium, the
drug will react 2ioni>e3 with the diffusing proton 21
N
3 and this will result in an effective
decrease in the thickness of the stagnant layer.
The effective thickness is now h0 not h. Also the bulk concentration of the drug is
effectively >ero. +or this reason weak bases will dissolve more 4uickly in the stomach.
%iffusion coefficient2 %
The value of " depends on the si>e 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.
%rug solubilit2 Cs
)A
!iopharmaceutics-Absorption class note
;olubility is another determinant of dissolution rate. As ,s increases so does the
dissolution rate. 9e can look at ways of changing the solubility of a drug.
%. 9alt form
If we look at the dissolution profile of various salts.
;alts of weak acids and weak bases generally have much higher a4ueous solubility
than the free acid or base, therefore if the drug can be given as a salt the solubility can be
increased and we should have improved dissolution. /ne example is (enicillin J.
This can lead to 4uite different ,p versus
time results after oral administration. The
tmax values are similar thus ka is probably the
same. ,max might show a good
correlation with solubility. $aybe site
limited 2only drug in solution by the time the
drug gets to the 0window0 is absorbed3. Ese the potassium salt for better absorption orally.
These results might support the use of the ben>athine or procaine salts for I$ depot use.
Plot of %issolved %rug
Concentration versus $ime
1-...? Plot of Cp versus $ime
)7
!iopharmaceutics-Absorption class note
). Crstal form
;ome drugs exist in a number of crystal
forms or polymorphs. These different forms
may well have different solubility properties
and thus different dissolution characteristics.
,hloramphenicol palmitate is one example
which exists in at least two polymorphs. The ! form is apparently more bioavailable.
The recommendation might be that manufacturers should use polymorph ! for
maximum solubility and absorption. 1owever, a method of controlling and determining
crystal form would be necessary in the 4uality control process. ;helf-life could be a
problem as the more soluble 2less stable3 form may transform into the less soluble form.
In time the suspension may be much less soluble with variable absorption.
&. %rug stabilit and hdrolsis in /8$
Acid and en>ymatic hydrolysis of drugs in GIT is one of the reasons for poor
bioavailability.
(enicillin G 2half life of degradation M min at p1M 3
#apid dissolution leads to poor bioavailability 2due to release large portion of the
drug in the stomach, p1 M .)3
(rodrug 2 conversion in the GIT to parent compound is rate limiting step in
bioavailability, either positively or negatively3
/. Comple*ation
,omplexation of a drug in the GIT fluids may alter rate and extent of drug absorption.
Intestinal mucosa N ;treptomycin M poorly absorbed complex
Plot of Cp versus $ime for $hree
&ormulations of Chloramphenicol
Palmitate
):
!iopharmaceutics-Absorption class note
,alcium N Tetracycline M poorly absorbed complex 2+ood-drug interaction3
,arboxyl methylcellulose 2,$,3 N Amphetamine M poorly absorbed complex
2tablet additive Q drug interaction3
(olar drugs N complexing agent M well-absorbed lipid soluble complex
2 dialkylamides N prednisone3
6ipid soluble drug N water soluble complexing agent M well-absorbed water
soluble complex 2 cyclodextrine3
,. Adsorption
,ertain insoluble susbstance may adsorbed co-administrated drugs leadin to poor
absorption.
,harcoal 2antidote in drug intoxication3.
,holestyramine 2 insoluble anionic exchange resins3
.. &ormulation &actors Affecting Oral Absorption
+ole of dosage forms !outline"
I. ;olutions
F. ;uspensions
@. ,apsules
6. Tablets
$. In vitro correlation of drug absorption
i. "isintegration testing ii. "issolution testing
The role of the drug formulation in the delivery of drug to the site of action should
not be ignored. 9ith any drug it is possible to alter its bioavailability considerably by
formulation modification. 9ith some drugs an even larger variation between a good
formulation and a bad formulation has been observed. ;ince a drug must be in solution to
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!iopharmaceutics-Absorption class note
be absorbed efficiently from the G-I tract, you may expect the bioavailability of a drug to
decrease in the order solution R suspension R capsule R tablet R coated tablet. This order
may not always be followed but it is a useful guide. /ne example is the results for
pentobarbital. 1ere the order was found to be a4ueous solution R a4ueous suspension M
capsule R tablet of free acid form. This chapter will briefly discuss each of these
formulation types particularly in regard to the relative bioavailability.
8. 9olution dosage forms
"rugs are commonly given in solution in coughIcold remedies and in medication for
the young and elderly. In most cases absorption from an oral solution is rapid and
complete, compared with administration in any other oral dosage form. The rate limiting
step is often the rate of gastric emptying. ;ince absorption will generally be more rapid in
the intestine.
9hen an acidic drug is given in the form of a salt, it may precipitate in the stomach.
1owever, this precipitate is usually finely divided and is readily redissolved and thus
causes no special absorption problems. There is the possibility with a poorly water
soluble drug such as phenytoin that a well formulation suspension, of finely divided
powder, may have a better bioavailability.
;ome drugs which are poorly soluble in water may be dissolved in mixed
waterIalcohol or glycerol solvents. This is particularly useful for compounds with tight
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crystal structure and higher melting points that are not ionic. The crystal structure is
broken by solution in the mixed solvent. An oily emulsion or soft gelatin capsules have
been used for some compounds with lower a4ueous solubility to produce improved
bioavailability.
88. 9uspension dosage forms
A well formulated suspension is second only to a solution in terms of superior
bioavailability. Absorption may well be dissolution limited, however a suspension of a
finely divided powder will maximi>e the potential for rapid dissolution. A good
correlation can be seen for particle si>e and absorption rate. 9ith very fine particle si>es
the dispersibility of the powder becomes important. The addition of a surface active agent
will improve dispersion of a suspension and may improve the absorption of very fine
particle si>e suspensions otherwise caking may be a problem. As a suspension ages there
is potential for increased particle si>e with an accompanying decrease in dissolution rate.
;maller particles have higher solubility and will tend to disappear with the drug coming
out of solution on larger particles.
888. Capsule dosage forms
In theory a capsule dosage form should be 4uite efficient. The hard gelatin shell
should disrupt rapidly and allow the contents to be mixed with the G-I tract contents. The
capsule contents should not be sub=ected to high compression forces which would tend to
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reduce the effective surface area, thus a capsule should perform better than a tablet. This
is not always the case. If a drug is hydrophobic a dispersing agent should be added to the
capsule formulation. These diluents will work to disperse the powder, minimi>e
aggregation and maximi>e the surface area of the powder. Tightly packed capsules may
have reduced dissolution and bioavailability.
85. $ablet dosage forms
The tablet is the most commonly used oral dosage form. It is also 4uite complex in
nature. The biggest problem is overcoming the reduction in effective surface area
produced during the compression process. /ne may start with the drug in a very fine
powder, but then proceeds to compress it into a single dosage unit.
8ngredients
Tablet ingredients include materials to break up the tablet formulation.
"rug H may be poorly soluble, hydrophobic
6ubricant H usually 4uite hydrophobic
Granulating agent H tends to stick the ingredients together
+illerH may interact with the drug, etc., should be water soluble
9etting agent H helps the penetration of water into the tablet
"isintegration agentH helps to break the tablet apart
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,oated tablets are used to mask an unpleasant taste, to protect the tablet ingredients
during storage, or to improve the tablets appearance. This coating can add another barrier
between the solid drug and drug in solution. This barrier must break down 4uickly or it
may hinder a drug0s bioavailability.
9ustained release tablet
Another form of coating is enteric coated tablets which are coated with a material which
will dissolve in the intestine but remain intact in the stomach. (olymeric acid compounds
have been used for this purpose with some success. This topic and the area of sustained
release products has been discussed in more detail in other courses.
Benefits
for short half-life drugs, sustained release can mean less fre4uent dosing and
thus better compliance.
reduce variations in plasmaIblood levels for more consistent result.
Problems
$ore complicated formulation, may produce more erratic results. A sustained
release product may contain a larger dose, i.e. the dose for two or three 2or
more3 0normal0 dosing intervals. A failure of the controlled release mechanism
may result in release of a large potentially toxic dose.
more expensive technology
$pes of products
erosion tablets
waxy matrix
o matrix erodes or drug leaches from matrix
coated pellets
o different pellets 2colors3 have different release properties
coated ion exchange
osmotic pump
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o insoluble coat with small hole. /smotic pressure pushes the drug out
at a controlled rate.
"isintegration time is the time re4uired for the tablet to break down into particles
which can pass through a sieve while agitated in a specified fluid. Indicates the time to
break down into small particles. <ot necessarily solution. In the process of tablet
manufacturer the drug is often formulated into a granular state 2that is small but not fine3
particles. This is done as the granule often has better flow properties than the a fine
powder and there is less de-mixing leading to better uniformity. The granules are then
compressed to produce the tablet. The disintegration test may lead to an end point of
tablet to granule only, although the granules may be larger than the sieve opening.
58. %issolution
The time is takes for the drug to dissolve from the dosage form is a measure of drug
dissolution. <umerous factors affect dissolution. Thus the dissolution medium, agitation
and temperature are carefully controlled. The dissolution medium maybe water, simulated
gastric =uice, or ..$ 1,l. The temperature is usually *7S,. The apparatus and
specifications may be found in the E.;.(. The E.;.(. methods are official however there
is a wide variety of methods based on other apparatus. These are used because they may
be faster, cheaper, easier, sensitive to a particular problem for a particular drug, or
developed by a particular investigator.
"issolution tests are used as 4uality control to measure variability between batches
which maybe reflected by in vivo performance. Thus the in vitro test may be a 4uick
method of ensuring in vivo performance. Thus there has been considerable work aimed at
defining the in vitroIin vivo correlation.
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