Drug delivery factors

DRUG DELIVERY FACTORS
ANUSIKTA GHOSH
18MPH102
M Pharm 2nd Sem

Introduction
• Drugs must be present in a solution form to cross
biologic barriers such as the gastrointestinal
mucosa.
• Thus the process of dissolution is an integral part
of the various rate-limiting steps leading to a
clinical response.
• However, dissolution alone is not sufficient to
provide the absorption of drugs.
• The drug molecules must have the characteristics
required for crossing the various lipoid layers or
membranes in order to reach the general
circulation.

• Lack of sufficient aqueous solubility is usually
the rate limiting step in the dissolution
process & lack of sufficient lipophilic
properties is usually the rate limiting step in
the penetration of lipoid barriers.
• A fine balance is therefore needed between
the hydrophilic and lipophilic properties to
provide optimum delivery of drugs to the site
of action.

• The variations in bioavailability extend to
almost all classes of drugs & as a result the
chemical modifications required for optimum
bioavailability are difficult to summarize.
• For e.g. the bioavailability of many antibiotics
in the same class varies widely.
• Besides chemical modifications, formulation
manipulation also significantly affect the
bioavailability. For e.g. almost 60-fold
differences have been reported in the rates of
absorption of different formulations of
spironolactone.

• An identical variation in the bioavailability
results in a significantly higher variation in the
pharmacologic response of for high potency
drugs when compared with low potency
drugs.
• The purpose of dosage formulation is to
design a dosage form with a suitable
combination of the following attributes:-
1. Contains the labelled amount of drug in an
active form.
2. Is free from extraneous materials.

3. Consistently delivers the drug to the general
circulation at an optimum rate & to an
optimum extent.
4. Suitable for administration through an
appropriate route.
5. Acceptable to patients.
• The dosage form characteristics such as
particle size, salt form, solvent type &
dissolution rate as well as the various
additives all contribute to the dosage form
design.

• The additives may be pharmacologically inert as
with tablet binders and lubricants or they may
have the function of modifying the absorption,
biotransformation or the excretion of the primary
therapeutic agents.
• A large number of formulation factors are
common to many dosage forms & some of these
are summarized below to make the reader aware
f their complexity:
1. The vehicle must be either miscible or spreadable
throughout the biologic tissue before partitioning
& absorption can take place.

2. Sugars in the formulation increase viscosity
delayed gastric emptying & also alter passive
drug diffusion by fluid uptake & other
mechanisms.
3. Various buffer systems affect surface tension, pH
,fluid uptake & this causes altered drug
absorption.
4. Surfactants affect solubility, dissolution, diffusion
across lumen & gastrointestinal membrane
permeability.
5. Complexing agents affect solubility, partition
coefficient can form nonabsorbable complexes.
6. Chelating agents added to retard oxidation affect
intestinal membrane permeability.

7. Dyes absorb on crystal surfaces & often retard
dissolution.
8. Absorbents such as kaolin, talc, activated
charcoal etc. reduce the rate & the extent of
drug absorption.
• In many instances,several different dosage
forms are available for a given drug & an
appropriate selection must be made based on
the attributes listed above. In general the
dissolution & hence absorption of drugs from
the dosage forms depends on the degree of
dispersion.

SOLID DOSAGE FORM
CONSIDERATIONS
• Most pharmaceutical companies would rather
have their new molecule enter the market as a
tablet or a capsule for a variety of safety, cost &
marketing considerations. As a result 70% of all
drugs administered today are in solid dosage
form.
• The typical parameters studied for solid dosage
forms relate to the ability of a powder to mix, to
flow well in manufacturing machines as well as to
the intrinsic characteristics that make it
compressible.

• Some examples of properties studied include:
a) Crystal structures(polymorphs)
b) External shapes (habits)
c) compression properties
d) cohesion
e) Powder flow
f) Micromeretics
g) Crystallization
h) Yield strengths
i) Effects of moisture & hygroscopicity

j) Particle size
k) True, bulk & tapped density
l) Surface area
Particle Size
• The particle size of new drug substance is a critical
parameter as it effects every phase of formulation & its
effectiveness.
• Appropriate particle size is required to achieve optimal
dissolution rate in solid dosage forms, control
sedimentation & flocculation in suspensions, small
particle size(2-5μm) is required for inhalation therapy
content uniformity & uniformity is governed by particle
size.

• As a result the preformulation studies must
develop a specification of particle size as early as
possible in the course of studies & develop
specifications that need to be adhered to
throughout the studies.
• Conventional methods of grinding in mortar or
ball milling or micronization techniques are used
to reduce the particle size.
• The method used can have significant effect on
the crystallinity, polymorphic structures(often to
amorphous forms) & drug substance stability that
can range from discoloration to significant
chemical degradation.

• Changes in polymorphic forms can be determined
by performing X-ray powder diffraction(XPRD)
before & after milling.
• Micronization where possible allows increase in
the surface area to the maximum which can
impact on the solubility, dissolution & as a result,
bioavailability.
Surface area
• Since the area exposed to the site of
administration determines how fast a particle
dissolves in accordance with the Noyes-Whitney
equation, these determinations are important.

• In addition, in those instances where the
particle size is difficult to measure a gross
estimation of the surface area is the second
best parameter to have to characterize the
drug. The most common methods of surface
area measurement including gas
adsorption(nitrogen or krypton) based on
what is most commonly described as the
Braunauer,Emmet & Teller or BET, method
applied either as a multipoint or single point
determination.

Porosity
• Most solid powders contain a certain void volume
of empty space. This is distributed within the
solid mass in the form of pores, cavities & cracks
of various shapes & sizes. The total sum of void
volume is called porosity. Porosity strongly
determines important physical properties of
materials, predicting their behavior.
• There are two main & important typologies of
pores: closed & open pores.
• Closed pores are completely isolated from
external surface not allowing the access of
external fluids in neither liquid nor gaseous
phase.

• Closed pores influence parameters like
density, mechanical & thermal properties.
• Open pores are connected to the external
surface & are therefore accessible to fluids,
depending on the pore nature/size & the
nature of fluid.
• Open pores are further divided in dead –end
or interconnected pores.

• The characterization of solids in terms of
porosity consists in determing the following
parameters:
1. Pore size:- pore dimensions cover a wide
range. Pores are classified according to three
main groups depending upon the access size:
a) Micro pores – less than 2nm diameter
b) Meso pores – between 2 & 50 nm diameter
c) Macro pores – larger than 50nm diameter.

2. Specific pore volume & Porosity: The internal void
space in a porous material can be meaured. It is
generally expressed as a void volume(in cc or mL)
divided by a mass unit(g).
3. Pore size distribution:- it is generally represented as the
relative abundance of the pore volume (as a
percentage or a derivative) as a function of the pore
size.
4. Bulk Density:- Bulk density (or envelope density) is
calculated by the ratio between dry sample mass & the
external shape volume.
5. Percentage porosity:- the percentage porosity is
represented by ratio between the total pore volume &
the external (envelope) sample volume multiplied by
100.

6. Surface area:- Since the surface area exposed to
the site of administration determines how fast a
particle dissolves in accordance with the Noyes-
Whitney equation, these determinations are
important.
In addition, in those instances where the particle
size is difficult to measure a gross estimation of
the surface area is the second best parameter to
have to characterize the drug. The most common
methods of surface area measurement including
gas adsorption(nitrogen or krypton) based on
what is most commonly described as the
Braunauer,Emmet & Teller or BET, method
applied either as a multipoint or single point
determination.

7. True density:- density is the ratio of the mass of an
object to its volume & for solids it describes the
arrangement of molecules.
The study of compaction of powders is described by
the Heckel equation:
ln[1/1-D]=KP+A
where D= relative density of a powder
P= compact at pressure P.
Constant k= measure of the plasticity of a
compressed material.
Constant A= die filling & particle rearrangement
before deformation & bonding of the discrete particles.
Thus a Heckel plot allows for the interpretation of the
mechanism of bonding.

• Information of the true density of a powder
can be used to predict whether a compound
will cream or sediment in a suspension such as
a metered dose inhaler(MDI) formulation.
Therefore suspensions of compounds that
have a true density less than these figures will
cream(rise to the surface), & those that are
denser will sediment.
• The true density is a property of the material
& is independent of the method of
determination.

• In this respect,the true density can be
determined using three methods:
displacement of a liquid
displacement of a gas(pycnometry) or
floatation in a liquid
• The liquid displacement is tedious & tends to
underestimate the true density, displacement of
a gas is more accurate but needs relatively
expensive instrumentation. As an alternative, the
floatation method is simple to use & inexpensive.

FLOW AND COMPACTION OF
POWDERS
• The flow properties of powder will determine
the nature & quantity of excipients needed to
prepare a compressed or powder dosage
form.
• This refers to factors such as ability to process
the powder through machines.

1. Electrostaticity:- When subjected to attrition, powders can
acquire an electrostatic charge, the intensity of which is
often proportional to physical force applied as static
electrification of two dissimilar materials occurs by the
making & breaking of surface contacts.
Electrostatic charges are often used to induce adhesive
character to bind drugs to carrier systems, e.g. glass beads
coated with HPMC containing drugs. The net charge on a
powder may be either electropositive or electronegative
depending on the direction of electron transfer.
The mass charge density can vary from 10^-5 to 100μC/kg
depending on the stress, ranging from gentle seiving to
micronization process.This can be determined using
electric detectors to determine polarity as well as the
electrostatic field.The electrostaticity results in significant
changes in the powder flow properties.

2. Caking:- Powders cake due to agglomeration as a result
of factors such as static electricity, hygroscopicity,
particle size, impurities of the powder & storage
conditions like stress temperature, relative
humidity(RH) & storage time etc.
The mechanism involved in caking are based on the
formation of five types of interparticle bonds such as
bonding resulting from the mechanical tangling,
bonding resulting from steric effects, bonds via static
electricity, bonds due to free liquid & bonds due to
solid bridges.
During the process of micronization, the formation of
localized amorphous zones can lead to caking as these
zones are more reactive to factors described above
specially when exposed to moisture.

3. Polymorphism:- Because polymorphism can have an
affect on so many aspects of drug development, it is
important to fix the polymorph (usually the stable
form) as early as possible in the development cycle.
Whereas it is not necessary to create additional solid
state forms by techniques or conditions unrelated to
the synthetic process for the purpose of clinical
trials,regulatory submission of a thorough study of the
effects of solvent,temperature & possibly pressure on
the stability of the solid state forms is advised.
A conclusion that polymorphism does not occur with a
compound must be substantiated by crystallization
experiments from a range of solvents. This should also
include solvents that may be involved in the
manufacture of the drug product, e.g. during
granulation.

4. Powders:- The formulation & bioavailability
problems associated with suspensions are also
characteristics of powders, whereby the active
ingredient is mixed with inert diluents &
administered either directly or in a capsulated
form.
An additional problem therefore arises due to
possible adsorption of drugs onto diluents, from
which the drug may not be released quickly
enough for adequate absorption.
For e.g. only 40% of thiamine & 79% of riboflavine
are available for absortion from capsules
containing Fuller’s earth which adsorbs these
drugs.

continued….
• The particle size of powders is significant in their
dissolution& bioavailability, as demonstrated by
spironolactone & griseofulvin, the micronization of
which leads to significantly higher absorption in
humans. However smaller particle powders have a
greater tendency to adsorb moisture from the
atmosphere, which results n possibly unstable
preparations. Smaller particle size also means
increased electrostatic charges on the particle surface,
especially with hydrophobic drugs.This might result in
aggregation & the consequent loss of an effective or
exposed surface area for dissolution. An example in
which smaller particle size is not always desirable even
though it does not increase bioavailability, is in the use
of nitrofurantoin.

5. Tablets:- Complexities in dissolution & bioavailability
are generally inversely proportional to the degree of
dispersion-compressed tablets & thus most prone to
bioavailability problems. This is primarily due to
smaller surface area exposed for dissolution until the
tablets breakdown into smaller particles. Factors
responsible for the primary breakdown of tablets into
granules & their subsequent breakdown into finer
particles include such parameters as the
concentrations of binder, disintegrant & lubricant. The
hydrophobicity of the drug & adjuvants; therefore it
can be expected that a significant difference is always
possible in the dissolution & bioavailability of various
tablets. The problem of disintegration is well
demonstrated for drugs such as dipyridamole,
thioridazine & digoxin which exhibit higher blood levels
if the tablets are crushed before administration.

Continued…
• Film coatings are generally less problematic,
but enteric coating used to protect both the
gastric mucosa from the drigs & drugs from
the gastric fluids give most variable
bioavailability, since their disintegration is
often dependent upon the gastrointestinal pH
& other highly variable physiologic &
physicochemical factors.

6. Solutions:- Solutions are thermodynamically stable
monomolecular dispersions of drug molecules in liquid or
solid phase. Absorption from aqueous solutions is generally
very fast & complete from all sites of administration,
provided that penetration through the absorption barrier
(such as the gastrointestinal membrane) is not a rate
limiting factor. The rate limiting steps like disintegration &
dissolution are minimal in the case of solutions.For e.g.
potassium penicillin V give higher blood levels than
benzathine penicillin V when both are administered orally
in tablet form, but solutions of these two drugs yield
essentially equal blood levels of penicillin.
In some instances the use of solutions is a crucial part of the
drug delivery. For example calcium must be administered as
a solution in its citrate form to achlorhydric patients, since
the solid carbonate form will not dissolve sufficiently in the
gastrointestinal tract without the presence of hydrochloric
acid.

7. Solubility:- Where a solution form is desired & the
compound has low solubility, there are several
techniques, some very simple to some very complex,
to achieve the desirable property of the lead drug
including pH manipulation, use of cosolvents,
surfactants, emulsion formation & adding complexing
agents. On a more complex stage, the liposomes or
similar drug delivery systems can be used.
Since many compounds are weak acids or weak bases
their solubility will then be a function of pH. However
ionic strength of medium plays a significant role & as a
result most parentral formulations are buffered to
prevent crystallization of drugs. The use of cosolvents
improves the solubility as a result of the polarity of the
cosolvent mixture being closer to the drug than it is in
water.

Continued…..
log Sm = f log Sc +(1-f)log Sw
where Sm = solubility of the compound in the
solvent mix.
Sw= solubilty in water.
Sc = solubility of the compound in pure
cosolvent.
f= the volume fraction of cosolvent
σ= the slope of the plot of log(Sm/Sw)
versus f.

Continued……
There is a definite correlation between the S value
to indices of cosolvent polarity such as the
dielectric constant, solubility parameter, surface
tension, interfacial tension & octanol-water
partition coefficient.
The aprotic cosolvents give a much higher
degree of solubility than the amphiprotic
cosolvents. This means that if a cosolvent can
donate a hydrogen bond, it may be an important
factor in determining whether it is a good
cosolvent. Use of cosolvents with polar drugs can
reduce the solubility.

8. Emulsion formulations:- For drugs with poor
solubility & emulsion formulation such as oil-in-
water(o/w) where the drug has good partitioning
in the oil phase chosen offers an excellent choice.
The particle size & its stability (physical &
chemical) then become significant factors since
larger globule sizes may lead to phlebitis. To
achieve smaller particle size the technique of
microfluidization is often used among other such
homogenization available methods.
Phospholipids added stabilize emulsions through
surface charge changes as well as providing a
good mechanical barrier.

9. Suspensions:- Where the drug has limitations in
its solubility & efforts to enhance fail, where
there is a tendency for fast crystallization from
solutions or even where chemical stability is a
problem, often formulating suspension dosage
forms obviates some of these drawbacks.
Suspension by nature must have higher viscosity
to prevent settling of particles & thus create
problems in pourability, syringability, etc.
Appropriate selection of a vehicle that provides
an ideal compromise among all characteristics
thus becomes a critical factor because the intent
is to have as little solubility in the vehicle as
possible to prevent crystallization from the
solution that surrounds the suspended particles.

Continued….
A significant thermodynamic problem in suspension
formulation comes from Ostwald ripening, crystal
growth, not due to phase change but as a result of
differences in the solubility as a function of crystal size:
RT/M ln(S2/S1)= 2σ/ρ(1/r1-1/r2)
where R = gas constant
T = absolute temperature
S1, S2 = solubilities of crystals of radii
r1 & r2
σ = specific surface energy
ρ = density
M = molecular weight of the solute molecules

Temperature fluctuations are obviously one factor that promotes
Ostwald ripening. Whereas phase changes can be studied using
standard techniques as DSC, hot stage microscopy or XRPD.
Ostwald ripening is best studied using microscopic methods.
The art of suspension formulation is complex as large number of
factors including additives can have significant influence on crystal
growth; for e.g. dyes molecules often attach to high-energy points
on crystals affecting their growth; similarly it is reported that PVP a
common ingredient of many suspension formulation inhibits crystal
growth. The choice of additives is also governed by the final form of
suspension; if it has to be sterilized the additives must be able to
sustain autoclave temperatures. Besides autoclaving it can affect
both physical & chemical stability of the drug. Zeta potential
measurements of suspension often prove useful. Suspensions will
provide better absorption than such other dosage forms as capsules
& tablets such as shown by trimethoprim & sulfamethoxazole
combinations & sulfadimethoxine.
Continued

Continued…
Suspensions are also used when a slow release of the drug is
desired, as with intramuscular administration of
triaminocolone acetonide or with tetracycline ophthalmic
suspensions.
A majority of official oral suspensions in current use involve
antiinfective agents, e.g. thiabendazole, chloramphenicol
palmitate, oxytetracycline, penicillin, tetracycline etc. Most
of the anti infective agents are chemically unstable & can
cause gastrointestinal irritation, often erratically absorbed
from such solid dosage forms as tablets & capsules. The use
of suspensions is also advantageous in pediatric or geriatric
practice, where they can be accurately & conveniently
administered using droppers or oral syringes. Suspension
dosage form are utilized for all routes of administration
except intravascular.

CONTROLLED- RELEASE DOSAGE
FORMS
• Unless specific formulation efforts are made to control
the release of drugs the rate of drug absorption are
generally proportional to the amount of drug at the
site of absorption.
• The design of oral prolonged-action dosage forms
include modifications such as:-
1. Barrier coating, whereby the drug diffuses out
through a membrane within which it may be
dissolved by the penetrating gastrointestinal fluids.
2. Fat embedment, which involves suspending the drug
in a fatty medium in a solid dosage form from which
the drug is released by erosion, hydrolysis of fat &
direct dissolution.

Continued….
3. Repeat action tablets, utilizing a double coating
which releases an intial dose followed by another
dose released either instanteneously or by slow
diffusion.
4. Ion exchange resins, which provide prolonged
dissolution by the formation of drug salts with
resins, which then react with HCl acid in the
stomach or NaCl in the intestine to exchange the
drug.
5. Hydrophilic matrices, utilizing hydrophilic gums
for compression of tablets which undergo gelatin
formation & release the drug by diffusion.

Continued….
The release of drugs administered parenterally
can also be controlled by the following methods:-
1. Pharmacologic methods- Intramuscular or
subcutaneous administration instead of
intravenous. Simultaneous administration of
vasoconstrictors (adrenaline or ephedrine)
blocking elimination of drugs through the kidney
by simultaneous administration of a blocking
agent such as the penicillin, probenecid or para
amino salicylic acid.
2. Chemical methods- Use of salts, esters,
ethers,complexes of the active ingredient with
low solubility.

Continued…
.3. Physical methods- Selection of a proper vehicle
giving prolonged release as with the use of
oleaginous solutions instead of aqueous solution;
the addition of macro molecules which increase
the viscosity, such as
carboxmethylcellulose(CMC), tragacanth etc; the
use of swelling material to increase the viscosity
of oleaginous solutions as with aluminium
monostearate; the addition of absorbents; the
use of solution from which the drug is
precipitated upon contact with body fluids; the
use of aqueous & oleaginous suspensions & the
use of implants.

Therapeutic Systems
• Several dosage forms, termed Therapeutic
Systems, have recently been marketed.
• The Therapeutic System is a dosage form that
provides preprogrammed, unattended delivery of
drugs at a rate & for a given period of time,
designed to meet a specific therapeutic need.
These systems have been developed for
introducing drug substances both via the systemic
circulation & directly to specific target organs.

Continued….
• Many new drug delivery techniques have been developed,
including:
1. Diffusion of drugs through rate controlling membranes.
2. Osmotic pumping
3. Biodegradable polymer matrices
4. Polymer- bound active species
5. Nanosystems
• The Therapeutic Systems are composed of an active drug
in a delivery module, which consists of adrug reservoir,
which may be a single or multicompartment element; a
rate controller; & an energy source to release the drug
molecules through a delivery orifice. The drug delivery
module is housed in a “platform” which is compatible
with the tissues & couples the system to the body site in
which it is deployed.

Continued…..
• The platform may be either fixed or mobile within a
defined area.
• Some e.g. include ocular platform which is designed so
thatit can be able to float comfortably &
inconspicuously in the tear film on the eye beneath the
eyelid for controlled delivery of (Ocusert); & the T-
shaped progesterone impregnated polymer unit for
intrauterine deployment for fertility
control(Progestasert)
• Other novel ideas include a transdermal therapeutic
system consisting of a disc of 0.2mm thick & 2cm in
diameter which is worn behind the ear like a tiny
adhesive bandage & releases scopolamine for its
antemetic properties & the use of nitroglycerin patches
for angina pectoris.

EVALUATION OF DRUG DELIVERY
SYSTEMS
• It is not possible to predict if the administered dose will
result in a consistent desirable therapeutic response.
However, several tests can be conducted to assure some
measure of reliability in dosage form functions. These
include the following:
1. Chemical content:- It is essential that the dosage form
contains the labeled amount of the active drug. Chemicals
which are biologically active & are also highly reactive can
therefore undergo chemical decomposition reactions
which result in a loss of content. For e.g. aspirin
decomposes to salicylic acid & acetic acid. Salicylic acid is
undesirable because it causes more gastrointestinal
irritation than aspirin & also because it may not posses a
therapeutic activity equivalent to aspirin.

Continued…
2. Content Uniformity:- The chemical
equivalence testing described above is
generally performed on a large number of
dosage form units(e.g. 20tabs) at one time.
This testing determines the average amount of
active ingredients. It will not however reveal
variations in drug content among the units.
The problem of content uniformity therefore
exists for all products containing minute
amounts of active ingredients as shown in
table:-

Continued….
TABLETS CONTAININGACTIVE DRUG
COMPONENT
DRUG AVAILABLE TABLET STRENGTH
Atroping Sulfate 0.3
Colchicine 0.5
Dexamethasone 0.25
Diethylstilbesterol 0.1
Ethinyl estradiol 0.05
Digitoxin 0.05
Digoxin 0.125

Continued…
• The problems of content uniformity mainly arises from
the mixing of small amounts of drugs into large batches
where a uniform distribution must be assured.
3. Disintegration test:- The disintegration test ascertains
the time required for a compressed tablet to break up
into granules. The first official disintegration test was
included in Pharmacopeia Helvetica in 1934.
A large number of formulation factors can affect the
rate of tablet or capsule disintegration including,
a) Diluents or Fillers
b) Hardness

Continued…4.Dissolution test:- A dissolution is much more discriminating than the
disintegration test. It is a better estimate of bioavailability, though it
is still not full proof. Dissolution rate test can be used to predict
bioavailability if these two conditions are met:
a) The dissolved drug remains free & intact in the gastrointestinal
tract. If the dissolved drug complexes with a component of the
gastrointestinal tract & if the drug decomposition occurs in the
gastrointestinal tract then the dissolution test cannot be a very
good index of bioavailability.
b) Absorption is not the rate-limiting step. If the solution formed is
quickly absorbed then the amount absorbed can be correlated
with the in vitro dissolution rate. However, when absorption is
slow or limited, bioavailability may not be proportional to the
dissolution rate.

Continued…
• The fillers & diluents used in a formulation have a
significant effect on its dissolution. If the drug is
hydrophobic a hydrophilic filler will tend to enhance
dissolution, especially if the filler is at the same time
disintegrant. Starch has hydrophilic property & at the same
time is an effective disintegrant & thus proves to be an
excellent filler.
• The effect of compression pressure on dissolution rates is
the most difficult to predict. Dissolution rates will generally
decrease with increasing compression pressure due to a
closer binding of the granules to each other. At higher
pressure a crushing of the granules & perhaps even of the
drug crystals would occur, resulting in an increased surface
area & an increased dissolution rate. A further increase in
the pressure may make the bonding more important

Continued…
than the crushing resulting in a decrease in the dissolution
rates. Where the bonding is not significant, a direct
increase in the dissolution rates can be expected with
increasing compression pressure at higher pressures.
• The effect of tablet storage on the dissolution rates can also
be important & reports have been made suggesting both
increasing & decreasing dissolution rates.
• In view of the importance of dissolution tests in predicting
drug bioavailability, the official compendia continues to
require dissolution tests as part of the regulatory
requirements such as for acetohexamide, nitrofurantoin,
digoxin, phenylbutazone, ergotamine tartarate & caffeine
tablets, Prednisolone, Hydrochlorthiazide, Prednisone,
Lithium carbonate etc.

Continued…..
5. Absorption principles:- When a drug is introduced into the
gastrointestinal tract & is presen tin forms which can be
absorbed, the process of absorption may be categorized as
either passive diffusion or active transport.
a) Passive diffusion:- This process describes the movement
of drug molecules from a region of high relative
concentration to a region of lower relative concentration.
It also includes the movement of ions from a region of
high ionic charge of one type to a region of lower charge
of the same type or of opposite charge:
dXa/dt = -DA(Cgut-C) where Xa is amount of drug at the
absorption site; D is diffusion coefficient; A is area of
absorption surface; Cgut is concentration of drug in the
gastrointestinal tract; C is concentration of drug in the
plasma.

Continued….
b) Active transport:- Active transport is a specialized
process which requires the expenditure of
energy. The various active transport processes
found in the GIT are relatively structure specific &
serve primarily in the absorption of natural
substances, such as monosaccharides, 1-amino
acids, pyrimidines, bile salts & certain vitamins.
The anticancer drug 5-fluorouracil is an example
of an actively transported drug. It is similar in
structure to the natural substance uracil, which is
absorbed by means of the pyrimidine transport
system.

Continued…
• The other absorption principles are
c) Solvent drag
d) Facilitated Transport
e) Ion-pair Transport
f) Pinocytosis.

Continued….
6. Absorption factors:- The gastrointestinal tract is composed
of heterogeneous anatomic regions. As drug molecules
descend through the gastrointestinal tract, they encounter
different environments which vary in pH, nature &
concentration of enzymes, fluidity of contents as well as in
the area available for absorption.
7. Gastrointestinal Fluids:- Drugs must dissolve in the
gastrointestinal fluids before they can be absorbed; poorly
water soluble drugs have therefore inherent problems in
their bioavailability. Any changes in the composition of
gastrointestinal fluids such as inceased viscosity due to
ingestion of meal can reduce the dissolution of drugs. A
moderate volume of fluid is also essential for optimal
absorption since in addition to providing dissolution it also
helps spread the drug over a larger area for absorption.

Continued…
The pH of the gastrointestinal fluids varies
from about 1 to 3 in the stomach & about 8 in
the large intestine. The factors which affect
the pH include:
a) Type of diet
b) Use of soft drinks
c) Stress
d) Gastrointestinal disease
e) General health.

Continued…
8. Gastric emptying:- The gastric emptying rates affect the
absorption rate primarily because of the pH differences
between the stomach & intestine. For example, weakly
basic drugs such as amphetamine & codeine will be
absorbed primarily from the small intestine rather than
from the stomach & any delay in the gastric emptying will
tend to delay the absorption & thus the therapeutic
response. Slow gastric emptying will tend to delay the
absorption & thus the therapeutic response.
Some of the factors which affect the gastric emptying rates
are as follows:
a) Type of food
b) Volume of fluid or food
c) Osmotic pressure
d) Acidity

e) Food temperatures
f) Viscosity
g) Psychologic state
h) Body posture
i) Drugs
j) Intestinal transit
k) Blood flow
Continued…

9. Gastrointestinal Drug Biotransformation:- The bioavailability of
orally administered drugs can be affected due to biotransformation
in the gastrointestinal tract & the various organs(e.g. the liver)
through which the drug molecules pass before reaching the general
circulation. For e.g. the chromotropic activity if isoproterenol is
about 1000 times greater when administered intraveneously than
through oral administration, largely due to the biotransformation of
isoproterenol into an inactive sulfate during the transfer across the
gut wall & passage through the liver.
10. Food Interactions:- Food affects drug bioavailability by several
mechanisms including:
a) Changes in gastric & intestnal transit times
b) Increased gastointestinal secretions
c) Adsorption of drug onto food
d) Competition of food components with drug for absorption
e) Physicochemical interactions between food & drug
f) Increased viscosity of gastrointestinal fluids.
Continued…

Several aspects must be considered in studying the effect of food on
the bioavailability of drugs:
a) Food induces changes in the gastric emptying rate, intestinal
transit time &/or in gastroenterohepatic secretion of HCl,
bicarbonate enzymes & bile.
b) Specific food components & contaminants can alter metabolic
transformation of drugs in the gut & in the liver.
c) Food refers to different kind of meals & that one type of meal or
food component may have both qualitatively & quantitatively
different effects on drug bioavailability than other
d) Different preparations of same drug may interact differntly with
food.
e) Findings based on single meal, single dose studies in healthy
volunteers may not necessarily be relevant as to food effects on
the steady plasma level of drug during its long term use in
patients.
Continued…

11. Pathophysiologic Disorders:- Drug bioavailability is significantly
alteredin the presence of various pathophysiologic disorders. The
fllowing are some specific observations. Alterations in gastric Ph
have following implications:-
a) pH partitioning & dissolution of poorly soluble drugs can be
significantly affected, e.g. aspirin is better absorbed in
achlorhydric patients
b) Changes secondary to pH change may include epithelium integrity
& blood flow rates which can directly affect the rate & extent of
drug absorption.
c) Stability of acid labile drugs can be significantly altered.
d) Several disease states including gastric cancer have been
identified when the gastric pH is elevated.
A variety of drugs administered to treat pathophysiologic orders
show interaction resulting in alteration of absorption.
Continued…

12. Age:- several gastrointestinal functions
mature with age including specialized
absorption mechanisms. For e.g. sugar
absorption is very inefficient in younger
children. Whereas significant changes in the
structural & the functional properties of
gastrointestinal tract & blood flow occur in the
elderly, no studies have demonstrated
changes in the bioavailability of drugs in the
elderly.
Continued…

13. First Pass Biotransformation:- A distinction can be made between
the biotransformation in the intestine & in the liver during the first
pass by administering the drugs either intraperitoneally or directly
into the portal vein. The hepatic clearance of drugs depends on two
factors:-
a) Blood flow to liver
b) Capacity of liver to remove drug.
14. Sublingual/Buccal Administration:- Some drugs are administered by
placing them beneath the tongue or in the cheek pouch. A rapid
absorption of the drugs is thereby generally expected due to high
vascularity of this region. A significant advantage of this route is
that gastrointestinal degradation & biotransformation are
bypassed along with hepatic first pass biotransformation. A variety
of drugs can be administered through this route like nitrates,
hormones like methyltesterone, testosterone propionate &
oxytocin.
Continued…

15. Rectal Administration:- Some drugs are
administered rectally either in suppository or in
solution form, e.g. retention enema. The
suppositories are the most commonly used
dosage forms for both systemic & local effect.
Examples of drugs administered rectally for
systemic action include aspirin, diazepam,
theophylline, barbiturates.
The absorption mechanism mainly involves
passive diffusion with no sites for active
transport. The use of enema before drug
administration generally increases the absorption
significantly.
Continued…

16. Intravenous administration:- The direct administration of drugs into veins
is the only route where bioavailability considerations are not relevant. This
route provides an almost instantaneous response with controllability of
the rate of drug input into the body. This route is especially suitable for
those drugs which cannot be absorbed adequately from the
gastrointestinal tract or tissue depots(e.g. intramuscular administration)
or where there is a significant first pass effect upon oral administration.
The drugs which are intolerably painful in the subcutaneous or muscle
tissues by virtue of their irritant properties may be injected slowly into a
vein without much difficulty e.g. nitrogen mustard in cancer
chemotherapy.
17. Intra arterial administration:- This route is used for the injection of
substances used in diagnosis. A typical injection is the injection of a
radiopaque compound into the carotid artery to trace the circulation of
brain by roentgnography. In addition,certain specialized techniques in
cancer chemotherapy call for regional infusion of drugs by arterial routes,
which may provide a significant advanyage over other routes.
Continued…

18. Intra muscular administration:- More than 50% of hospitalized
patients receive intra muscular drug administration. The popularity
of this route is that it decreases the hazard of administration when
compared with the intravenous route. Large volumes of solutions
can be injected(2-10mL) by this route. The side effects of IM
administration include pain elevation of serum creatine
phosphokinase as a result of trauma & often sciatic nerve damage
following gluteal injections. Other complications include skin
pigmentation, hemorrhage, septic or sterile abcesses, cellulitis,
gangrene etc.
19. Subcutaneous Administration:- The factors affecting intramuscular
drug absorption also determine subcutaneous drug availability. The
blood flow rates are poorer than in muscles & so are the rates of
absorption. Yet some drugs are absorbed as rapidly from a
subcutaneous site as from intramuscular administration e.g. anionic
dye, insulin.
Continued…

20. Percutaneous Administration:- The absorption of drugs through the skin
should be difficult since the function of the skin is to act as a barrier
between the outside environment & the vulnerable tissues under the skin.
Yet drugs are absorbed, sometimes quite efficiently from the skin.
21. Pulmonary administration:- Drugs can be introduced into the pulmonary
system as gases or in aerosol forms. An almost instantaneous absorption
can be expected due to the extremely large surface area available for
absorption. The primary mechanism of absorption is passive diffusion but
lipid solubility tends to play a smaller role in the gastrointestinal
absorption.Most of these drugs are administered as aerosols & their
delivery to a great extent is dependent on the particle size distribution. In
order for a drug to be absorbed from an aerosol its particle must impact ,
preferably in the alveolar sacs & dissolve in the available fluids. Pulmonary
administration has been used mainly for local therapy. For e.g. aerosols of
epinephrine, isoproterenol, dexamethasone are commonly used for acute
asthmatic attacks & antibiotics are sometimes incorporated for the
treatment of complicated bronchopulmonary infections.
Continued…

22. Ophthalmic administration:- As with permeability in
most other routes of administration, the permeability
of drugs into & through the cornea is function of their
lipoid & aqueous solubility. The cornea is composed of
three distinct layers The outer epithelium, an inner
stroma & the endothelium. The epithelium &
endothelium are much more lipoidal than stroma.
Therefore drugs must posses biphasic solubility
characteristics in order to be absorbed through this
route. Weakly basic drugs such as tropicanade,
epinephrine, pilocarpine, atropine, freely penetrate the
cornea because of rapid equilibration between their
lipid soluble unionized form & their water soluble
ionized form.
Continued…

23.Nasal administration:- The nasal cavity provides an ideal
opportunity for the delivery of drugs. The nasal mucose has high
vascularity & offers very little formability of local biotransformation.
The pH of the surface is 7.2 & the drugs are generally absorbed by
passive diffusion based on their lipid solubility. A number of drugs
are administered intranasally for their local effects such as an
antibiotics, decongestants, antihistamines.
Drug developers & researchers are discovering that the accessibility
& the vascular structure of the nose make nasal drug delivery an
attractive method for delivering both small molecule drugs &
biologics, systemically as well as across the blood-brain-barrier to
the CNS.
Recent developments have suggested that insulin, contraceptives,
promabotol, lorazepam & several steroid hormones, vaccines can
be administered intranasally for their systemic effects.
Continued…

24. Miscellaneous routes:- Drugs are also administered
through such routes as urethra, vagina, spinal cord. For e.g.
urethral suppostories are frequently used for treatment of
localized infections. Anaesthetics are often administered in
the spinal fluid as are other drugs on occasion for localized
effect. Recent studies suggest that vaginal administration of
drugs for systemic effect may be a valid alternative to rectal
or even oral administration because of fast & comlete
absorpton from this site. Direct controlled delivery of
fertility controlling hormones have been succesfully made.
Smart dosage forms embedded with electronic sensors are
likely to make drug delivery systems more controllable from
outside of the body opening up an entirely new area of
bioequivalence testing.
Continued…

REFERENCE
• Handbook of Bioequivalence Testing, Ch 8:-
Drug Delivery Factors, By Sarfaraz K Niazi.

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