Dr.

Ghalib Albaaj
Phd Pharmaceuticals
Carol Davila university
bucharest /Romania
 Is
the science that study relation of
physicochemical properties of
drug, dosage form, & route of
administration on rate and
extent of drug absorption.
 It is the study of the kinetics of
absorption, distribution, metabolism,
and excretion (ADME) of drugs and
their pharmacologic, therapeutic, or
toxic effects in animals and man.

 drugs given IV go directly into blood.

 elimination refers to both metabolism and.
excretion.
 drug in blood exists in equilibrium with drug in
tissues.
 In equilibrium concentration of the drug in blood
different (greater or lesser) than the concentration of the
drug in tissues. This is due to the physicochemical
properties of the drug.


 the rate of transfer of a drug from one compartment

to another is proportional to concentration of the
drug in the compartment from which it exits; the
greater the concentration, the greater is the amount
of drug transfer.
 During metabolism a drug substance may be
biotransformed into:
1. pharmacologically active,
2. inactive metabolites,
3. or both.
For example, anticonvulsant drug carbamazepine is
metabolized in the liver to active epoxide
metabolite.
 metabolism of drug to inactive products is
irreversible process.
 (kel) : elimination rate constant for drug describe
its rate of elimination from body.
Passive Diffusion:
1. From high to low concentration
2. depends on the molecule's lipid solubility, particle
size, degree of ionization, and area of absorptive
surface.
3. Primary mechanism for most drugs
4. No need for energy or carrier.

 Fick's law of Absorbtion, drug molecules
diffuse from a region of high drug concentration
to a region of low drug concentration.

 Where dQ/dt = rate of diffusion, D = diffusion

coefficient,
 K = lipid water partition coefficient
 A = surface area of membrane;
 h = membrane thickness, and
 CGI – C p = difference between the concentrations
of drug in the gastrointestinal tract and in the
plasma.
 Because D, A, K, and h are constants under
usual conditions for absorption, a combined
constant P or permeability coefficient may be
defined.

 drug concentration in plasma, C p, is

extremely small compared to the drug
concentration in the gastrointestinal tract, C
GI. If C p is negligible and P is substituted
1. From high to low concentration
2. Need Carrier in the membrane
combines reversibly with the
substrate molecule outside the cell
membrane
3. No need for energy.
4. specific molecular configuration
5. Limited number of carrier
1. Against concentration gradient.
2. selective,
3. requires energy
4. limited to drugs structurally similar to
endogenous substances (eg, ions, vitamins,
sugars, amino acids).
5. These drugs are usually absorbed from
specific sites in the small intestine.
 The process by which a drug particle dissolves.
For a drug to be absorbed, it must first dissolved in the
fluid at absorption site.
 As a drug particle undergoes dissolution, the drug
molecules on the surface are the first to enter into
solution, creating a saturated layer of drug solution that
envelops the surface of the solid drug particle. This layer
of solution is the diffusion layer.
 From diffusion layer the drug molecules pass throughout
the dissolving fluid and make contact with biologic
membranes, and absorption ensues.
 If dissolution is rapid or if the drug is
administered as a solution the rate at
which the drug becomes absorbed depends
mainly on its ability to traverse the
membrane barrier.
 If dissolution slow because of the
physicochemical characteristics of the
drug substance or dosage form,
dissolution is a rate-limiting step in
absorption.
 Drug remain in stomach :2 to 4 hours.
 In small intestine: 4 to 10 hours.
Various techniques used to determine gastric
emptying time like:
 Gamma scintigraphy: tracking dosage forms
labeled with gamma-emitting radionuclides.
 The gastric emptying time for a drug is
rapid with fasting stomach.
1. slower as food content is increased.
Changes in gastric emptying time or intestinal
motility can affect drug transit time and thus
opportunity for drug dissolution and
absorption.
a. anticholinergic drug, slows gastric emptying.
Which increases drugs absorption from stomach
and reduce drugs absorption from small intestine.

b. drugs that enhance gastric motility, for example,

laxatives, reduce amount of drug absorbed.

c. Aging decrease absorption (geriatrics)

 decrease in gastric emptying time is advantageous for

drugs absorbed from stomach but disadvantage for
drugs prone to acid degradation, like penicillins and
erythromycin, or inactivated by stomach enzymes, like
L-dopa.
 Rate of dissolution described by Noyes-Whitney
equation :
 where
 dw/dt is the rate of dissolution,
 D is the dissolution rate constant,
 A is the surface area of dissolving solid,
 cs is saturation concentration of drug in
diffusion layer (which may be approximated
by the maximum solubility of the drug in the
solvent, because the diffusion layer is
considered saturated), and
 ct is the concentration of the drug in
dissolution medium at time t (cs - ct is
concentration gradient).
 L: length of diffusion layer.
 rate of dissolution governed by rate of diffusion of solute
through diffusion layer.
dissolution rate increased by:
1. increasing surface area (reducing the particle size),
2. by increasing the solubility of drug in diffusion layer, by factors
embodied in dissolution rate constant, D, including the intensity of
agitation of the solvent and diffusion coefficient of dissolving
drug. For a given drug, the diffusion coefficient and usually
concentration of the drug in diffusion layer will increase with
increasing temperature.
3. Increasing rate of agitation of the dissolving medium
will increase the rate of dissolution.
4. reduction in the viscosity of solvent enhance dissolution rate
of a drug.
5. Changes in pH or nature of solvent that influence the solubility
of the drug may be used to increase dissolution rate.
 for acidic drugs

unionized
pH= pKa + log ionized for basic drugs
 Drug movement not always affected by pH.
 Very weak acids and bases completely non ionized at
physiological p H ,their transfer rapid and independent
of p H. .
 strong acids and bases are completely ionized and so
their transfer is usually slow and pH-independent.
 drugs include acids within the pK range 3 to
7.5 and bases in the pK range 7 to 11
 Stomach pH: 1-2
 Duodenum pH: 2-4
 Small intestine pH: 4-6
 Large intestine 6-7.8
Surface area
 When a drug particle is broken up, surface
area increased. For drug substances that are
poorly or slowly soluble, this generally
results in increase in the rate of dissolution.

 To increase surface area, use micronized

powders in their solid products. micronized
powders consist of drug particles reduced in size
to about 5 µm and smaller.
 Solid drug materials may occur as crystalline or amorphous.
 Amorphous usually more soluble than crystalline form, different
extents of drug absorption :
 antibiotic chloramphenicol palmitate, are inactive when
administered in crystalline, but when administered amorphous,
absorption from GIT rapidly, with good therapeutic response.

 In other instances: crystalline forms of drugs may be used

because of greater stability than amorphous forms.
For example, the crystalline forms of penicillin G as potassium
salt or sodium salt are more stable than amorphous forms.
Thus, in formulation work on penicillin G, the crystalline forms
are preferred and result in excellent therapeutic response.
 The amorphous, or Prompt Insulin Zinc Suspension,
USP, is rapidly absorbed upon intramuscular. The
larger crystalline material, called ultralente insulin or
Extended Insulin Zinc Suspension, USP, is more
slowly absorbed and has a resultant longer duration of
action.
 By combining the two types in various proportions, a
physician can provide patients with intermediate-acting
insulin of varying degrees of onset and duration of
action. A physical mixture of 70% of the crystalline
form and 30% of the amorphous form, called lente
insulin or Insulin Zinc Suspension, USP, is
intermediate acting and meets the requirements of
many diabetics.
 Polymorphism:
 Only one form of a pure drug is stable, the other is
metastable forms, converting in time to the stable
crystalline form. It is therefore fairly common for a
metastable form of a medicinal agent to change form
even in a completed pharmaceutical preparation.
 time required for a complete change may exceed
the normal shelf life of the product.
 any change in crystal structure of agent
affect the stability and therapeutic efficacy of
the product .
 Salt forms
 The dissolution rate of a salt of a drug is different
from that of the parent compound.
 Sodium and potassium salts of weak organic acids
and hydrochloride salts of weak organic bases
dissolve more than free acids or bases.
 The addition of the ethylenediamine moiety to
theophylline increases the water solubility of
theophylline fivefold.

 The use of the ethylenediamine salt of theophylline

has allowed the development of oral aqueous
solutions of theophylline.
 A drug's solubility in GIT can be affected by pH also
by food.
 A drug may interact with agents present to form a
chemical complex that result in reduced drug
solubility and decreased absorption.
 The classic example of this complexation: between
tetracycline and calcium, magnesium, and
aluminum, resulting in decreased absorption of the
tetracycline.
 bioavailability is the rate and extent of drug
absorption from site of administration to the
general circulation.
 The term bioequivalence refers to a
comparison of bioavailabilities of different
formulations, drug products, or batches of the
same drug product.
 Bioavailability used to determine
1. amount of drug absorbed from a
formulation or dosage form,
2. rate at which the drug was
absorbed,
3. duration of the drug's presence in
biologic fluid or tissue correlated with the
patient's response, and
4. relationship between drug blood levels
and clinical efficacy and toxicity.
During product development stage:
1. studies bioavailability to compare different
formulations of the drug substance to ascertain which
one allows the most desirable absorption pattern.
2. Later bioavailability studies used to compare the
availability of the drug substance in different
production batches.
3. They may also be used to compare the availability of
the drug substance in different dosage forms (e.g.,
tablets, capsules, elixirs),
4. or in the same dosage form produced by different
(companies) manufacturers.
 Following oral administration of drug, blood samples are withdrawn
at specific time intervals and analyzed for drug content.
 The vertical presents the concentration of drug in blood, and
horizontal axis presents time the samples were obtained following
drug administration.
 time zero the blood concentration of drug should be zero.
 As the drug passes into the stomach and/or intestine, dissolves, and absorbed. As the
sampling and analysis continue, the blood samples reveal increasing concentrations
of drug until maximum (peak) concentration (Cmax) is reached. Then the blood level
of the drug decreases.
 Absorption does not terminate after the peak blood level is reached; it may continue
for some time.
 process of drug elimination is continuous. It begins as soon as the
drug first appears in the blood stream and continues until all the drug has
been eliminated.
 The positive or negative slope of the curve indicates which process is faster.
 Following oral administration of single doses of two
formulations of the same drug :
 The peak height concentration (Cmax)
 The time to peak concentration (Tmax)
 The area under the blood (or serum or plasma)
concentration time curve (AUC)
 Cmax observed in blood following a dose of the
drug, indicating a slope of zero, meaning the
rates of absorption and elimination are equal.
When the rate of absorption is decreased, the Cmax is
lowered and Tmax occurs at a later time.
 The AUC of concentration-time curve)
represent total amount of drug absorbed
following administration of a single dose of
that drug.
 If similar doses of drug in different formulas
produce different AUC values, differences
exist in extent of absorption between
formulations.
 In general, the smaller AUC, the lesser drug
absorbed.
 F: bioavailability of orally administered drug
calculated by comparison of AUC after oral
administration with that obtained after
intravenous administration:
 F = (AUC)oral/(AUC)IV×DOSE IV/DOSE oral

 The absolute bioavailability following oral

dosing is generally compared to intravenous
dosing.
 Bioavailability: rate and extent to which a drug in a
dosage form becomes available for biologic
absorption.
 the same drug when formulated in different dosage
forms have different bioavailability and exhibit
different clinical effectiveness.
 Furthermore, two identical or equivalent products of
same drug in the same dosage strength and in the
same dosage form but differing in formulative
materials or method of manufacture may vary widely
in bioavailability and thus, in clinical effectiveness.
 FDA uses the following terms to define type or
level of equivalency between drug products.

 Pharmaceutical equivalents: are drug products that

contain identical amounts of identical active
ingredient, that is, the same salt or ester of the same
therapeutic moiety, in identical dosage forms but not
necessarily containing the same inactive ingredients.
 Pharmaceutical alternatives are drug products that
contain the identical therapeutic moiety or its precursor
but not necessarily in the same amount or dosage form
or as the same salt or ester.
 bioequivalent drug products are pharmaceutical
equivalents or pharmaceutical alternatives whose
rate and extent of absorption are similar.
 Some pharmaceutical equivalents or pharmaceutical
alternatives equivalent in extent absorption but not in rate
of absorption and yet may be considered bioequivalent.
because such differences in rate of absorption are intentional and
are reflected in the labeling, are not essential to the attainment of
effective body drug concentrations on chronic use, or are
considered medically insignificant for the drug product studied.

 therapeutic equivalents: used to indicate pharmaceutical

equivalents that provide same therapeutic effect when
administered to same individuals in same dosage regimens.
 The most common experimental plan to compare the bioavailability of two
drug products :is simple crossover design study.
 12 to 24 individuals carefully matched subjects (usually healthy men aged 18 to
40 years and having similar height and weight) is administered both products
under fasting conditions.
 each test subject is randomly assigned one of the two products for the first
phase of the study.
 Once the first assigned product is administered, samples of blood or plasma are
drawn from the subjects at predetermined times and analyzed for the active
drug moiety and its metabolites as a function of time.
 The same procedure is then repeated (crossover) with the second product after
an appropriate interval, that is, a washout period to ensure that there is no residual drug
from the first administered product that would artificially inflate the test results of the
second product. Afterward, the patient population data are tabulated and the parameters
used to assess and compare bioavailability; that is, Cmax, Tmax, and AUC are analyzed
with statistical procedures. Statistical differences in bioavailability parameters may not
always be clinically significant in therapeutic outcomes.
 The value in the crossover experiment is that each individual serves as his own control
by taking each of the products. Thus, inherent differences between individuals are
minimized.
 Absolute bioequivalency between drug products
rarely occurs. Such absolute equivalency would
yield serum concentration-time curves for the
products that would be exactly superimposable.
 This simply is not expected of products that are made
at different times, in different batches, or indeed by
different manufacturers.
 In most studies of bioavailability, the originally
marketed product (brand name drug product) is
recognized as the established product of the drug and
is used as the standard for the bioavailability
comparative studies.
 According to the FDA: generic drug is considered
bioequivalent if the rate and extent of
absorption do not show a significant difference
from that of standard drug when administered
at the same molar dose of the therapeutic
ingredient under the same experimental
conditions.
 Because in the case of a systemically absorbed drug
blood levels even if from identical product may vary in
different subjects, in bioequivalence studies each
subject receives both the standard and the test drug and
thus serves as his own control.
Under the 1984 act, to gain FDA approval a generic
drug product must have these characteristics:
1. The same active ingredients as the standard drug .
2. Identical strength, dosage form, and route of
administration
3. The same indications and precautions for use .
 Bioequivalency
 The same batch-to-batch requirements for identity,
strength, purity, and quality
 If a standard manufacturer reformulates an FDA-
approved product, the subsequent formulation must
meet the same bioequivalency standards that are
required of generic manufacturers of that product .
 The difference in absorption between
dosage forms is a function of the
formulation and the route of
administration.
 the bioavailable fraction is determined by
the fraction of drug that is absorbed from
the gastrointestinal tract and the fraction
that escapes metabolism during its first
pass through the liver.
 most drug absorbed from various surfaces along
GIT.
 oral route is considered natural, uncomplicated,
convenient, and safe means of administering
drugs.
 Disadvantages of the oral route include:
1. slow response.
2. chance of irregular absorption of drugs,
depending on factors : amount or type of food
in GIT and destruction of certain drugs by the acid
of stomach or by enzymes.
 tablets, capsules, suspensions, and various pharmaceutical
solutions. Briefly, tablets contains medicinal substances
with or without suitable diluents, disintegrants, coatings,
colorants, and other pharmaceutical adjuncts.
 Diluents are fillers used to prepare tablets of the proper size and
consistency.
 Disintegrants are used for the breakup or separation of the tablet's compressed
ingredients. This ensures prompt exposure of drug particles to the dissolution
process, enhancing drug absorption, .
 Tablet coatings are of several types and for several purposes. Some, called
enteric coatings, are employed to permit safe passage of a tablet through the acid
environment of the stomach, where certain drugs may be destroyed, to the more
suitable juices of the intestines, where tablet dissolution safely takes place.
 Other coatings protect the drug substance from the destructive influences of
moisture, light, and air during storage or to conceal a bad or bitter taste from the
taste buds of a patient.
 Capsules are solid dosage forms contain, fillers, are
enclosed in either a hard or a soft shell, .
 Drug materials are released from capsules faster than
from tablets.
 Capsules of gelatin rapidly disfigured within GIT
permitting the gastric juices to permeate and reach the
contents.
 Also, capsule-shaped and coated tablets, called
caplets, are increasingly used. These are easily
swallowed, but their contents are sealed and protected
from tampering like tablets.
 Suspensions aqueous vehicle, whereas those
employed for other purposes may use a different
vehicle. Suspensions of certain drugs to be used for
intramuscular injection, for instance, may be
maintained in a suitable oil.
 To be suspended, the drug particles must be insoluble
in the vehicle. Nearly all suspensions must be shaken
before use because they tend to settle.
 Suspensions are a useful to administer large amounts
of solid drugs that would be inconvenient to take in
tablet or capsule form. In addition, suspensions have
the advantage over solid dosage forms in that they are
presented to body in fine particle size, ready for
dissolution immediately upon administration.
 Drugs administered in aqueous solution are
absorbed much more rapidly than those
administered in solid form.
 Pharmaceutical solutions may differ in type of solvent
employed and fluidity characteristics.
 Among the solutions frequently administered orally are
elixirs, which are solutions in a sweetened hydroalcoholic
vehicle and are more mobile than water; syrups, which
generally use a sucrose solution as the sweet vehicle,
resulting in a viscous preparation; and solutions themselves,
which officially are preparations in which the drug
substance is dissolved predominantly in an aqueous vehicle
and do not for reasons of their method of preparation (e.g.,
injections, which must be sterilized.
 Absorption of drugs after oral administration
may occur at various body sites between mouth
and rectum.
 In general, the higher up a drug is absorbed
along the alimentary tract, the more rapid will
be its action, a desirable feature in most
instances. Because of the differences in
chemical and physical nature among drug
substances, a given drug may be better absorbed
from one site than from another in the
alimentary tract.
 Sometimes the oral cavity is the absorption site.
Physically, oral absorption of drugs is managed by
allowing the drug substance to dissolve within the
oral cavity with little or no swallowing until the taste
of the drug has dissipated. This process is
accommodated by providing the drug as extremely
soluble and rapidly dissolving uncoated tablets.
 Drugs capable of being absorbed in the mouth
present themselves to the absorbing surface in a
much more concentrated form than when swallowed,
because drugs become progressively more diluted
with gastrointestinal secretions and contents as they
pass along the alimentary tract.
 Nitroglycerin, a coronary vasodilator used in the
prophylaxis and treatment of angina pectoris, is
available in the form of tiny tablets that are allowed
to dissolve under the tongue, producing therapeutic
effects a few minutes after administration. The dose
of nitroglycerin is so small (usually 400 µg) that if it
were swallowed,
 nitroglycerin is rapidly destroyed by the liver
through the first-pass effect.
 Retaining drug substances in the mouth is
unattractive because of the bitter taste of most drugs.
 Drugs altered within the gastrointestinal tract to
render them less available for absorption. This may
result from the drug's interaction with or binding to
some normal constituent of the gastrointestinal
tract or a food stuff or even another drug.
 For instance, the absorption of the tetracycline group
of antibiotics is greatly interfered with by the
simultaneous presence of calcium. Because of this,
tetracycline drugs must not be taken with milk or
other calcium-containing foods or drugs.
 Gastric emptying time increased by presence of fatty
foods or lying on the back when bedridden (lying on
the right side facilitates passage in many instances), or
decreased, as by the presence of drugs (e.g.,
morphine) .

 If a drug is administered in the form of a solution, it

may be expected to pass into the intestines more
rapidly than drugs administered in solid form.
 As a rule, large volumes of water facilitate gastric
emptying and passage into the intestines.
 pH 1 in stomach, pH 8 at the far end of the intestines.
 pH affect degree of ionization of most drugs, and this in turn
affects lipid solubility, membrane permeability, and
absorption.
 lipid-water partition coefficient and the pKa of the drugs are
of prime importance to both the degree and the site of
absorption.
 As a general rule, weak acids are largely un-ionized in the
stomach and are absorbed fairly well from this site.
 weak bases are highly ionized in the stomach and are not
significantly absorbed from the gastric surface.
 Alkalinization of the gastric environment by artificial means
(simultaneous administration of alkaline or antacid drugs)
would be expected to decrease the gastric absorption of weak
acids and to increase that of weak bases. Strong acids and
bases are generally poorly absorbed because of their high degree
of ionization.
 The small intestine is the major absorption pathway
for drugs because:
1. suitable pH .
2. great surface area available for drug absorption
along its approximately 20-foot length.
The pH of intestine lumen is 6.5 and both weakly acidic
and weakly basic drugs are well absorbed from
intestinal surface, which behaves in the ionization and
distribution of drugs between it and the plasma on the
other side of the membrane as though its pH were 5.3
 drugs are administered rectally for their local
effects or systemic effects.
 The composition of the suppository base, can
influence the degree and rate of drug release
and should be selected on an individual basis
for each drug.
 The use of rectal ointments is generally
limited to treat of local conditions.
 Rectal solutions are usually employed as
enemas or cleansing solutions.
 The rectum and colon can absorb many soluble
drugs.
 Rectal administration for systemic action preferred for
drugs destroyed or inactivated by the environments of
the stomach and intestines.
 rectal route also indicated when oral route is precluded
because of vomiting or when the patient is unconscious
or incapable of swallowing.
 Colon Protect from first pass effect
1. disadvantage of parenteral is that once the drug is injected,
there is no retreat.
2. Drugs in solution act more rapidly than drugs in suspension,
3. with an aqueous vehicle providing faster action in each instance
than an oleaginous vehicle.
4. suspension of a drug in a vegetable oil slowly absorbed than
an aqueous solution of the same drug.
 Slow absorption means prolonged drug action is referred to as a
depot or repository injection, because it provides a storage
reservoir of the drug substance within the body from which it is
slowly removed into the systemic circulation.
 the use of subcutaneous implantation of compressed tablets,
termed pellets, slowly dissolved, releasing their medication at a
fairly constant rate over several weeks to many months.
1. prepared as aqueous solutions or suspensions administered
small volumes, 2 mL or less.
2. blood supply to the site of injection is an important .
3. the more the capillaries, the more surface area for absorption
and the faster the rate of absorption.
4. The addition of a vasoconstrictor to the injection formulation
(or its prior injection) will diminish drug absorption by
causing constriction of the blood and reducing blood flow and the
capacity for absorption.
This principle is used in the administration of local anesthetics by
use of the vasoconstrictor epinephrine.
 Conversely, vasodilators may be used to enhance subcutaneous

absorption by increasing blood flow to the area.

Physical exercise can also influence the absorption of drug
from an injection site.
1. volumes (2 to 5 mL)
2. When a volume greater than 5 mL is to
be injected, it is frequently administered
in divided doses to two injection sites.
3. Injection sites are best rotated when a
patient is receiving repeated injections
over time.
 Bound drug is neither exposed to
metabolism nor filtered through the renal
glomeruli.
 Bound drug is inactive portion in the blood.
 unbound drug, with its ability to penetrate
cells, is active blood portion.
 The bound portion of drug serves as a
reservoir or depot from which the drug is
released as the free form when the level of free
drug in the blood no longer is adequate to
ensure protein saturation.
 Simplest pharmacokinetic model is one compartment
open-model system.
 This model depicts the body as one compartment
characterized by volume of distribution (Vd) that
remains constant. Each drug has its own distinct
volume of distribution, and this influenced by age and
disease.
 the drug is absorbed at a certain rate and is
characterized by absorption rate constant Ka.
Finally, the drug is eliminated from the compartment
at a certain rate that is characterized by an elimination
rate constant, Kel.
 It is influenced by the plasma protein
binding and tissue binding of a drug.
 the total amount of drug in the body (Qb) can
be calculated from the following equation:
 In two-compartment system: a drug enters and
distributed throughout the central compartment. Its
subsequent distribution into second or peripheral
compartment is slower.
 The central compartment is usually blood, the
extracellular space, and organs with good blood
perfusion, such as lungs, liver, kidneys, and heart.
 The peripheral compartment usually comprises tissues
and organs that are poorly perfused by blood, such as
skin, bone, and fat.
 The half-life (T1/2) of a drug is the
time required for a drug's blood or
plasma concentration to decrease by
half.
 T1/2= 0.693/k
 Clearance: Cl=Vd× k