Chapter 1.

Introduction to
Biopharmaceutics and Pharmacokinetics
Drugs are substances intended for use in the diagnosis, cure, mitigation, treatment, or prevention
of disease. Drugs are given in a variety of dosage forms or drug products such as solids (tablets,
capsules), semisolids (ointments, creams), liquids, suspensions, emulsions, etc, for systemic or
local therapeutic activity. Drug products can be considered to be drug delivery systems that
release and deliver drug to the site of action such that they produce the desired therapeutic effect
and are also designed specifically to meet the patient's needs including palatability, convenience,
and safety.
Drug product performance is defined as the release of the drug substance from the drug product
either for local drug action or for drug absorption into the plasma for systemic therapeutic activity.
Advances in pharmaceutical technology and manufacturing have focused on developing
quality drug products that are safer, more effective, and more convenient for the patient.
Biopharmaceutics examines the interrelationship of the physical/chemical properties of the drug,
the dosage form (drug product) in which the drug is given, and the route of administration on the
rate and extent of systemic drug absorption. The importance of thedrug substance and the drug
formulation on absorption, and in vivo distribution of the drug to the site of action, is described as
a sequence of events that precede elicitation of a drug's therapeutic effect. A general scheme
describing this dynamic relationship is illustrated in Fig. 1-1.
First, the drug in its dosage form is taken by the patient either by an oral, intravenous,
subcutaneous, transdermal, etc, route of administration. Next, the drug is released from the
dosage form in a predictable and characterizable manner. Then, some fraction of the drug is
absorbed from the site of administration into either the surrounding tissue, into the body (as with
oral dosage forms), or both. Finally, the drug reaches the site of action. A pharmacologic
response results when the drug concentration at the site of action reaches or exceeds
the minimum effective concentration (MEC). The suggested dosing regimen, including starting
dose, maintenance dose, dosage form, and dosing interval, is determined in clinical trials to
provide the drug concentrations that are therapeutically effective in most patients. This sequence

of events is profoundly affectedin fact, sometimes orchestratedby the design of the dosage
form and the physicochemical properties of the drug.
Historically, pharmaceutical scientists have evaluated the relative drug availability to the body in
vivo after giving a drug product by different routes to an animal or human, and then comparing
specific pharmacologic, clinical, or possible toxic responses.

BCS classes[edit]
According to the Biopharmaceutical Classification System (BCS) drug substances are classified
to four classes upon their solubility and permeability: [1]

Class I - high permeability, high solubility

Example: metoprolol

Those compounds are well absorbed and their absorption rate is usually higher
than excretion.

Class II - high permeability, low solubility

Example: glibenclamide, bicalutamide, ezetimibe, phenytoin, aceclofenac

The bioavailability of those products is limited by their solvation rate. A correlation

between the in vivo bioavailability and the in vitro solvation can be found.

Class III - low permeability, high solubility

Example: cimetidine

The absorption is limited by the permeation rate but the drug is solvated very fast.
If the formulation does not change the permeability or gastro-intestinal duration time,
then class I criteria can be applied.

Class IV - low permeability, low solubility

Example: Bifonazole

Those compounds have a poor bioavailability. Usually they are not well absorbed
over the intestinal mucosa and a high variability is expected.

The drugs are classified in BCS on the basis of following parameters:

1. Solubility
2. Permeability
3. Dissolution
The class boundaries for these parameters are:
1. Solubility class boundaries It is based on the highest dose strength of an immediate
release product. A drug is considered highly soluble when the highest dose strength is
soluble in 250 ml or less of aqueous media over the pH range of 1 to 7.5. The volume
estimate of 250 ml is derived from typical bioequivalence study protocols that prescribe
administration of a drug product to fasting human volunteers with a glass of water.
2. Permeability class boundaries It is based indirectly on the extent of absorption of a drug
substance in humans and directly on the measurement of rates of mass transfer across
human intestinal membrane. Alternatively non-human systems capable of predicting
drug absorption in humans can be used (such as in-vitro culture methods).
A drug substance is considered highly permeable when the extent of absorption in humans is
determined to be 90% or more of the administered dose based on a mass-balance determination
or in comparison to an intravenous dose.
1. Dissolution class boundaries An immediate release product is considered rapidly
dissolving when no less than 85% of the labeled amount of the drug substance dissolves
within 15 minutes using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at 50
RPM in a volume of 900 ml or less in the following media: 0.1 N HCl or simulated gastric
fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.

In the physical sciences, a partition-coefficient (P) or distribution-coefficient (D) is the ratio

of concentrations of a compound in a mixture of two immiscible phases atequilibrium. This ratio is
therefore a measure of the difference in solubility of the compound in these two phases. The
partition-coefficient generally refers to the concentration ratio of un-ionized species of compound
whereas the distribution-coefficient refers to the concentration ratio of all species of the
compound (ionized plus un-ionized).[1]
In the chemical and pharmaceutical sciences, both phases usually are solvents.[2] Most
commonly, one of the solvents is water while the second is hydrophobic such as 1-octanol.
[3]

Hence the partition coefficient measures how hydrophilic ("water-loving")

or hydrophobic ("water-fearing") a chemical substance is. Partition coefficients are useful in

estimating the distribution of drugs within the body. Hydrophobic drugs with high octanol/water
partition coefficients are mainly distributed to hydrophobic areas such as lipid bilayers of cells.
Conversely hydrophilic drugs (low octanol/water partition coefficients) are found primarily in
aqueous regions such as blood serum.[4]

If one of the solvents is a gas and the other a liquid, a gas/liquid partition coefficient can be
determined. For example, the blood/gas partition coefficient of a general anestheticmeasures
how easily the anesthetic passes from gas to blood. [5] Partition coefficients can also be defined
when one of the phases is solid, for instance, when one phase is a molten metal and the second
is a solid metal,[6] or when both phases are solids.[7] The partitioning of a substance into a solid
results in a solid solution.
Partition coefficients can be measured experimentally in various ways (by shake-flask, HPLC,
etc.) or estimated via calculation based on a variety of methods (fragment-based, atom-based,
etc.).
The partition coefficient, abbreviated P, is defined as a particular ratio of the concentrations of
a solute between the two solvents (a biphase of liquid phases), specifically for un-ionized solutes,
and the logarithm of the ratio is thus log P.[10]:275ff When one of the solvents is water and the other
is a non-polar solvent, then the log P value is a measure of lipophilicity or hydrophobicity.
[10]:275ff [11]:6

The defined precedent is for the lipophilic and hydrophilic phase types to always be in

the numerator and denominator, respectively; for example, in a biphasic system of noctanol (hereafter simply "octanol") and water:
To a first approximation, the non-polar phase in such experiments is usually dominated by
the un-ionized form of the solute, which is electrically neutral, though this may not be true for
the aqueous phase.[citation needed] To measure the partition coefficient of ionizable solutes,
the pH of the aqueous phase is adjusted such that the predominant form of the compound in
solution is the un-ionized, or its measurement at another pH of interest requires
consideration of all species, un-ionized and ionized (see following).
A corresponding partition coefficient for ionizable compounds, abbreviated log P I, is
derived for cases where there are dominantionized forms of the molecule, such that one
must consider partition of all forms, ionized and un-ionized, between the two phases (as well
as the interaction of the two equilibria, partition and ionization). [11]:57ff,69f[12] M is used to indicate
the number of ionized forms; for the I-th form (I = 1, 2, ... , M) the logarithm of the
corresponding partition coefficient, , is defined in the same manner as for the un-ionized
form. For instance, for an octanol-water partition, it is:
To distinguish between this and the standard, un-ionized, partition coefficient, the unionized is often assigned the symbol log P0, such that the indexed expression for
ionized solutes becomes simply an extension of this, into the range of values

The octanol/water partition coefficient (Kow) is defined as the ratio of a chemical's concentration
in the octanol phase to its concentration in the aqueous phase of a two-phase octanol/water
system.
Kow = Concentration in octanol phase / Concentration in aqueous phase
Values of Kow are thus, unitless. The parameter is measured using low solute concentrations,
where Kow is a very weak function of solute concentration. Values of Kow are usually measured
at room temperature (20 or 25'C. The effect of temperature on Kow is not great - usually on the
order of 0.001 to 0.01 Iog Kow units per degree - and may be either positive or negative.

Measured values of Kow for organic chemicals have been found as low as 10-3 and as high
as 107, thus encompassing a range of ten orders of magnitude. In terms of log Kow, this
range is from -3 to 7. It is frequently possible to estimate log Kow with an uncertainty (i.e.,
method error) of no more than 10.1-0.2 Iog Kow units.
The octanol/water partition coefficient is not the same as the ratio of a chemical's solubility in
octanol to its solubility in water, because the organic and aqueous phases of the binary
octanol/water system are not pure octanol and pure water. At equilibrium, the organic phase
contains 2.3 mol/L of water, and the aqueous phase contains 4.5 X 10-8 mol/L of octanol.
Moreover, Kow is often found to be a function of solute concentration. The chemical in
question is added to a mixture of octanol and water whose volume ratio is adjusted
according to the expected value of Kow. Very pure octanol and water must be used, and the
concentration of the solute in the system should be less than 0.01 mol/L. The system is
shaken gently until equilibrium is achieved (15 min to 1 hr). Centrifugation is generally
required to separate the two phases, especially if an emulsion has formed. An appropriate
analytical technique is then used to determine the solute concentration in each phase. A
rapid laboratory estimate of Kow may be obtained by measuring the retention time in a highpressure liquid chromatography system (If interested in retention time prediction refer to this
article); the logarithm of the retention time and the logarithm of Kow have been found to be
linearly related.
In recent years the octanol/water partition coefficient has become a key parameter in studies
of the environmental fate of organic chemicals. It has been found to be related to water
solubility (I checked my logS prediction function with endocrine disrupting chemicals),
soil/sediment adsorption coefficients, and bioconcentration factors for aquatic life. Because
of its increasing use in the estimation of these other properties, Kow is considered a required
property in studies of new or problematic chemicals.

Values of Kow can be considered to have some meaning in themselves, since they
represent the tendency of the chemical to partition itself between an organic phase (e.g., a
fish, a soil) and an aqueous phase. Chemicals with low Kow values (e.g., less than 10) may
be considered relatively hydrophilic; they tend to have high water solubilities, small
soil/sediment adsorption coefficients, and small bioconcentration factors for aquatic life.
Conversely, chemicals with high Kow values (e.g., greater than 104) are very hydrophobic.

What is Tablet Dissolution?

Tablets or capsules taken orally remain one of the most effective means of treatment available. The
effectiveness of such dosage forms relies on the drug dissolving in the fluids of the gastrointestinal
tract prior to absorption into the systemic circulation. The rate of dissolution of the tablet or capsule is
therefore crucial.
One of the problems facing the pharmaceutical industry is to optimise the amount of drug available to
the body, i.e. itsbioavailability. Inadequacies in bioavailability can mean that the treatment is
ineffective and at worst potentially dangerous (toxic overdose).
Drug release in the human body can be measured in-vivo by measuring the plasma or urine
concentrations in the subject concerned. However, there are certain obvious impracticalities involved
in employing such techniques on a routine basis. These difficulties have led to the introduction of
official in-vitro tests which are now rigorously and comprehensively defined in the respective
Pharmacopoeia.
Tablet Dissolution is a standardised method for measuring the rate of drug release from a dosage
form. The principle function of the dissolution test may be summarised as follows:

Optimisation of therapeutic effectiveness during product development and stability assessment.

Routine assessment of production quality to ensure uniformity between production lots.

Assessment of bioequivalence, that is to say, production of the same biological availability from discrete
batches of products from one or different manufacturers.

Prediction of in-vivo availability, i.e. bioavailability (where applicable).

Although initially developed for oral dosage forms, the role of the dissolution test has now been
extended to drug release studies on various other forms such as topical and transdermal systems and
suppositories

Absorption (pharmacokinetics)
From Wikipedia, the free encyclopedia

In pharmacology (and more specifically pharmacokinetics), absorption is the movement of a

drug into the bloodstream.
Absorption involves several phases. First, the drug needs to be introduced via some route of
administration (oral, topical-dermal, etc.) and in a specific dosage form such as
atablet, capsule, solution and so on.
In other situations, such as intravenous therapy, intramuscular injection, enteral nutrition and
others, absorption is even more straightforward and there is less variability in absorption
and bioavailability is often near 100%. It is considered that intravascular administration (e.g. IV)
does not involve absorption, and there is no loss of drug. [1] The fastest route of absorption
is inhalation, and not as mistakenly considered the intravenous administration. [2]
Absorption is a primary focus in drug development and medicinal chemistry, since the drug must
be absorbed before any medicinal effects can take place. Moreover, the drug's pharmacokinetic
profile can be easily and significantly changed by adjusting factors that affect absorption.
Contents
[hide]

1Dissolution

2Ionization

3Other factors

4References

5Further reading

6External links

Dissolution[edit]
In the most common situation, a tablet is ingested and passes through the esophagus to
the stomach.
The rate of dissolution is a key target for controlling the duration of a drug's effect, and as such,
several dosage forms that contain the same active ingredient may be available, differing only in
the rate of dissolution. If a drug is supplied in a form that is not readily dissolved, the drug may be
released more gradually over time with a longer duration of action. Having a longer duration of
action may improve compliance since the medication will not have to be taken as often.
Additionally, slow-release dosage forms may maintain concentrations within an acceptable
therapeutic range over a long period of time, as opposed is quick-release dosage forms which
may result in sharper peaks and troughs in serum concentrations.
The rate of dissolution is described by the NoyesWhitney equation as shown below:
Where:

is the rate of dissolution.

A is the surface area of the solid.

C is the concentration of the solid in the bulk dissolution medium.

is the concentration of the solid in the diffusion layer surrounding the solid.

D is the diffusion coefficient.

L is the diffusion layer thickness.

As can be inferred by the Noyes-Whitney equation, the rate of dissolution may be modified
primarily by altering the surface area of the solid. The surface area may be adjusted by
altering the particle size (e.g. micronization). For many drugs, reducing the particle size leads
to a reduction in the dose that is required to achieve the same therapeutic effect. However, it

should be noted that although the reduction of particle size increases the specific surface
area and the dissolution rate, it does not affect solubility.
The rate of dissolution may also be altered by choosing a suitable polymorph of a compound.
Different polymorphs exhibit different solubility and dissolution rate characteristics.
Specifically, crystalline forms dissolve slower than amorphous forms, since crystalline forms
require more energy to leave lattice during dissolution. The most stable crystalline polymorph
has the lowest dissolution rate. Dissolution is also different for anhydrous and hydrous forms
of a drug. Anhydrous often dissolve faster than hydrated; however, anhydrous forms
sometimes exhibit lower solubility.
Chemical modification by esterification is also used to control solubility. For example,
stearate and estolate esters of a drug have decreased solubility in gastric fluid. Later,
esterases in the GIT wall and blood hydrolze these esters to release the parent drug.
Also, coatings on a tablet or a pellet may act as a barrier to reduce the rate of dissolution.
Coating may also be used to modify where dissolution takes place. For example,enteric
coatings may be applied to a drug, so that the coating only dissolves in
the basic environment of the intestines. This will prevent release of the drug before reaching
the intestines.
Since solutions are already dissolved, they do not need to undergo dissolution before being
absorbed. Lipid-soluble drugs are less absorbed than water-soluble drugs, especially when
they are enteral.
Drug absorption is determined by the drugs physicochemical properties, formulation, and route
of administration. Dosage forms (eg, tablets, capsules, solutions), consisting of the drug plus
other ingredients, are formulated to be given by various routes (eg, oral, buccal, sublingual,
rectal, parenteral, topical, inhalational). Regardless of the route of administration, drugs must be
in solution to be absorbed. Thus, solid forms (eg, tablets) must be able to disintegrate and
deaggregate.
Unless given IV, a drug must cross several semipermeable cell membranes before it reaches the
systemic circulation. Cell membranes are biologic barriers that selectively inhibit passage of drug
molecules. The membranes are composed primarily of a bimolecular lipid matrix, which
determines membrane permeability characteristics. Drugs may cross cell membranes by

Passive diffusion

Facilitated passive diffusion

Active transport

Pinocytosis

Sometimes various globular proteins embedded in the matrix function as receptors and help
transport molecules across the membrane.

Passive diffusion
Drugs diffuse across a cell membrane from a region of high concentration (eg, GI fluids) to one of
low concentration (eg, blood). Diffusion rate is directly proportional to the gradient but also
depends on the molecules lipid solubility, size, degree of ionization, and the area of absorptive
surface. Because the cell membrane is lipoid, lipid-soluble drugs diffuse most rapidly. Small
molecules tend to penetrate membranes more rapidly than larger ones.
Most drugs are weak organic acids or bases, existing in un-ionized and ionized forms in an
aqueous environment. The un-ionized form is usually lipid soluble (lipophilic) and diffuses readily
across cell membranes. The ionized form has low lipid solubility (but high water solubilityie,
hydrophilic) and high electrical resistance and thus cannot penetrate cell membranes easily.
The proportion of the un-ionized form present (and thus the drugs ability to cross a membrane) is
determined by the environmental pH and the drugs p K a (acid dissociation constant). The p K a is
the pH at which concentrations of ionized and un-ionized forms are equal. When the pH is lower
than the p K a, the un-ionized form of a weak acid predominates, but the ionized form of a weak
base predominates. Thus, in plasma (pH 7.4), the ratio of un-ionized to ionized forms for a weak
acid (eg, with a p K a of 4.4) is 1:1000; in gastric fluid (pH 1.4), the ratio is reversed (1000:1).
Therefore, when a weak acid is given orally, most of the drug in the stomach is un-ionized,
favoring diffusion through the gastric mucosa. For a weak base with a p K a of 4.4, the outcome is
reversed; most of the drug in the stomach is ionized.

Theoretically, weakly acidic drugs (eg, aspirin) are more readily absorbed from an acid medium
(stomach) than are weakly basic drugs (eg,quinidine). However, whether a drug is acidic or
basic, most absorption occurs in the small intestine because the surface area is larger and
membranes are more permeable (see Oral Administration).

Facilitated passive diffusion

Certain molecules with low lipid solubility (eg, glucose) penetrate membranes more rapidly than
expected. One theory is facilitated passive diffusion: A carrier molecule in the membrane
combines reversibly with the substrate molecule outside the cell membrane, and the carriersubstrate complex diffuses rapidly across the membrane, releasing the substrate at the interior
surface. In such cases, the membrane transports only substrates with a relatively specific
molecular configuration, and the availability of carriers limits the process. The process does not
require energy expenditure, and transport against a concentration gradient cannot occur.

Active transport
Active transport is selective, requires energy expenditure, and may involve transport against a
concentration gradient. Active transport seems to be limited to drugs structurally similar to
endogenous substances (eg, ions, vitamins, sugars, amino acids). These drugs are usually
absorbed from specific sites in the small intestine.

Pinocytosis
In pinocytosis, fluid or particles are engulfed by a cell. The cell membrane invaginates, encloses
the fluid or particles, then fuses again, forming a vesicle that later detaches and moves to the cell
interior. Energy expenditure is required. Pinocytosis probably plays a small role in drug transport,
except for protein drugs.

ORAL ADMINISTRATION
To be absorbed, a drug given orally must survive encounters with low pH and numerous GI
secretions, including potentially degrading enzymes. Peptide drugs (eg, insulin) are particularly

susceptible to degradation and are not given orally. Absorption of oral drugs involves transport
across membranes of the epithelial cells in the GI tract. Absorption is affected by

Differences in luminal pH along the GI tract

Surface area per luminal volume

Blood perfusion

Presence of bile and mucus

The nature of epithelial membranes

The oral mucosa has a thin epithelium and rich vascularity, which favor absorption; however,
contact is usually too brief for substantial absorption. A drug placed between the gums and cheek
(buccal administration) or under the tongue (sublingual administration) is retained longer,
enhancing absorption.
The stomach has a relatively large epithelial surface, but its thick mucous layer and short transit
time limit absorption. Because most absorption occurs in the small intestine, gastric emptying is
often the rate-limiting step. Food, especially fatty food, slows gastric emptying (and rate of drug
absorption), explaining why taking some drugs on an empty stomach speeds absorption. Drugs
that affect gastric emptying (eg, parasympatholytic drugs) affect the absorption rate of other
drugs. Food may enhance the extent of absorption for poorly soluble drugs (eg, griseofulvin),
reduce it for drugs degraded in the stomach (eg, penicillin G), or have little or no effect.
The small intestine has the largest surface area for drug absorption in the GI tract, and its
membranes are more permeable than those in the stomach. For these reasons, most drugs are
absorbed primarily in the small intestine, and acids, despite their ability as un-ionized drugs to
readily cross membranes, are absorbed faster in the intestine than in the stomach. The
intraluminal pH is 4 to 5 in the duodenum but becomes progressively more alkaline, approaching
8 in the lower ileum. GI microflora may reduce absorption. Decreased blood flow (eg, in shock)
may lower the concentration gradient across the intestinal mucosa and reduce absorption by
passive diffusion.

Intestinal transit time can influence drug absorption, particularly for drugs that are absorbed by
active transport (eg, B vitamins), that dissolve slowly (eg, griseofulvin), or that are polar (ie, with
low lipid solubility; eg, many antibiotics).
To maximize adherence, clinicians should prescribe oral suspensions and chewable tablets for
children < 8 yr. In adolescents and adults, most drugs are given orally as tablets or capsules
primarily for convenience, economy, stability, and patient acceptance. Because solid drug forms
must dissolve before absorption can occur, dissolution rate determines availability of the drug for
absorption. Dissolution, if slower than absorption, becomes the rate-limiting step. Manipulating
the formulation (ie, the drugs form as salt, crystal, or hydrate) can change the dissolution rate
and thus control overall absorption.