Biopharmaceutics.pptx

Introduction to biopharmaceutics
Tsegaye N. (B.Pharm., MSc in Pharmaceutics)
Arba Minch University, College of Health Sciences
Department of Pharmacy, pharmaceutics and social pharmacy course team
Biopharmaceutics 1
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Outline
• Definitions, concepts and applications
• Barriers of drug transport
• Mechanisms of drug transport
• Passive diffusion
• Carrier-mediated transport (Active transport, facilitated diffusion)
• Vesicular transport
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Cont…
• Bio–life
Pharmaceutics
• General area of study concerned with the formulation, manufacture, stability and
effectiveness of pharmaceutical dosage forms.
Biopharmaceutics
• Biopharmaceutics is a branch of pharmaceutical sciences that concerns the
interrelationship b/n the
 Route of administration,
 Physicochemical properties of a drug,
 Dosage form,
 Rate and extent of systemic drug absorption
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Intro….
• According to American pharmaceutical association, 1972
• Study of the factors influencing the bioavailability of a drug in man and
animals and the use of this information to optimize pharmacological or
therapeutic activity of drug products in clinical application.
• → Pharmacologic, toxicological, clinical response observed
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Introduction
 The objective of drug therapy is to deliver the right drug, in the right
concentration, to the right site of action, and at the right time to produce the
desired effect.
 Critical determinants of the in-vivo performance, safety and efficacy of the drug
product are:
 The physicochemical characteristics of the API
 The dosage form
 The route of administration
 The properties of the drug and its dosage form are carefully engineered and tested
to produce a stable drug product that upon
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Cont…
• Biopharmaceutics involves factors that influence
I. The stability of the drug within the drug product,
II. The release of the drug from the drug product,
III. The rate of dissolution/release of the drug at the absorption site, and
IV. The systemic absorption of the drug.
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Cont…
• For a drug to be effective, enough of it needs to reach its site of action(s) and stays
there long enough to be able to exert its pharmacological effect.
• Hence, it is the aim of biopharmaceutics to adjust the delivery of drug to the
general circulation (bioavailability) in such a manner as to provide optimal
therapeutic activity for the patient.
• The development of biopharmaceutical principles allowed
• For the rational design of drug products, which would enhance the delivery of active
drug, and optimize the therapeutic efficacy of the drug in the patient.
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Cont…
• The study of biopharmaceutics is based on fundamental scientific principles and
experimental methodology.
• Biopharmaceutic studies must be performed to ensure that
• The dosage form does not irritate, cause an allergic response or allow systemic
drug absorption.
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Cont…
• Studies in biopharmaceutics use both in-vitro and in-vivo methods.
• In-vitro methods
• Are procedures employing test apparatus and equipment without involving
laboratory animals or humans.
• E.g. disintegration tests, dissolution tests etc.
• In-vivo methods
• Are more complex studies involving human subjects or laboratory animals.
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Applications of biopharmaceutics
 Formulation development
 Bioavailability enhancement
 Pharmacokinetics studies
 Drug delivery system
 Generic drug development
 Drug safety and efficacy assessment
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Cont…
• Pharmacokinetics
• The quantitative study and characterization of time course of ADME of drugs and
their corresponding pharmacologic, therapeutic, or toxic responses in man and
animals (American Pharmaceutical Association, 1972).
• Characterization of drug disposition is an important prerequisite for determination
or modification of dosing regimens for individuals and groups of patients.
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Cont…
• Lord Kelvin:
• “when you can measure what you are speaking about, and express it in numbers,
you know something about it, but when you can not express it in numbers your
knowledge is unsatisfactory”.
• Translating words and phrases into mathematical symbols and equations and
finally clinically meaningful conclusions is the core of pharmacokinetics.
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Cont…
• The study of pharmacokinetics involves both experimental and theoretical
approaches.
• The experimental approach involves the
• Development of biological sampling techniques
• analytical methods development for the measurement of drugs and metabolites and
the procedures for data collection and manipulation.
• The theoretical aspect of pharmacokinetics involves the development of
pharmacokinetic models that predicts drug disposition after drug administration.
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Cont…
• Clinical pharmacokinetics:
• Application of pharmacokinetic methods to drug therapy.
• Individually optimized dosing strategies based on the patient's disease state and
patient-specific considerations
• Readjustment of dosage regimens when necessary
• Investigate the reason behind an unusual response
• Therapeutic drug monitoring (TDM) for very potent drugs such as those with a
narrow therapeutic range, in order to optimize efficacy and to prevent any adverse
toxicity
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Barriers of drug transport
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Cont…
• In order for a drug to reach a site of action it must pass from an ‘external’ site (for
example the surface of the skin or the small intestine) to an ‘internal’ site (the
bloodstream or the cytoplasm of a particular cell group).
• In doing so it will have to pass through a number of tissues and epithelia, either by
going through the cells themselves (and thus penetrating their plasma membranes)
or by finding pathways between the cells.
• Overcoming these barriers to absorption
• Requires a detailed knowledge of the structure and behavior of the cell membranes
and epithelial tissues and
• Drug delivery process,
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Nature of Cell Membranes
• Many drugs administered by extravascular routes are intended for local effect.
• Other drugs are designed to be absorbed from the site of administration into the
systemic circulation.
• For systemic drug absorption, the drug must cross cellular membranes.
• After oral administration, drug molecules must cross the intestinal epithelium by
going either through or between the epithelial cells to reach the systemic
circulation.
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Cont…
• The permeability of a drug at the absorption site into the systemic circulation is
intimately related to the molecular structure of the drug and to the physical and
biochemical properties of the cell membranes.
• Once in the plasma, the drug may have to cross biological membranes to reach the
site of action.
• Therefore, biological membranes potentially pose a significant barrier to drug
delivery.
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Cont…
• Membranes are major structures in cells, surrounding the entire cell (plasma
membrane) and acting as a boundary between the cell and the interstitial fluid.
• In addition, membranes enclose most of the cell organelles (eg, the mitochondrion
membrane).
• Functionally, cell membranes are semipermeable partitions that act as selective
barriers to the passage of molecules.
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Cont…
• Cell membranes are composed primarily of phospholipids in the form of a
bilayer interdispersed with carbohydrates and protein groups.
• The lipid layer in the middle of the membrane is impermeable to the usual water-
soluble substances, such as ions, glucose and urea.
• Conversely, fat-soluble substances, such as oxygen, carbon dioxide, and alcohol,
can penetrate this portion of the membrane with ease.
• There are several theories as to the structure of the cell membrane.
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Cont…
The lipid bilayer or unit membrane theory
• Considers the plasma membrane to be composed of two layers of phospholipid
between two surface layers of proteins, with the hydrophilic "head" groups of the
phospholipids facing the protein layers and the hydrophobic "tail" groups of the
phospholipids aligned in the interior.
• Explains that lipid-soluble drugs tend to penetrate cell membranes more easily
than polar molecules.
• However, the bilayer cell membrane structure does not account for the diffusion of
water, small-molecular-weight molecules such as urea, and certain charged ions.
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• The fluid mosaic model
• Explains the transcellular diffusion of polar molecules.
• According to this model, the cell membrane consists of globular proteins
embedded in a dynamic fluid, lipid bilayer matrix.
• These proteins provide a pathway for the selective transfer of certain polar
molecules and charged ions through the lipid barrier.
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• Model of the plasma membrane including proteins and carbohydrates as well as
lipids.
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Cont…
• Membranes in different parts of the body have somewhat different characteristics
which influence drug action and distribution.
• In particular, pore size and pore distribution is not uniform between different
parts of the body
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• Examples of Some Membrane Types
• Blood-brain barrier:
• The membranes between the blood and brain have effectively no pores.
• This will prevent many polar materials (often toxic materials) from entering the
brain.
• However, smaller lipid materials or lipid soluble materials, such as diethyl ether,
halothane, can easily enter the brain.
• These compounds are used as general anesthetics.
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Cont…
• Renal tubules: for reabsorption and elimination
• In the kidney there are a number of regions important for drug elimination.
• In the tubules drugs may be reabsorbed.
• However, because the membranes are relatively non-porous, only lipid compounds
or non-ionized species (dependent of pH and pKa) are reabsorbed.
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Cont…
• Blood capillaries and renal glomerular membranes
• These membranes are quite porous allowing non-polar and polar molecules (up to
a fairly large size, just below that of albumin, M.Wt69,000) to pass through.
• This is especially useful in the kidney since it allows excretion of polar (drug and
waste compounds) substances.
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Mechanism of drug transport
Transport through the cell membrane, either directly through the lipid bi-layer or
through the proteins, occurs by one of two basic processes: passive transport or
active transport.

Cont…
Mechanism…
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Passive Diffusion
• It is the process by which molecules spontaneously diffuse from a region of higher
concentration to a region of lower concentration.
• If the drug has a low molecular weight and is lipophilic, the lipid cell membrane
is not a barrier to drug diffusion and absorption.
• This process is passive because no external energy is expended.
• The rate of transfer is called flux, and is represented by a vector to show its
direction in space.
• The tendency of molecules to move in all directions is natural, because molecules
possess kinetic energy and constantly collide with one another in space.
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Cont…
Passive diffusion of molecules.
• Molecules in solution diffuse randomly in all directions.
• As molecules diffuse from left to right and vice versa (small arrows), a net
diffusion from the high-concentration side to the low-concentration side results.
• This results in a net flux (J) to the right side.
• Flux is measured in mass per unit area (eg, mg/cm2).
• Passive diffusion is the major absorption process for most drugs.
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Cont…
• The driving force for passive diffusion is higher drug concentrations on the
mucosal side compared to the blood.
• According to Fick's law of diffusion, 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 of
drug in the biologic membrane that controls drug permeation, A = surface area of membrane, h =
membrane thickness, CGI–Cp= difference between the concentrations of drug in the
gastrointestinal tract and in the plasma
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Cont…
• Because the drug distributes rapidly into a large volume after entering the blood,
the concentration of drug in the blood initially will be quite low with respect to the
concentration at the site of drug absorption.
• For example, a drug is usually given in milligram doses, whereas plasma
concentrations are often in the microgram-per-milliliter or nanogram-per-milliliter
range.
• If the drug is given orally, then CGl>> Cp and a large concentration gradient is
maintained, thus driving drug molecules into the plasma from the gastrointestinal
tract
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Cont…
• Given Fick's law of diffusion, several factors can be seen to influence the rate of
passive diffusion of drugs.
• The degree of lipid solubility of the drug influences the rate of drug absorption.
• The partition coefficient, K, represents the lipid–water partitioning of a drug
across the hypothetical membrane in the mucosa.
• Drugs that are more lipid soluble have a larger value of K.
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Cont…
• The surface area, A, of the membrane also influences the rate of absorption.
• Drugs may be absorbed from most areas of the gastrointestinal tract.
• However, the duodenal area of the small intestine shows the most rapid drug
absorption, due to such anatomic features as villi and microvilli, which provide a
large surface area.
• These villi are less abundant in other areas of the gastrointestinal tract.
• The thickness of the hypothetical model membrane, h, is a constant for any
particular absorption site.
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Cont…
• Drugs usually diffuse very rapidly through capillary plasma membranes in the
vascular compartments, in contrast to diffusion through plasma membranes of
capillaries in the brain.
• In the brain, the capillaries are densely lined with glial cells, so a drug diffuses
slowly into the brain as if a thick lipid membrane existed.
• The term blood–brain barrier is used to describe the poor diffusion of water-
soluble molecules across capillary plasma membranes into the brain.
• However, in certain disease states such as meningitis these membranes may be
disrupted or become more permeable to drug diffusion
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Cont…
• The diffusion coefficient, D, is a constant for each drug and is defined as
• The amount of a drug that diffuses across a membrane of a given unit area per unit
time when the concentration gradient is unity.
• The dimensions of D are area per unit time—for example, cm2/sec.
• Because D, A, K, and h are constants under usual conditions for absorption, a
combined constant P or permeability coefficient may be defined.
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Cont…
• Furthermore, in Equation 13.1
• The drug concentration in the plasma, Cp, is extremely small compared to the
drug concentration in the gastrointestinal tract, CGI.
• If Cp is negligible and P is substituted into the above equation, the following
relationship for Fick's law is obtained:
• This equation is an expression for a first-order process
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Cont…
• In practice, the extravascular absorption of most drugs tends to be a first-order
absorption process.
• Moreover, because of the large concentration gradient between CGI and Cp, the
rate of drug absorption is usually more rapid than the rate of drug elimination
• Many drugs have both lipophilic and hydrophilic chemical substituents.
• Those drugs that are more lipid soluble tend to traverse cell membranes more
easily than less lipid-soluble or more water-soluble molecules.
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Cont…
• For drugs that act as weak electrolytes, such as weak acids and bases, the extent
of ionization influences the rate of drug transport.
• The ionized species of the drug contains a charge and is more water soluble than
the non-ionized species of the drug, which is more lipid soluble.
• The extent of ionization of a weak electrolyte will depend on both the pKa of the
drug and the pH of the medium in which the drug is dissolved.
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Cont…
Henderson and Hasselbalch used the following expressions pertaining to weak
acids and weak bases to describe the relationship between pKa and pH:
• For weak bases,
• With the above equations, the proportion of free acid or free base existing as the
non-ionized species may be determined at any given pH, assuming the pKa for the
drug is known.
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Cont…
• In a simple system, the total drug concentration on either side of a membrane
should be the same at equilibrium, assuming Fick's law of diffusion is the only
distribution factor involved.
• For diffusible drugs, such as nonelectrolyte drugs or drugs that do not ionize, the drug
concentrations on either side of the membrane are the same at equilibrium.
• However, for electrolyte drugs or drugs that ionize, the total drug concentrations on
either side of the membrane are not equal at equilibrium if the pH of the medium
differs on respective sides of the membrane.
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Cont…
 According to the pH–partition hypothesis, if the pH on one side of a cell
membrane differs from the pH on the other side of the membrane, then
 The drug (weak acid or base) will ionize to different degrees on respective sides of
the membrane;
 The total drug concentrations (ionized plus non-ionized drug) on either side of the
membrane will be unequal; and
 The compartment in which the drug is more highly ionized will contain the greater
total drug concentration.
 For these reasons, a weak acid (such as salicylic acid) will be rapidly absorbed
from the stomach (pH 1.2), whereas a weak base (such as quinidine) will be
poorly absorbed from the stomach
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Cont…
 Another factor that can influence drug concentrations on either side of a
membrane is a particular affinity of the drug for a tissue component, which
prevents the drug from moving freely back across the cell membrane.
 For example, a drug such as dicumarol binds to plasma protein, and digoxin
binds to tissue protein.
 In each case, the protein-bound drug does not move freely across the cell
membrane.
 In addition, a drug such as tetracycline might form a complex with calcium in the
bones and teeth.
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Cont…
 Finally, a drug may concentrate in a tissue due to a specific uptake or active
transport process.
 Such processes have been demonstrated for
 iodide in thyroid tissue, potassium in the intracellular water, and certain
catecholamines into adrenergic storage sites.
 Such drugs may have a higher total drug concentration on the side where binding
occurs, yet the free drug concentration that diffuses across cell membranes will be
the same on both sides of the membrane
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Carrier-Mediated Transport
 In the intestine, drugs and other molecules can go through the intestinal epithelial
cells by either diffusion or a carrier-mediated mechanism.
 Numerous specialized carrier-mediated transport systems are present in the body,
especially in the intestine for the absorption of ions and nutrients required by the
body.
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Active Transport
 Active transport is a carrier-mediated transmembrane process that plays an
important role in the gastrointestinal absorption and in renal and biliary secretion
of many drugs and metabolites.
 A few lipid-insoluble drugs are absorbed from the gastrointestinal tract by this
process. E.g. 5-fluorouracil
 Active transport is characterized by the transport of drug against a concentration
gradient—that is, from low to high drug concentrations.
• Therefore, this is an energy-consuming system.
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Cont…
 The carrier molecule may be highly selective for the drug molecule.
 If the drug structurally resembles a natural substrate that is actively transported,
then it is likely to be actively transported by the same carrier mechanism.
 Therefore, drugs of similar structure may compete for sites of adsorption on the
carrier.
 Furthermore, because only a fixed number of carrier molecules are available, all
the binding sites on the carrier may become saturated if the drug concentration
gets very high.
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Cont…
 Notice that for a drug absorbed by passive diffusion, the rate of absorption
increases in a linear relationship to drug concentration.
 In contrast, when a drug is absorbed by a carrier-mediated process, the rate of drug
absorption increases with drug concentration until the carrier molecules are
completely saturated.
 At higher drug concentrations, the rate of drug absorption remains constant, or
zero order
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 Comparison of the rates of drug absorption of a drug absorbed by passive
diffusion (line A) and a drug absorbed by a carrier-mediated system (line B
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Cont…
 Various carrier-mediated systems (transporters) are present at the intestinal brush
border and basolateral membrane for the absorption of specific ions and nutrients
essential for the body
 Many drugs are absorbed by these carriers because of the structural similarity to
natural substrates
 A transmembrane protein, P-glycoprotein transporters (PGP, MDR-1) has been
identified throughout the body including liver, brain, kidney and the intestinal tract
epithelia.
• They appear to be an important component of drug absorption acting as reverse
pumps generally inhibiting absorption.
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Cont…
 This is an active, ATP-dependent process which can have a significant effect
on drug bioavailability.
 P-glycoprotein works against a range of drugs of molar weight 250 -1850
Dalton.
 This process has been described as multi-drug resistance (MDR).
 Clinically significant substrates of PGP include digoxin and phenytoin.
 A number of compounds can act as PGP inhibitors including
 atorvastatin (digoxin AUC increased),
 cyclosporine (increased paclitaxel absorption),
 grapefruit juice (increased paclitaxel absorption)
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Cont…
 Other transporters are also present in the intestines.
 For example, many oral cephalosporins are absorbed through the amino acid
transporter.
 Cefazolin, a parenteral-only cephalosporin, is not available orally because it
cannot be absorbed to a significant degree through this mechanism.
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Cont…
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Cont…
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Facilitated Diffusion
• Facilitated diffusion is also a carrier-mediated transport system, differing from
active transport in that the drug moves along a concentration gradient
• Therefore, this system does not require energy input.
• However, because this system is carrier mediated, it is saturable and structurally
selective for the drug and shows competition kinetics for drugs of similar
structure.
• In terms of drug absorption, facilitated diffusion seems to play a very minor role.
e.g. vitamin B12 transport
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Cont…
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Vesicular Transport
• Vesicular transport is the process of engulfing particles or dissolved materials by
the cell.
• Pinocytosis and phagocytosis are forms of vesicular transport that differ by the
type of material ingested.
• Pinocytosis refers to the engulfment of small solutes or fluid, whereas
phagocytosis refers to the engulfment of larger particles or macromolecules,
generally by macrophages.
• Endocytosis and exocytosis are the processes of moving specific macromolecules
into and out of a cell, respectively.
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Cont…
• During pinocytosis or phagocytosis, the cell membrane invaginates to surround
the material and then engulfs the material, incorporating it into the cell
• Subsequently, the cell membrane containing the material forms a vesicle or
vacuole within the cell.
• Vesicular transport is the proposed process for the absorption of orally
administered Sabin polio vaccine and various large proteins
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Diagram showing exocytosis and endocytosis
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Cont…
• An example of exocytosis is the transport of a protein such as insulin from
insulin-producing cells of the pancreas into the extracellular space.
• The insulin molecules are first packaged into intracellular vesicles, which then
fuse with the plasma membrane to release the insulin outside the cell.
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Pore (Convective) Transport
• Very small molecules (such as urea, water, and sugars) are able to cross cell
membranes rapidly, as if the membrane contained channels or pores.
• Although such pores have never been directly observed by microscopy, the model
of drug permeation through aqueous pores is used to explain renal excretion of
drugs and the uptake of drugs into the liver
• A certain type of protein called a transport protein may form an open channel
across the lipid membrane of the cell.
• Small molecules including drugs move through the channel by diffusion more
rapidly than at other parts of the membrane
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Ion-Pair Formation
• Strong electrolyte drugs are highly ionized or charged molecules
• Strong electrolyte drugs maintain their charge at all physiologic pH values and
penetrate membranes poorly.
• When the ionized drug is linked up with an oppositely charged ion, an ion pair is
formed in which the overall charge of the pair is neutral.
• This neutral drug complex diffuses more easily across the membrane.
• For example, the formation of ion pairs to facilitate drug absorption has been
demonstrated for propranolol, a basic drug that forms an ion pair with oleic acid,
and quinine, which forms ion pair with hexylsalicylate.
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Ion-pair transport of a cationic drug
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Cont…
• An interesting application of ion pairs is the complexation of amphotericin B and
DSPG (disteroylphosphatidyl glycerol) in some amphotericin B/liposome
products.
• Ion pairing may transiently alter distribution, reduce high plasma free drug
concentration, and reduce renal toxicity.
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Factors affecting oral drug
absorption

Outline
GIT anatomy and physiology
Physiologic factors
 Gastrointestinal pH, Stability in the GIT, GIT motility; emptying and
transit times, blood flow, effect of food, disease states, other drugs, pre-
systemic metabolism
Physiochemical factors
 Drug dissolution, particle size and surface area, crystal forms, salt
formation, Pka and PH, lipid solubility, pH-partition hypothesis
Formulation factors
 Drug release from different dosage form (Solution, suspension, capsules
and tablets), effects of excipients

Route of drug administration
 Drugs may be given by parenteral, enteral, inhalation, transdermal (percutaneous),
or intranasal route for systemic absorption.
 Each route of drug administration has certain advantages and disadvantages.
 The systemic availability and onset of drug action are affected by
• Blood flow to the administration site
• The physicochemical characteristics of the drug and the drug product and by
• Any pathophysiologic condition at the absorption site

• Many drugs are not administered orally because of drug instability in the
gastrointestinal tract or drug degradation by the digestive enzymes in the intestine.
• For example, erythropoietin and human growth hormone (somatrophin) are
administered intramuscularly, and insulin is administered subcutaneously or
intramuscularly, because of the potential for degradation of these drugs in the stomach
or intestine.
• Biotechnology products are often too labile to be administered orally and therefore
are usually given parenterally.
Cont…

• The oral route of administration is the most common and popular route of drug
dosing.
• The oral dosage form must be designed to account for
• Extreme pH ranges
• The presence or absence of food
• Degradative enzymes
• Varying drug permeability in the different regions of the intestine and
• Motility of the gastrointestinal tract
• Moreover, the physical, chemical, and pharmacologic properties of the drug itself
will affects absorption from the alimentary canal
Cont…

GI Anatomy and Physiology

Cont…
• Drugs administered orally pass through various parts of the enteral canal,
including the oral cavity, esophagus, and various parts of the gastrointestinal tract.
• Residues eventually exit the body through the anus.
• The total transit time, including gastric emptying, small intestinal transit, and colonic
transit, ranges from 0.4 to 5 days.
• The most important site for drug absorption is the small intestine.
• Small intestine transit time (SITT) ranges from 3 to 4 hours for most healthy subjects.

 If absorption is not completed by the time a drug leaves the small intestine,
absorption may be erratic or incomplete.
 The small intestine is normally filled with digestive juices and liquids, keeping
the lumen contents fluid.
 In contrast, the fluid in the colon is reabsorbed, and the luminal content in the
colon is either semisolid or solid, making further drug dissolution erratic and
difficult.
Cont…

Oral cavity
• Saliva is the main secretion of the oral cavity, and it has a pH of about 7
• Saliva contains ptyalin (salivary amylase), which digests starches.
• Mucin, a glycoprotein that lubricates food, is also secreted and may interact with
drugs.
• About 1500 mL of saliva is secreted per day.
Cont…

Esophagus
• The esophagus connects the pharynx and the cardiac orifice of the stomach.
• The pH of the fluids in the esophagus is between 5 and 6.
• The lower part of the esophagus ends with the esophageal sphincter, which prevents
acid reflux from the stomach.
• Tablets or capsules may lodge in this area, causing local irritation.
• Very little drug dissolution occurs in the esophagus
Cont…

Stomach
• The stomach is innervated by the vagus nerve.
• However, local nerve plexus, hormones, mechanoreceptors sensitive to the stretch
of the GI wall, and chemoreceptors control the regulation of gastric secretions,
including acid and stomach emptying.
• The fasting pH of the stomach is about 2 to 6.
• In the presence of food, the stomach pH is about 1.5 to 2, due to hydrochloric acid
secreted by parietal cells.
• Stomach acid secretion is stimulated by gastrin and histamine
Cont…

• Gastrin is released from G cells, mainly in the antral mucosa and also in the
duodenum.
• Gastrin release is regulated by stomach distention (swelling) and the presence of
peptides and amino acids.
• A substance called intrinsic factor for vitamin B-12 absorption and various gastric
enzymes, such as pepsin, which initiates protein digestion, are secreted into the
gastric lumen to initiate digestion.
• Basic drugs are solubilized rapidly in the presence of stomach acid.
Cont…

• Mixing is intense and pressurized in the antral part of the stomach, a process of
breaking down large food particles described as antral milling
• Food and liquid are emptied by opening the pyloric sphincter into the duodenum.
• Stomach emptying is influenced by the food content and osmolality.
• Fatty acids and mono-and diglycerides delay gastric emptying
• High-density foods generally are emptied from the stomach more slowly.
Cont…

Duodenum
• A common duct from the pancreas and the gallbladder enters into the duodenum.
• The duodenal pH is about 6 to 6.5, because of the presence of bicarbonate that
neutralizes the acidic chyme emptied from the stomach.
• The pH is optimum for enzymatic digestion of protein and peptide food.
• Pancreatic juice containing enzymes is secreted into the duodenum from the bile
duct.
• Trypsin, chymotrypsin, and carboxypeptidase are involved in the hydrolysis of
proteins into amino acids.
Cont…

Cont…
• Amylase is involved in the digestion of carbohydrates.
• Pancreatic lipase secretion hydrolyzes fats into fatty acid.
• The complex fluid medium in the duodenum helps to dissolve many drugs with
limited aqueous solubility.
• The duodenum is a site where many ester prodrugs are hydrolyzed during
absorption.
• The presence of proteolytic enzymes also makes many protein drugs unstable in
the duodenum, preventing adequate absorption

Jejunum
• The jejunum is the middle portion of the small intestine, between the duodenum
and the ileum.
• Digestion of protein and carbohydrates continues after addition of pancreatic
juice and bile in the duodenum.
• This portion of the small intestine generally has fewer contractions than the
duodenum and is preferred for in-vivo drug absorption studies
Cont…

Ileum
• The ileum is the terminal part of the small intestine.
• The pH is about 7, with the distal part as high as 8.
• Due to the presence of bicarbonate secretion, acid drugs will dissolve.
• Bile secretion helps to dissolve fats and hydrophobic drugs.
• The ileocecal valve separates the small intestine from the colon.
Cont…

Colon
• The colon lacks villi and has limited drug absorption also, because of the more
viscous and semisolid nature of the lumen contents.
• The colon is lined with mucin that functions as lubricant and protectant.
• The pH in this region is 5.5 to 7.
• A few drugs, such as theophylline and metoprolol, are absorbed in this region.
• Drugs that are absorbed well in this region are good candidates for an oral
sustained-release dosage form.
Cont…

• The colon contains both aerobic and anaerobic microorganisms that may
metabolize some drugs.
• For example, L-dopa and lactulose are metabolized by enteric bacteria.
• Crohn's disease affects the colon and thickens the bowel wall.
• Absorption of clindamycin and propranolol are increased, whereas other drugs
have reduced absorption with this disease
Cont…

Rectum
• The rectum is about 15 cm long, ending at the anus.
• In the absence of fecal material, the rectum has a small amount of fluid
(approximately 2 mL) with a pH about 7.
• The rectum is perfused by the superior, middle, and inferior hemorrhoidal veins.
• The inferior hemorrhoidal vein (closest to the anal sphincter) and the middle
hemorrhoidal vein feed into the vena cava and back to the heart.
• The superior hemorrhoidal vein joins the mesenteric circulation, which feeds into
the hepatic portal vein and then to the liver
Cont…

Drug Absorption in the Gastrointestinal Tract
• Drugs may be absorbed by passive diffusion from all parts of the alimentary canal
including: sublingual, buccal, GI and rectal absorption.
• For most drugs, the optimum site for drug absorption after oral administration is
the upper portion of the small intestine or duodenum region.
• The unique anatomy of the duodenum provides an immense surface area for the
drug to diffuse passively.
Cont…

• The large surface area of the duodenum is due to the presence of valve like folds
in the mucous membrane on which are small projections known as villi.
• These villi contain even smaller projections known as microvilli, forming a brush
border.
• In addition, the duodenal region is highly perfused with a network of capillaries,
which helps to maintain a concentration gradient from the intestinal lumen and
plasma circulation.
Cont…

Physiologic factors affecting oral drug absorption
 Gastrointestinal pH
 Stability in the GIT
 GIT motility; emptying and transit times
 Blood flow
 Effect of food
 Disease states
 Other drugs
 Pre-systemic metabolism

I. Gastrointestinal pH
• The pH of fluids varies along the length of the GIT.
• The gastrointestinal pH may influence the absorption of drugs in a variety of
ways:
• It may affect the chemical stability of the drug in the lumen e.g. penicillin G,
erythromycin
• Affect the drug dissolution or absorption e.g. weak electrolyte drug
Cont…

II. Stability in the GIT
• The primary enzyme found in gastric juice is pepsin. lipases, amylases and
proteases are secreted from the pancreas into the small intestine.
• Pepsins and proteases are responsible for the digestion of protein and peptide drugs in
the lumen.
• HCl can also destroy a lot of acid labile drugs
• lipases may affect the release of drugs from fat / oil –containing dosage forms.
• Bacteria which are localized within the colonic region of the GIT secrete enzymes
which are capable of a range of reactions.
Cont…

III. Gastric Emptying
• The time a dosage form takes to traverse the stomach is usually termed: the gastric
residence time, gastric emptying time or gastric emptying rate.
• Relatively few drugs are believed to be absorbed from the stomach.
• Most are retained there temporarily, largely in solution, and are progressively
delivered to the small intestine, because it has the greatest capacity for the
absorption of drugs
Cont…

• A delay in the gastric emptying time for the drug to reach the duodenum will slow
the rate and possibly the extent of drug absorption, thereby prolonging the
onset time for the drug.
• For example, a good correlation has been found between stomach emptying time and
peak plasma concentration for acetaminophen.
• The quicker the stomach emptying (shorter stomach emptying time) the higher the plasma
concentration.
Cont…

• Some drugs, such as penicillin, are unstable in acid and decompose if stomach
emptying is delayed.
• Other drugs, such as aspirin, may irritate the gastric mucosa during prolonged
contact.
• A number of factors affect gastric emptying time
• Some factors that tend to delay gastric emptying include consumption of meals
high in fat, cold beverages, and anticholinergic drugs
• Liquids and small particles less than 1 mm are generally not retained in the stomach.
• Large particles, including tablets and capsules, are delayed from emptying for 3 to 6
hours by the presence of food in the stomach.
Cont…

Factors affecting gastric emptying

IV. Intestinal Motility: SITT
• Normal peristaltic movements mix the contents of the duodenum, bringing
the drug particles into intimate contact with the intestinal mucosal cells.
• The drug must have a sufficient time (residence time) at the absorption site
for optimum absorption.
• In the case of high motility in the intestinal tract, as in diarrhea, the drug has
a very brief residence time and less opportunity for adequate absorption
Cont…

• The average normal small intestine transit time (SITT) is about 3 to 4 hours.
• Thus a drug may take about 4 to 8 hours to pass through the stomach and small
intestine during the fasting state.
• During the fed state, SITT may take 8 to 12 hours.
• For modified-release or controlled-dosage forms, which slowly release the drug
over an extended period of time, the dosage form must stay within a certain
segment of the intestinal tract so that the drug contents are released and absorbed
before loss of the dosage form in the feces.
Cont…

• V. Perfusion of the Gastrointestinal Tract
• The blood flow to the GI tract is important in carrying absorbed drug to the
systemic circulation.
• A large network of capillaries and lymphatic vessels perfuse the duodenal region
and peritoneum.
• The splanchnic circulation receives about 28% of the cardiac output and is
increased after meals.
• Once the drug is absorbed from the small intestine, it enters via the mesenteric
vessels to the hepatic-portal vein and the liver prior to reaching the systemic
circulation.
Cont…

• Any decrease in mesenteric blood flow, as in the case of congestive heart failure,
will decrease the rate of drug removal from the intestinal tract, thereby reducing
the rate of drug bioavailability
• Drugs are absorbed through the lacteal or lymphatic vessels under the microvilli.
• Absorption of drugs through the lymphatic system bypasses the first-pass effect due
to liver metabolism, because drug absorption through the hepatic-portal vein is
avoided.
Cont…

• The lymphatics are important in the absorption of dietary lipids and may be
partially responsible for the absorption for some lipophilic drugs.
• Many poorly water-soluble drugs are soluble in oil and lipids, which may dissolve
in chylomicrons and be absorbed systemically via the lymphatic system.
• Bleomycin or aclarubicin were prepared in chylomicrons to improve oral
absorption through the lymphatic system
Cont…

VI. Effect of Food
 The presence of food in the GI tract can affect the bioavailability of the drug from
an oral drug product.
 Digested foods contain amino acids, fatty acids, and many nutrients that may
affect intestinal pH and solubility of drugs.
 The effects of food are not always predictable and can have clinically
significant consequences.
Cont…

Some effects of food on the bioavailability of a drug from a drug product include:
 Complexation of drugs with components in the diet
 A change in the pH of the GI tract
 Delay in gastric emptying
 Stimulation of gastrointestinal secretions: Enzymes and SAAs
 Competition between food components and drugs for specialized absorption
mechanisms
 Increased viscosity of gastrointestinal contents
 Food-induced changes in pre-systemic metabolism
 Food-induced changes in blood flow
Cont…

Complexation of drugs with components in the diet
• Can cause reduced, delayed, increased, accelerated or no effect of drug absorption
• e.g. Tetracycline forms non-absorbable complexes with calcium and iron, and
• thus it is advised that patients do not take products containing calcium or iron, such as
milk, iron preparations or indigestion remedies, at the same time of day as the
tetracycline.
Cont…

A change in the pH of the GI tract
 For some basic drugs (e.g., cinnarizine) with limited aqueous solubility, the
presence of food in the stomach stimulates hydrochloric acid secretion, which
lowers the pH, causing more rapid dissolution of the drug and better absorption.
 Absorption of this basic drug is reduced when gastric acid secretion is reduced
 Co-administration of sodium bicarbonate raises the stomach pH and reduces
tetracycline dissolution and absorption
Cont…

Delay in gastric emptying
 The nutrient and caloric contents of the meal, the meal volume, and the meal
temperature can cause physiologic changes in the GI tract in a way that affects
drug product transit time, luminal dissolution, drug permeability, and systemic
availability.
 In general, meals that are high in total calories and fat content are more likely to
affect GI physiology and thereby result in a larger effect on the bioavailability of a
drug substance or drug product.
 The GI transit time for enteric-coated and non-disintegrating drug products may
also be affected by the presence of food.
Cont…

 Enteric-coated tablets may stay in the stomach for a longer period of time because
food delays stomach emptying.
 Thus, the enteric-coated tablet does not reach the duodenum rapidly, delaying drug
release and systemic drug absorption.
 Fine granules (smaller than 1 to 2 mm in size) and tablets that disintegrate are not
significantly delayed from emptying from the stomach in the presence of food
Cont…

Stimulation of gastrointestinal secretions: Enzymes and SAAs
 Gastrointestinal secretions (e.g. pepsin) produced in response to food may result in
the degradation of drugs that are susceptible to enzymatic metabolism, and hence a
reduction in their bioavailability.
 Fats stimulate the secretion of bile. Bile salts are surface active agents (SAA)
which increase the dissolution of poorly soluble drugs (griseofulvin)
 Bile salts can form insoluble and non-absorbable complexes with some drugs,
such as neomycin, nystatin and kanamycin and fatty meals not recommended
Cont…

Competition between food components and drugs for specialized absorption
mechanisms
 There is a possibility of competitive inhibition of drug absorption in case of drugs that
have a chemical structure similar to nutrients required by the body for which
specialized absorption mechanisms exist.
Increased viscosity of gastrointestinal contents
 The presence of food in the GIT provides a viscous environment which may
result in:
 Reduction in the rate of drug dissolution
 Reduction in the rate of diffusion of drug in solution from the lumen to the absorbing
membrane lining the GIT.
 Hence, both of these effects tend to decrease the drug bioavailability.
Cont…

Food-induced changes in pre-systemic metabolism (increase or decrease)
 Certain foods may increase the bioavailability of drugs that are susceptible to pre-
systemic intestinal metabolism by interacting with the metabolic process.
 E.g. Grapefruit juice is capable of inhibiting intestinal cytochrome P450 (CYP3A4)
and thus taken with drugs that are susceptible to CYP3A4 metabolism which result in
increase of their bioavailability.
 Clinically relevant interactions with grape juice is reported for the following drugs:
Terfenadine, cyclosporine, saquinavir, verapamil
Cont…

Food-induced changes in blood flow
 Food serve to increase the bioavailability of some drugs (e.g. propranolol) that
are susceptible to first-pass metabolism.
 Blood flow to the GIT and liver increases shortly after a meal.
 The faster the rate of drug presentation to the liver; the larger the fraction of drug
that escapes first-pass metabolism.
 This is because the enzyme systems responsible for their metabolism become
saturated by increased rate of presentation of the drug to the site of
biotransformation.
 For this reason, the effects of food serve to increase BA of some drugs that are
susceptible to 1st pass metabolism.
Cont…

Effect of fluid intake
 Most drugs should be taken with a full glass (approximately 8 fluid ounces) of
water to ensure that drugs will wash down the esophagus.
 Generally, the bioavailability of drugs is better in patients in the fasted state and
with a large volume of water
 The solubility of many drugs is limited, and sufficient fluid is necessary for
dissolution of the drug.
 Fluid volume tends to distend the stomach and speed up stomach emptying
Cont…

Irritant drugs and food
 Some drugs, such as erythromycin, iron salts, aspirin, and nonsteroidal anti-
inflammatory agents (NSAIDs), are irritating to the GI mucosa and are given
with food to reduce this irritation.
 For these drugs, the rate of absorption may be reduced in the presence of food, but
the extent of absorption may be the same and the efficacy of the drug is retained
Cont…

Timing of drug administration in relation to meals
 Pharmacists regularly advise patients to take a medication either 1 hour before or 2
hours after meals to avoid any delay in drug absorption.
 Since fatty foods may delay stomach emptying time beyond 2 hours, patients who
have just eaten a heavy, fatty meal should take these drugs 3 hours or more after the
meal, whenever possible.
Cont…

• Drugs with absorption reduced, delayed, increased, increased, or not affected by
the presence of food

Cont…
VII. Effect of Disease States on Drug Absorption
 Drug absorption may be affected by any disease that causes changes in
1. Intestinal blood flow,
2. Gastrointestinal motility,
3. Changes in stomach emptying time,
4. Gastric pH that affects drug solubility,
5. Intestinal pH that affects the extent of ionization,
6. The permeability of the gut wall,
7. Bile secretion,
8. Digestive enzyme secretion, or
9. Alteration of normal GI flora.

Several clinical examples are given below:
 Achlorhydria
 Patients may not have adequate production of acids in the stomach; stomach HCl
is essential for solubilizing insoluble free bases.
 Many weak-base drugs that cannot form soluble salts will remain undissolved in
the stomach when there is no hydrochloric acid present and are therefore
unabsorbed.
 Salt forms of these drugs cannot be prepared because the free base readily precipitates
out due to the weak basicity
 Dapsone, itraconazole, and ketoconazole may be less well absorbed in the presence
of achlorhydria.
Cont…

 Achlorhydria may or may not decrease absorption, depending on the acidity
needed for absorption of a specific drug.
 Indinavir, for example, requires a normal acidic environment for absorption.
 In patients with acid reflux disorders, proton pump inhibitors, such as
omeprazole, render the stomach achlorhydric, which may also affect drug
absorption.
 Co-administering orange juice, colas, or other acidic beverages can facilitate the
absorption of some medications requiring an acidic environment
 Patients in an advanced stage of Parkinson's disease may have difficulty
swallowing and greatly diminished gastrointestinal motility.
Cont…

HIV-AIDS
 Patients are prone to a number of gastrointestinal (GI) disturbances, such as
increased gastric transit time, diarrhea, and achlorhydria.
 Rapid gastric transit time and diarrhea can alter the absorption of orally
administered drugs.
Cont…

Congestive heart failure (CHF)
 Patients with persistent edema have reduced splanchnic blood flow and develop
edema in the bowel wall.
 In addition, intestinal motility is slowed.
 The reduced blood flow to the intestine and reduced intestinal motility results in a
decrease in drug absorption.
 For example, furosemide (Lasix), a commonly used loop diuretic, has erratic and
reduced oral absorption in patients with CHF and a delay in the onset of action
Cont…

 Is an inflammatory disease of the distal small intestine and colon.
 The disease is accompanied by regions of thickening of the bowel wall,
overgrowth of anaerobic bacteria, and sometimes obstruction and deterioration of
the bowel.
 The effect on drug absorption is unpredictable, although impaired absorption may
potentially occur because of reduced surface area and thicker gut wall for
diffusion.
 For example, higher plasma propranolol concentration has been observed in patients
with Crohn's disease after oral administration of propranolol
Crohn's disease

Celiac disease
 An inflammatory disease affecting mostly the proximal small intestine.
 Patients with celiac disease generally have an increased rate of stomach emptying
and increased permeability of the small intestine.
 Cephalexin absorption appears to be increased in celiac disease, although it is not
possible to make general predictions about these patients.
 Other intestinal conditions that may potentially affect drug absorption include
 Corrective surgery involving peptic ulcer,
 Antrectomy with gastroduodenostomy, and
 Selective vagotomy.

Cont…
VIII. Drugs that affect absorption of other drugs
 Anticholinergic drugs in general may reduce stomach acid secretion.
 Propantheline bromide is an anticholinergic drug that may slow stomach emptying
and motility of the small intestine.
 Tricyclic antidepressants and phenothiazines also have anticholinergic side effects
that may cause slower peristalsis in the GI tract.

 Metoclopramide is a drug that stimulates stomach contraction, relaxes the pyloric
sphincter, and, in general, increases intestinal peristalsis, which may reduce the
effective time for the absorption of some drugs and thereby reduce the peak drug
concentration and the time to reach peak drug concentration.
 For example, digoxin absorption from a tablet is reduced by metoclopramide but
increased by an anticholinergic drug, such as propantheline bromide.
Cont…

 Antacids containing aluminum, calcium, or magnesium may complex with drugs
such as tetracycline, ciprofloxacin, and indinavir, resulting in a decrease in drug
absorption.
 To avoid this interaction, antacids should be taken 2 hours before or 6 hours after
drug administration.
 As mentioned, proton pump inhibitors, such as omeprazole, render the stomach
achlorhydric, which may also affect drug absorption
 Cholestyramine adsorbs warfarin, thyroxine, and loperamide, similar to activated
charcoal, thereby reducing absorption of these drugs
Cont…

 Absorption of calcium in the duodenum is an active process facilitated by vitamin
D, with calcium absorption as much as four times more than that in vitamin D
deficiency states.
 It is believed that a calcium-binding protein, which increases after vitamin D
administration, binds calcium in the intestinal cell and transfers it out of the base
of the cell to the blood circulation
Cont…

IX. Nutrients that interfere with drug absorption
 Many nutrients substantially interfere with the absorption or metabolism of drugs
in the body
 Oral drug–nutrient interactions are often drug specific and can result in either an
increase or decrease in drug absorption
 Absorption of water-soluble vitamins, such as vitamin B-12 and folic acid, are
aided by special absorption mechanisms (intrinsic factors)
 Grapefruit juice often increases bioavailability, as observed by an increase in
plasma levels of many drugs that are substrates for cytochrome P450 (CYP) 3A4
Cont…

X. Pre-systemic metabolism
 Is a phenomenon of drug metabolism whereby the concentration of a drug is
greatly reduced before it reaches the systemic circulation.
 It is the fraction of drug lost during the process of absorption which is generally
related to the liver and gut wall.
 Notable drugs that experience a significant first-pass effect are imipramine,
morphine, propranolol, buprenorphine, diazepam, midazolam, pethidine,
cimetidine, lidocaine, and nitroglycerin.
 After a drug is swallowed, it is absorbed by the digestive system and enters the
hepatic portal system.
Cont…

 It is carried through the portal vein into the liver before it reaches the rest of the
body.
 The liver metabolizes many drugs, sometimes to such an extent that only a small
amount of active drug emerges from the liver to the rest of the circulatory system.
 The four primary systems that affect the first pass effect of a drug are the enzymes
of the gastrointestinal lumen, gut wall enzymes, bacterial enzymes, and
hepatic enzymes.
 Oral bioavailability is apparently increased in patients with severe liver diseases
like Cirrhosis.
 It is also increased if another drug competing with it in first pass metabolism given
concurrently.
 Eg. propranolol and chlorpromazine
Cont…

Physicochemical factors
affecting oral absorption
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Cont…
• The physicochemical properties of the drug that will influence its
passage into solution and transfer across membranes includes:
• Water Solubility/Lipophillicity (solubility and permeability)
• Crystal and amorphous forms of drugs
• pH-pKa (pH-partition theory)
• Particle size and Surface area
• Salt/solvate forms of the drug
• Chemical stability
• Complexation potential of drug
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Solubility and Permeability
• Solubility and intestinal permeability are the major physicochemical factors that
affect the rate and extent of absorption of an oral drug product
Solubility
• The first requirement for absorption is dissolution of the active compound
• Only compound in solution is available for permeation across the gastrointestinal
membrane.
• Solubility has long been recognized as a limiting factor in the absorption process.
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Noyes Whitney Equation
Where
• dC/dt: the rate of dissolution of the drug particles
• D: the diffusion coefficient of the drug in solution in the gastrointestinal fluids
• A: the effective surface area of the drug particles in contact with the
gastrointestinal fluids
• h: the thickness of the diffusion layer around each drug particle
• Cs: the saturation solubility of the drug in solution in the diffusion layer
• C: the concentration of the drug in the gastrointestinal fluids
h
C
C
A
D
dt
dC S )
( 


C
Diffusion layer
Cs
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Cont…
• Dissolution rate (solubility) of a drug can be affected by physiological and drug
factors;
• Presence of food in GIT may cause a decrease in dissolution rate of drug by reducing
the rate of diffusion of drug away from diffusion layer
• Surfactants in gastric juice and bile salts will affect both wettability of the drug and
effective surface area exposed to GI fluids and solubility via micellization
• Increase in GI motility may increase dissolution rate of sparingly soluble drug
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Cont…
Permeability
 Permeability is another important factor in achieving desirable oral bioavailability.
 The structure of cellular membranes is described as an interrupted phospholipid
bilayer capable of both hydrophilic and hydrophobic interaction
 The two most common ways for the absorption of drugs are:
 Passive transfer by diffusion across the lipid membranes (transcellular, for lipophilic
molecules) and
 Passive diffusion through the aqueous pores (paracellular, for hydrophilic molecules)
at the tight junctions between cells.
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Biopharmaceutics

Cont…
 Some drugs are poorly absorbed after oral administration even though they are
non-ionized in small intestine.
 Low lipid solubility of them may be the reason.
 The best parameter to correlate between water and lipid solubility is partition
coefficient.
Partition coefficient (p) = [ L] conc / [W] conc
 where, [ L] conc. is the concentration of the drug in lipid phase, [W] conc is the
concentration of the drug in aqueous phase.
 The higher p value, the more absorption is observed.
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Biopharmaceutics

Cont…
• For example, the barbiturates, barbitone and thiopentone, have similar
dissociation constants - pKa 7.8 and 7.6, respectively - and therefore similar
degrees of ionization at intestinal pH.
• However, thiopentone is absorbed much better than barbitone.
• Thiopentone, being more lipid soluble than barbitone, exhibits a greater affinity for
the gastrointestinal membrane and is thus far better absorbed.
• Hence, the lipophilicity of a drug is critical in the drug discovery process.
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Cont…
• Lipid soluble drugs with favorable partition coefficients (i.e. log P > 0) are usually
absorbed in adequately sufficient amount after oral administration.
• Polar molecules, (log P < 0) and relatively large, such as gentamicin, ceftriaxone,
heparin and streptokinase, are poorly absorbed after oral administration and
therefore have to be given via I.V. injection.
• Smaller molecules that are poorly lipid soluble, i.e. hydrophilic in nature, such as
the Beta-blocker atenolol, can be absorbed via the paracellular route.
• Drugs which are very lipid soluble (log P >3) tend to be well absorbed but are
also more likely to be susceptible to metabolism and biliary clearance.
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Polymorphism
• Polymorphism is the ability of a solid material to exist in more than one form
or crystal structure
• Materials in the solid state can be crystalline or amorphous (or a combination of
both).
• Crystalline materials are those in which the molecules are packed in a defined
order, and this same order repeats over and over again throughout the particle.
• Amorphous forms refers to absence of crystalline structure.
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Cont…
• The amorphous or crystalline character of a drug substance may be of
considerable importance to:-
• formulation and handling, its chemical stability, and biological activity.
• The differences are manifested as long as the drug is in solid state.
• Once solution is effected, the different forms are indistinguishable one from
another
• Therefore, differences in drug action, pharmaceutically and therapeutically, can be
expected from polymorphs contained in solid dosage forms and/or in liquid
suspension
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Cont…
• Many drugs can exist in more than one crystalline form, e.g. Chloramphenicol
palmitate, cortisone acetate, tetracyclines and sulphathiazole
• The various polymorphic forms of the same chemical generally differ in many
physical properties including:
• Solubility and dissolution characteristics (prime importance to rate and extent of drug
absorption into the body’s system),
• Density,
• Hardness and
• Compression and powder flow characteristics
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Cont…
• Stable polymorphic crystals have much lower aqueous solubility than the
metastable forms, causing a product to be incompletely absorbed.
• E.g. Chloramphenicol palmitate (designated as A, B and C forms)
• At normal temperature and pressure
• A is the stable polymorph,
• B is the metastable polymorph and
• C is the unstable polymorph.
• Polymorph C is too unstable to be included in a dosage form, but polymorph B,
the metastable form, is sufficiently stable to be included in a dosage form.
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Cont…
• Polymorph A is not included in formulation as it is therapeutically ineffective.
• It is possible for the commercial products of two manufacturers to differ in
stability and therapeutic effect, depending upon crystalline form of drug used
• The plasma profiles of chloramphenicol from orally administered suspensions
containing varying proportions of the polymorphic forms A and B were
investigated.
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Cont…
• The extent of absorption of chloramphenicol increases as
the proportion of the polymorphic form B of
chloramphenicol palmitate is increased in each suspension.
• This was attributed to the more rapid in vivo rate of
dissolution of the metastable polymorphic form, B, of
chloramphenicol palmitate.
• Following dissolution, chloramphenicol palmitate, B, is
hydrolysed to give free chloramphenicol in solution, which
is then absorbed.
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Cont…
• The stable polymorph A dissolves slowly and consequently is hydrolyzed so
slowly to chloramphenicol in vivo that this polymorph is virtually ineffective.
• In general , a change in crystal form may cause problems in manufacturing the
product (compressibility problem), stability and biological activity.
• For example, a change in crystal structure of the drug may cause cracking in a
tablet or even inability for a granulation to be compressed to form a tablet.
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Cont…
• For drugs that are freely soluble in water the bioavailability is not likely to be
limited by the dissolution, so it would be surprising for polymorphism to influence
bioavailability in this way.
• However, for drugs with low aqueous solubility the polymorphic form must be
well controlled to ensure that the bioavailability is the same each time the product
is made, and throughout the shelf-life of the product.
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Cont…
• A classic example of the influence of amorphous versus crystalline forms of a
drug on its bioavailability is provided by that of the antibiotic Novobiocin and
Insulin.
• The more soluble and rapidly dissolving amorphous form of novobiocin was
readily absorbed following oral administration of an aqueous suspension.
• However, the less soluble and slower-dissolving crystalline form of novobiocin
was not absorbed to any significant extent and thus therapeutically ineffective.
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Cont…
• Insulin presents another striking example of different degree of activity that may
result from the use of different physical forms.
• The amorphous form, referred to as semilente insulin or promt insulin zinc
suspension is rapidly absorbed upon IM or SC (under skin) injection
• The larger crystalline material (ultra lente insulin or extended insulin zinc
suspension) is more slowly absorbed with resultant longer duration of action
• A physical mixture of 70% of crystalline form and 30% of amorphous form
(Lente insulin) is commercially available and provides an intermediate acting
insulin preparation that meets the requirements of many diabetics.
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pH-Partition Theory
• According to the pH-partition hypothesis,
• Gastrointestinal epithelia acts as a lipid barrier towards drugs which
are absorbed by passive diffusion, and those that are lipid soluble will
pass across the barrier.
• As most drugs are weak electrolytes, the unionized form of weakly
acidic or basic drugs (the lipid-soluble form) will pass across the
gastrointestinal epithelia, whereas the gastrointestinal epithelia is
impermeable to the ionized (poorly-lipid soluble) form of such drugs.
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Cont…
• Consequently, the absorption of a weak electrolyte will be determined by the
extent to which the drug exists in its unionized form at the site of absorption.
• The extent to which a weakly acidic or basic drug ionizes in solution in the
gastrointestinal fluid may be calculated using Henderson - Hasselbach equation.
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Cont…
Limitations of the pH-partition hypothesis:
• Despite their high degree of ionization, weak acids are highly absorbed from the
small intestine and this may be due to:
• The large surface area available for absorption in the small intestine.
• A longer small intestine residence time.
• Some drugs are poorly absorbed after oral administration even though they are
non-ionized in small intestine
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Particle Size and Surface Area
• The smaller the particle size the greater the effective surface area of drug particle
the higher the dissolution rate and absorption or bioavailability.
• When a drug particle is reduced to a larger number of small particles the total
surface created is increased
• For drug substances that are poorly or sparingly soluble, this generally results in
an increase in the rate of dissolution
• Particle size reduction is thus likely to result in increased bioavailability, provided
the absorption of the drug is dissolution-rate limited.
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Cont…
• Example: Griseofulvin, where a reduction of particle size from about 10 µm to 2.7
µm was shown to produce approximately double the amount of drug absorbed.
• Such improvements in bioavailability can result in an increased incidence of side-
effects, thus for certain drugs it is important that the particle size is well
controlled.
• For some drugs, particularly those that are hydrophobic in nature, micronization
and other dry particle size-reduction techniques can result in aggregation of the
material
• Aggregation results in reduction in the effective surface area exposed to the
gastrointestinal fluids and hence their dissolution rate and bioavailability.
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Cont…
• Aspirin, phenacetin and phenobarbitone are all prone to aggregation during
particle size reduction
• One approach that may overcome this problem is to micronize or mill the drug
with a wetting agent or hydrophilic carrier.
• To overcome aggregation and to achieve particle sizes in the nano-size region, wet
milling in the presence of stabilizers has been used.
• The relative bioavailability of danazol has been increased 400% by administering
particles in the nano- rather than the micrometre size range.
11/21/2023 157
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Cont…
• the effective surface area of hydrophobic drugs can be increased by the addition of
a wetting agent to the formulation.
• The presence of polysorbate-80 in a fine suspension of phenacetin (particle size
less than 75 µm) greatly improved the rate and extent of absorption of the
phenacetin in human volunteers compared to the same size suspension without a
wetting agent.
• Polysorbate-80 helps by increasing the wetting and solvent penetration of
particles and by minimizing aggregation of suspended particles, thereby
maintaining large surface area
• If an increase in the effective surface area of a drug does not increase its
absorption rate it is likely that the dissolution process is not rate limiting.
11/21/2023 158
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Cont…
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Cont…
• For drugs such as penicillin G and erythromycin, which are unstable in gastric
fluids, their chemical degradation will be minimized if they remain in the solid
state.
• Thus particle size reduction would not only serve to increase their dissolution rate,
but would also increase chemical degradation and therefore reduce the amount of
intact drug available for absorption.
• Due to different rates and degrees of absorption obtainable from drugs of various
particle size, it is conceivable that the products of the same drug substance
prepared by two or more reliable pharmaceutical manufacturers may result in
different degrees of therapeutic response in the same individual.
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Cont…
 A classic example is phenytoin sodium capsules where there are two distinct
forms.
 Because of such differences in formulation for a number of drugs and drug products,
it is generally advisable for a person to continue taking the same brand of medication,
provided it produces the desired therapeutic effect.
 Patients who are stabilized on one brand of drug should not be switched to another
unless necessary.
 When change is necessary appropriate plasma concentrations should be monitored
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Salt Forms/Solvation
 Salts of weak acids and weak bases generally have much higher aqueous solubility
than the free acid or base, therefore if the drug can be given as a salt the solubility
can be increased and we should have improved dissolution.
 Salt forms of drugs are selected:
 To improve bioavailability
 To improve chemical stability
 To ease manufacturability (e.g. compressibility can be improved)
 To control the release of drug
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Cont…
 The dissolution rate of a weakly acidic drug in gastric fluid (pH 1-3.5) will be
relatively low, which could result in low bioavailability.
 If the pH in the diffusion layer could be increased, then the solubility, Cs,
exhibited by the acidic drug in this layer,
 hence its dissolution rate in gastric fluids, would be increased even though the
bulk pH of gastric fluids remained at the same low value.
 How pH increased?
 The pH of the diffusion layer would be increased if the chemical nature of the
weakly acidic drug were changed from that of the free acid to a basic salt, for
example the sodium or potassium form of the free acid.
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Cont…
• The pH of the diffusion layer surrounding each particle of the salt form would be
higher (e.g. 5-6) than the low bulk pH (1-3.5) of the gastric fluids
• because of the neutralizing action of the strong anions (Na+ or K+) ions present in the
diffusion layer
• Because the salt form of the weakly acidic drug has a relatively high solubility at
the elevated pH in the diffusion layer, dissolution of the drug particles will take
place at a faster rate.
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Cont…
• Many examples can be found of the effects of salts improving the rate and extent
of absorption. One example is Penicillin V.
• Use the potassium salt for better absorption orally.
• Use of the benzathine or procaine salts
for IM depot use.
11/21/2023 165
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Cont…
• Another example is tolbutamide
• The dissolution rate of oral hypoglycemic tolbutamide sodium in 0.1 M HC1
is 5000 times faster than that of free acid.
• It produces a very rapid decrease in blood sugar level as a consequence of the
rapid rate of drug absorption
• In contrast, the tolbutamide free acid produces a much slower rate of decrease
of blood sugar (a consequence of the slower rate of drug absorption)
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Cont…
• The barbiturates are often administered in the form of sodium salts to achieve a
rapid onset of sedation and provide more predictable effects.
• The non-steroidal anti-inflammatory drug naproxen was originally marketed as a
free acid for the treatment of rheumatoid and osteoarthritis.
• However, the sodium salt (naproxen sodium) is absorbed faster and is more effective
for mild to moderate pain.
11/21/2023 167
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Cont…
• Conversely, strongly acidic salt forms of weakly basic drugs, for example
chlorpromazine hydrochloride, dissolve more rapidly in gastric and intestinal
fluids than do the free bases (e.g. chlorpromazine).
• The presence of strongly acidic anions (e.g. Chloride ions) in the diffusion layer
around each drug particle ensures that the pH in that layer is lower than the
bulk pH in either the gastric or the intestinal fluid.
• This lower pH will increase the solubility of the drug in the diffusion layer (Cs)
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Cont…
• The oral administration of a salt form of a weakly basic drug in a solid oral dosage
form generally ensures that dissolution occurs in the gastric fluid before the drug
passes into small intestine
• Thus the drug should be delivered to the major absorption site, the small
intestine, in solution.
• The sodium salts of acidic drugs and the hydrochloride salts of basic drugs are
by far the most common.
• However, many other salt forms are increasingly being employed.
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• Some salts have a lower solubility and dissolution rate than the free form, for
example aluminium salts of weak acids and palmoate salts of weak bases.
• In these cases insoluble films of either aluminium hydroxide or palmoic acid are
found to coat the dissolving solids when the salts are exposed to a basic or an
acidic environment, respectively.
• In general, poorly soluble salts delay absorption and may therefore be used to
sustain the release of the drug.
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Cont…

• A poorly soluble salt form is generally employed for suspension dosage forms,
• e.g. Procain pencillin, benazanthaine pencillin for i.m. injection.
• Although salt forms are often selected to improve bioavailability, other factors,
such as
• Chemical stability, hygroscopicity, manufacturability and crystallinity, will all be
considered during salt selection and may preclude the choice of a salt.
• The sodium salt of aspirin, sodium acetylsalicylate, is much more prone to
hydrolysis than is aspirin, acetylsalicylic acid, itself.
11/21/2023 171
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Cont…

• One way to overcome chemical instabilities or other undesirable features of salts
is to add basic/acidic excipients to the formulation of a weakly acidic or weakly
basic drug.
• The presence of basic excipients in the formulation of acidic drugs ensures that a
relatively basic diffusion layer is formed around each dissolving particle.
• The inclusion of the basic ingredients aluminium dihydroxyaminoacetate and
magnesium carbonate in aspirin tablets was found to increase their dissolution rate
and bioavailability.
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Cont…

Chemical Stability
• Drugs that are susceptible to acidic or enzymatic hydrolysis in the GIT, suffer
from reduced bioavailability.
• How to protect drugs (erythromycin) from degradation in gastric fluid ??
• Preparing enteric coated tablets containing the free base of erythromycin. The
enteric coating resists gastric fluid but disrupts or dissolves at the less acid pH range
of the small intestine.
• Administration of chemical derivatives of the parent drug. These pro-drugs
(erythromycin stearate) exhibit limited solubility in gastric fluid, but liberate the drug
in the small intestine to be absorbed.
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Biopharmaceutics

Complexation potential of a drug
• Complexation of a drug in the GIT fluids may alter rate and extent of drug
absorption.
• Intestinal mucosa + Streptomycin = poorly absorbed complex
• Calcium + Tetracycline = poorly absorbed complex (Food-drug interaction)
• Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed complex
(tablet additive – drug interaction)
• Polar drugs + complexing agent = well-absorbed lipid soluble complex (
dialkylamides + prednisone)
• Lipid soluble drug + water soluble complexing agent = well-absorbed water soluble
complex (cyclodextrine)
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Formulation factors affecting oral
absorption
11/21/2023 175
Biopharmaceutics

Formulation…
• The rate and/or extent of absorption of a drug from the gastrointestinal tract have
been shown to be influenced by many physiological factors and physicochemical
properties associated with the drug itself.
• The bioavailability of a drug can also be influenced by changing:
• Dosage form or
• Excipients/manufacturing techniques
• Increasingly many dosage forms are being designed to affect the release and
absorption of drugs.

Influence of the type of dosage form
• The type of dosage form can influence bioavailability of drugs.
• Thus, whether a particular drug is incorporated and administered in the form of a
solution, suspension or solid dosage form can influence its rate and/or extent of
absorption from the gastrointestinal tract.
• The type of oral dosage form will influence the number of possible intervening
steps between administration and the appearance of dissolved drug in the
gastrointestinal fluids.
• In general, drugs must be in solution in the gastrointestinal fluids before
absorption can occur.

Cont…
• Hence the bioavailability of a given drug tends to decrease in the following order
of types of dosage form:
• Aqueous solutions > aqueous suspensions > solid dosage forms (hard gelatin
capsules or tablets).
• Although this ranking is not universal, it does provide a useful guideline.
• However, it should be noted that other factors (e.g. stability, patient acceptability
etc.) can also influence the type of dosage form in which a drug is administered
via the gastrointestinal route.

schematic outline of the influence of the dosage form on the appearance of drug in
solution in the gastrointestinal tract

Aqueous solutions
• For drugs that are water soluble and chemically stable in aqueous solution,
formulation as a solution normally eliminates the in vivo dissolution step and
presents the drug in the most readily available form for absorption.
• However, dilution of an aqueous solution of a poorly water-soluble drug whose
aqueous solubility had been increased by formulation techniques such as:
• Cosolvency,
• Complex formation or
• Solubilization can result in precipitation of the drug in the gastric fluids.

Cont…
• Similarly, exposure of an aqueous solution of a salt of a weak acidic compound to
gastric pH can also result in precipitation of the free acid form of the drug.
• In most cases the extremely fine nature of the resulting precipitate
• permits a more rapid rate of dissolution than if the drug had been administered in
other types of oral dosage forms, such as: Aqueous suspension, Hard gelatin capsule
or Tablet
• However, for some drugs this precipitation can have a major effect on
bioavailability.

Cont…
 Factors associated with the formulation of aqueous solutions that can influence
drug bioavailability
 The chemical stability exhibited by the drug in aqueous solution and the
gastrointestinal fluids;
 Complexation, i.e. the formation of a complex between the drug and an excipient
included to increase the aqueous solubility and chemical stability of the drug or the
viscosity of the dosage form;
 Solubilization, i.e. the incorporation of the drug into micelles in order to increase its
aqueous solubility;
 The viscosity of a solution dosage form, particularly if a viscosity-enhancing agent
has been included.

Aqueous suspensions
• An aqueous suspension is a useful dosage form for administering an insoluble or
poorly water-soluble drug.
• Usually the absorption of a drug from this type of dosage form is dissolution-rate
limited.
• The oral administration of an aqueous suspension results in a large total surface
area of dispersed drug being immediately presented to the gastrointestinal fluids.
• This facilitates dissolution and hence absorption of the drug.

Cont…
 In contrast to powder-filled hard gelatin capsule and tablet dosage forms,
dissolution of all drug particles commences(to start/begin) immediately on
dilution of the suspension in the gastrointestinal fluids.
 A drug contained in a tablet or hard gelatin capsule may ultimately achieve the
same state of dispersion in the gastrointestinal fluids, but only after a delay.
 Thus a well formulated, finely subdivided aqueous suspension is regarded as being
an efficient oral drug delivery system, second only to a non-precipitating solution-
type dosage form.

Cont…
 Factors associated with the formulation of aqueous suspensions that can influence
drug bioavailability
 The particle size and effective surface area of the dispersed drug;
 The crystal form of the drug;
 Any resulting complexation, i.e. the formation of a non-absorbable complex between
the drug and an excipient such as the suspending agent;
 The inclusion of a surfactant as a wetting, flocculating or deflocculating agent;
 The viscosity of the suspension.

Powder filled capsules
 Generally the bioavailability of a drug from a well formulated powder-filled hard
gelatin capsule will be better than or at least equal to that from the same drug in a
compressed tablet.
 Provided the hard gelatin shell dissolves rapidly in the gastrointestinal fluids and
the encapsulated mass disperses rapidly and efficiently,
 Relatively large effective surface area of drug will be exposed to the
gastrointestinal fluids, thereby facilitating dissolution.

Cont…
 The overall rate of dissolution of drugs from capsules appears to be a complex
function of the rates of different processes:
 The dissolution rate of the gelatin shell,
 The rate of penetration of the gastrointestinal fluids into the encapsulated mass,
 The rate at which the mass deaggregates (i.e. disperses) in the gastrointestinal fluids,
and
 The rate of dissolution of the dispersed drug particles.

Cont…
 The inclusion of excipients (e.g. diluents, lubricants and surfactants) in a capsule
formulation can have a significant effect on the rate of dissolution of drugs,
particularly those that are poorly soluble and hydrophobic.
 For example a hydrophilic diluent (e.g. sorbitol, lactose) often serves to increase
the rate of penetration of the aqueous gastrointestinal fluids into the contents of the
capsule, and to aid the dispersion and subsequent dissolution of the drug in these
fluids.
 However, the diluent should exhibit no tendency to adsorb or complex with the
drug, as either can impair absorption from the gastrointestinal tract.

Cont…
 Both the formulation and the type and conditions of the capsule-filling process can
affect the packing density and liquid permeability of the capsule contents.
 In general, an increase in packing density (i.e. a decrease in porosity) of the
encapsulated mass will probably result in a decrease in liquid permeability and
dissolution rate, particularly if the drug is hydrophobic

Cont…
 Formulation factors that can influence the bioavailabilities of drugs from hard
gelatin capsules include:
 The surface area and particle size of the drug
 The use of the salt form of a drug in preference to the parent weak acid or base;
 The crystal form of the drug;
 The chemical stability of the drug (in the dosage form and in gastrointestinal fluids);
 The nature and quantity of the diluent, lubricant and wetting agent;
 Drug-excipient interactions (e.g. adsorption, complexation);
 The type and conditions of the filling process;
 The packing density of the capsule contents;
 The composition and properties of the capsule shell (including enteric capsules);
 Interactions between the capsule shell and its contents.

Tablets
Uncoated tablets
• Tablets are the most widely used dosage form.
• When a drug is formulated as a compressed tablet there is an enormous reduction
in the effective surface area of the drug,
• owing to the granulation and compression processes involved in tablet making.
• These processes necessitate the addition of excipients, which serve to return the
surface area of the drug back to its original pre-compressed state.

Cont…
• Bioavailability problems can arise if a fine, well dispersed suspension of drug
particles in the gastrointestinal fluids is not generated following the administration
of a tablet
• Because the effective surface area of a poorly soluble drug is an important factor
influencing its dissolution rate,
• It is especially important that tablets containing such drugs should disintegrate rapidly
and completely in the gastrointestinal fluids if rapid release, dissolution and
absorption are required.

Cont…
• The overall rate of tablet disintegration is influenced by several interdependent
factors, which include:
• Concentration and type of drug
• Excipients: diluent, binder, disintegrant, lubricant and wetting agent
• Compaction pressure
• Disintegration of a tablet into primary particles is thus important, as it ensures that
a large effective surface area of a drug is generated in order to facilitate
dissolution and subsequent absorption.

Cont…
• However, simply because a tablet disintegrates rapidly this does not necessarily
guarantee that the liberated primary drug particles will dissolve in the
gastrointestinal fluids, and that the rate and extent of absorption are adequate.
• Note: in the case of poorly soluble drugs the rate-controlling step is usually the
overall rate of dissolution of the liberated drug particles in the gastrointestinal
fluids.

Cont…
Factors influencing the dissolution and bioavailabilities of poorly soluble drug
from uncoated conventional tablet
• The physicochemical properties of the liberated drug particles in the gastrointestinal
fluids, e.g. wettability, effective surface area, crystal form, chemical stability;
• The nature and quantity of the diluent, binder, disintegrant, lubricant and any wetting
agent;
• Drug-excipient interactions (e.g. complexation), the size of the granules and their
method of manufacture;
• The compaction pressure and speed of compression used in tabletting;
• The conditions of storage and age of the tablet.

Tablets
Coated Tablets
 Tablet coatings may be used simply for:
 Aesthetic reasons to improve the appearance of a tablet or to add a company logo,
 masking an unpleasant taste or odor
 protect an ingredient from decomposition during storage
 Protect GI irritation
 Bypassing gastric environment
 Currently the most common type of tablet coat is film; however, several older
preparations, such as vitamins and ibuprofen, still have sugar coats.

Cont…
 The presence of a coating presents a physical barrier between the tablet core and
the gastrointestinal fluids;
 Coated tablets therefore are subject to additional potential problem of being
surrounded by a physical barrier.
 In the process of sugar coating the tablet core is usually sealed with a thin
continuous film of a poorly water-soluble polymer such as shellac or cellulose
acetate phthalate.
 Hence the presence of this water-impermeable sealing coat can potentially retard
drug release from sugar-coated tablets.

Cont…
 The coating of a tablet core by a thin film of a water-soluble polymer, such as
hydroxypropyl methylcellulose, should have no significant effect on the rate of
disintegration of the tablet core and subsequent drug dissolution,
 Provided that the film coat dissolves rapidly and independently of the pH of the
gastrointestinal fluids.
 However, if hydrophobic water-insoluble film-coating materials, such as
ethylcellulose or certain acrylic resins, are used, the resulting film coat acts as a
barrier which delays and/or reduces the rate of drug release.

Enteric Coated Tablets
 The following Polymers can be used as enteric coatings.
 cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, the
copolymers of methacrylic acid and their esters and polyvinyl acetate phthalate
 These materials do not dissolve over the gastric pH range but dissolve rapidly at
the less acid pH (about 5) values associated with the small intestine.

Cont…
 Enteric coating thus provides a means of delaying the release of a drug until the
dosage form reaches the small intestine.
 Such delayed release provides a means of protecting drugs which would otherwise
be destroyed if released into gastric fluid.
 Hence, enteric coating serves to improve the oral bioavailability exhibited by such
drugs from uncoated conventional tablets.
 Enteric coating also protects the stomach against drugs which can produce
nausea or mucosal irritation (e.g. aspirin, ibuprofen) if released at this site.

Cont…
 In addition to the protection offered by enteric coating, the delayed release of drug
also results in a significant delay in the onset of the therapeutic response of a drug.
 The onset of the therapeutic response is largely dependent on the residence time of
the enteric-coated tablet in the stomach.
 The residence time of an intact enteric-coated tablet in the stomach can vary from
about 5 minutes to several hours.
 Hence there is considerable intra- and inter subject variation in the onset of
therapeutic action exhibited by drugs administered as enteric-coated tablets.

Cont…
 Hence enteric-coated granules and pellets exhibit a gradual but continual release
from the stomach into the duodenum.
 This type of release also avoids the complete dose of drug being released into
the duodenum, as occurs with an enteric-coated tablet.
 The intestinal mucosa is thus not exposed locally to a potentially toxic
concentration of drug.

Influence of Formulation Components of Dosage Forms
 Drugs are almost never administered alone but rather in the form of dosage forms
that generally consist of a drug (or drugs) together with a varying number of other
substances (called excipients).
 Excipients are added to the formulation in order to
 Facilitate the preparation
 Improve patient acceptability
 Functioning of the dosage form as a drug delivery system

Cont…
Excipients include:
 Disintegrating agents, diluents/fillers, lubricants, suspending agents, emulsifying
agents, organoleptic agents, chemical stabilizers, granulating agents, etc.
 They exert no therapeutic or biological action, or modify the biological action
of the drug present in the dosage form

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