Biopharmaceutic Considerations

of a Drug Design
Agnes L. Castillo, PhD

 Formulated drug products usually include

the active drug substance and selected
ingredients (excipients ) that make up the
dosage form.
Drug products are designed to deliver
drug for local or systemic effects

 Biopharmaceutics is the study of the in-vitro

impact of the physicochemical properties of
drugs and drug products on drug delivery to the
body under normal or pathologic conditions.
A primary concern in biopharmaceutics is the
bioavailability of drugs.
Bioavailability refers to the measurement of the
rate and extent of active drug that becomes
available at the site of action

 The aim of biopharmaceutics is to adjust

the delivery of drug from the drug product
in such a manner as to provide optimal
therapeutic activity and safety for the
patient

 Biopharmaceutic studies allow for the rational design

of drug products based on
(1) the physical and chemical properties of the drug substance;
(2) the route of drug administration, including the anatomic and
physiologic nature of the application site (eg, oral, topical,
injectable, implant, transdermal patch, etc);
(3) desired pharmacodynamic effect (eg, immediate or
prolonged activity);
(4) toxicologic properties of the drug;
(5) safety of excipients; and (6) effect of excipients and dosage
form on drug delivery.

 An eye medication may require special

biopharmaceutic considerations, including
appropriate pH, isotonicity, sterility, local
irritation to the cornea, draining by tears,
and concern for systemic drug absorption.

 Considerations in the design of a drug product

that will deliver active drug with the desired
bioavailability characteristics include
(1) the type of drug product (eg, solution,
suspension, suppository),
(2) the nature of the excipients in the drug
product,
(3) the physicochemical properties of the drug
molecule, and
(4) the route of drug administration.

RATE-LIMITING STEPS IN
DRUG ABSORPTION
disintegration of the drug product and subsequent
release of the drug,
dissolution of the drug in an aqueous environment, and
absorption across cell membranes into the systemic
circulation
drugs that have very poor aqueous solubility, the rate at
which the drug dissolves (dissolution ) is rate limiting step
often the slowest step

Disintegration
Complete disintegration is defined by the
USP () as "that state in which any residue
of the tablet, except fragments of insoluble
coating, remaining on the screen of the
test apparatus in the soft mass have no
palpably firm core.
Exceptions: troches, chewable tablets,
and modified-release drug products

Dissolution
Process in which a solid drug substance
becomes dissolved in a solvent
dynamic property
an important prior condition for systemic
absorption
dissolution tests may be used to predict
bioavailability and may be used to
discriminate formulation factors that affect
drug bioavailability

Steps in dissolution
drug dissolution at the
surface of the solid particle
forming a saturated
solution around the particle
called stagnant layer
This diffuses to the bulk of
the solvent from regions of
high drug concentration to
regions
of
low
drug
concentration

Drug dissolution
Noyes-Whitney
equation

dC /dt = rate of drug dissolution at time

t
D = diffusion rate constant,
A = surface area of the particle,
C S= concentration of drug (equal to
solubility of drug) in the stagnant layer,
C = concentration of drug in the bulk
solvent
h = thickness of the stagnant layer

The rate of dissolution, dC /dt , is

the rate of drug dissolved per time
expressed as concentration change
in the dissolution fluid

Dissolution

Factors that affect drug dissolution

(1) the physical and chemical nature of the
active drug substance,
(2) the nature of the excipients, and
(3) the method of manufacture

Absorption
Permeation of drug across the gut wall (a model lipid
membrane) is affected by the ability of the drug to diffuse
(D ) and to partition between the lipid membrane.
A favorable partition coefficient (K oil/water ) will facilitate
drug absorption
An increase in temperature will increase the kinetic
energy of the molecules and increase the diffusion
constant, D .
Moreover, an increase in agitation of the solvent medium
will reduce the thickness, h , of the stagnant layer,
allowing for more rapid drug dissolution.

Physicochemical Properties

Particle size and surface area

Smaller particle size results in an increase in the total
surface area of the particles, enhances water penetration
into the particles, and increases the dissolution rate.

Griseofulvin, nitrofurantoin, and many steroids

low aqueous solubility;
reduction of the particle size by milling to a micronized
form has improved the oral absorption
Hydrophobic drugs excessive particle size reduction
reaggregate into larger particles decreased dissolution
rate
PEG, PVP (polyvinylpyrrolidone), dextrose prevent
reaggregation enhance dissolution

Partition coefficient and extent

of ionization
Henderson-Hasselbalch equation
The ionized species of the drug contains a
charge and is more water soluble than the
nonionized species of the drug, which is
more lipid soluble

WEAK ELECTROLYTES AND

INFLUENCE OF pH
Acid liberates hydrogen ions (H+)
Base can bind H+
Strong acids, strong bases, as well as strong
electrolytes = completely ionized
Weak acids and weak bases are only partially
ionized = undissociated compound and ions.

Nonionized form
lipid-soluble and diffusible

Ionized form
lipid-insoluble and nondiffusible

 a weak acid (such as salicylic acid) will be rapidly

absorbed from the stomach (pH 1.2)

A weak base (such as quinidine) will be poorly

absorbed from the stomach

Salt formation
Depends on the physical, chemical or
pharmacologic properties
Provide slower dissolution, slower
bioavailability or longer duration of action
Basic drug more soluble in stomach forms
soluble salt
Acid drug more soluble in intestine form
soluble salt

Salt formation
Some soluble salt forms are less stable
than the non-ionized forms (e.g. sodium
aspirin)
Buffering agents- form an alkaline medium
in the GI tract to enhance dissolution
Inc. sol of ASA adding alkaline buffer

Salt formation
Buffering agents- form an alkaline medium
in the GI tract to enhance dissolution
Dissolved salt form diffuses into the bulk
fluid of the GI tract fine precipitate that
redissolves rapidly available for
absorption

Salt formation
Effervescent granules or tablets
Acid drug + NaHCO3, tartaric acid or citric
acid added to water just before oral
administration
Excess NaHCO3 forms an alkaline solution
in which the drug dissolves
CO2 is a by-product

Salt formation
Weak acids = Na, K salts are more soluble
than divalent cation salts (Ca, Mg) or
trivalent cation salts (Al) e.g. Voltaren,
Cataflam, Fern-C
Weak bases = HCl, SO4, citrate and
gluconate salts, estolate, napsilate and
stearate salts are less water soluble
e.g. L_______ HCl, E_______ estolate

Polymorphism
The ability of a drug to exist in more than one crystalline form
arrangement of a drug substance in various crystal forms or
polymorphs
Same chemical structure with different physical properties
(e.g. melting point, dissolution rate)
Amorphous forms are noncrystalline forms
solvates are forms that contain a solvent(solvate) or water
(hydrate),
desolvated solvates are forms that are made by removing the
solvent from the solvate.
Dissolution rate: amorphous, non-crystalline form (>,<,=?)
crystalline form

Polymorphism
In general, the crystalline form of drugs are more rigid
and thermodynamically more stable than the amorphous
form.
The crystal form with the lowest free energy is the most
stable polymorph.
A change in crystal form may cause problems in
manufacturing the product. 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

 Polymorphs have the same chemical

structure but different physical properties,
such as solubility, density, hardness, and
compression characteristics.
Some polymorphic crystals have much
lower aqueous solubility than the
amorphous forms, causing a product to be
incompletely absorbed
Chloramphenicol B polymorph - more
soluble and better absorbed

Chirality
Ability of a drug to exist as optically active
stereoisomers or enantiomers
Individual enantiomers (S & R) may not
have the same pharmacokinetic and
pharmacodynamic activity

Chirality
Most chiral drugs are racemic mixtures
results of studies with such mixtures may
be misleading because the drug is
assumed to behave as a single entity

In a racemic mixture, one

enantiomer could have:
No activity
Some activity
Antagonist activity against the active
enantiomer
Completely separate beneficial or adverse
activity from the active enantiomer

Chirality
Ibuprofen exists as the R- and Senantiomer; only the S-enantiomer is
pharmacologically active
When taken orally, R-enantiomer
undergoes presystemic inversion in the
gut to the S-enantiomer
Rate and extent of inversion are site
specific and formulation dependent,
activity may vary considerably

Pharmacodynamic effects
S)-ibuprofen is over 100-fold more potent
an inhibitor of cyclo-oxygenase I than (R)ibuprofen
(R)-methadone has a 20-fold higher
affinity for the opioid receptor than (S)methadone
(S)-citalopram is over 100-fold more
potent an inhibitor of the serotonin
reuptake transporter than (R)-citalopram

Pharmacodynamic effects
cardiotoxicity of bupivacaine is mainly
associated with the (R)-enantiomer, the
psychomimetic effects of ketamine are
more associated with the (R)-enantiomer,
and (S)-baclofen antagonizes the effects
of (R)-baclofen

Pharmacokinetic effects
the bioavailability of (R)-verapamil is more
than double that of (S)-verapamil due to
reduced hepatic first-pass metabolism
the volume of distribution of (R)methadone is double that of (S)methadone due to lower plasma binding
and increased tissue binding

Pharmacokinetic effects
the clearance of (R)-fluoxetine is about
four times greater than (S)-fluoxetine due
to a higher rate of enzyme metabolism
the renal clearance of (R)-pindolol is 25%
less than (S)-pindolol due to reduced renal
tubular secretion
enantiomers of warfarin can be
metabolized by different enzymes

Hydrates
Hydrated, solvated or anhydrous
Dissolution rates differ for hydrated and
anhydrous form
Dissolution rate: anhydrous form of
ampicillin (>,<,=?) hydrated form of
ampicillin
Erythormycin .2 H20 faster dissolution
Ampicillin .3H20 slow dissolution

Complex formation
Complex species formed by the
reversible or irreversible association of two
or more interacting molecules or ions

Complex formation
Chelates complexes that typically
involve a ring-like structure formed by the
interaction between a partial ring of atoms
and a metal

Complex formation
Alters the physical and chemical
properties of the drug
Chelate of t_________ with Ca is less
water soluble and poorly absorbed
Aminophylline ( + ethylenediamine) is
more water soluble than theophylline
parenteral and rectal administration

Complex formation
Cyclodextrins + drug = enhance water
solubility

Complex formation
Drug complexes cannot cross the cell
membrane easily

Drug Product and DDS

Design of an appropriate dosage

form or delivery system

Physical & chemical properties of a drug

Dose of the drug
Route of administration
Type of drug delivery desired

Design of an appropriate dosage

form or delivery system
Desired therapeutic effect
Physiologic release of a drug from the
delivery system
Bioavailability of a drug from the
absorption site
Pharmacokinetic and pharmacodynamics
of a drug

Rate-limiting step in bioavailability

Generally, solid dosage forms rapid
disintegration rate
Controlled- or sustained-release drug
product liberation or ____________

Solution
Homogenous mixtures of one or more
solutes dispersed molecularly in a
dissolving medium
Most bioavailable and consistent form
Reference preparation for solid peroral
formulations (e.g. relative bioavailability)

Solution
Elixir has a good bioavailability
Alcohol aids drug solubility = drug is
diluted in the GI tract fluid & other gut
contents (e.g. food) form a finely
divided precipitate extensive dispersion
& large surface area redissolution =
rapid absorption

Solution
Viscous drug solution (e.g. _______)
interfere with dilution & mixing in the GI
tract contents
Decreases gastric emptying rate
= d _ _ _ _ _ _ a______________

Suspension
Dispersion of finely divided solid particles
in a liquid medium in which a drug is not
readily soluble
Liquid medium comprises a saturated
solution of the drug in equilibrium with the
solid drug

Suspension
Bioavailability may be similar to a solution
finely divided particles are dispersed
Dependent on dissolution rate (e.g. good
or poor water solubility)

Suspension
Suspending agents (e.g. cellulose
derivatives, acacia, xanthan gum)
increases viscosity, inhibits agglomeration
and decrease the rate at which the
particles settle
_prolong gastric emptying time, slow drug
dissolution and _decreases absorption
rate

Capsules
Solid dosage forms with hard or soft
gelatin shells that contain a drug, usually
admixed with excipients
Coating affects bioavailability

Capsules
Hard gelatin capsules contain a powder
blend
Simpler & less compacted than a
compressed tablet

Capsules
Gelatin softens, swells and begins to
dissolve after ingestion
Released rapidly & dispersed easily, good
bioavailability
Preferred dosage forms for early clinical
trials

Capsules
Soft gelatin capsules may contain a
nonaqueous solution, powder or drug
suspension
Vehicle may be water-miscible (e.g. PEG)
Digoxin dispersed in a water-miscible
vehicle (Lanoxicaps) has better
bioavailability than compressed tablets
(Lanoxin)

Capsules
Soft gelatin capsule containing a drug
dissolved in a hydrophobic vehicle has a
poorer bioavailability than a compressed
tablet formulation

Capsules
Aging and storage conditions moisture
content of the gelatin component of the
capsule shell and bioavailability
Low moisture levels brittle and easily
ruptures
High moisture levels moist, soft &
distorted moisture may be transferred to
the capsule contents (esp. if hygroscopic)

Compressed tablets
Solid dosage forms in which high pressure
is used to compress a powder blend or
granules that contain the drug and other
ingredients, or excipients, into a solid
mass

Compressed tablets
Excipients (d________(fillers), d______,
b_____, l_______, g_______, s______,
d _ _, flavoring agents
Permit efficient manufacture of
compressed tablets
affect the physical & chemical
characteristics of the drug
affect bioavailability: higher the ratio of
excipient to active drug = greater likelihood
that the excipients affect bioavailability

Excipients of Compressed
Tablets
added to a formulation to provide certain functional properties
to the drug and dosage form.
Some of these functional properties of the excipients are used
to improve the compressibility of the active drug, stabilize the
drug against degradation, decrease gastric irritation, control the
rate of drug absorption from the absorption site, increase drug

bioavailability

Disintegrant
e.g. starch, croscamellose, sodium starch
glycolate
Vary in action depending on:
1. concentration
2. method by which they are mixed with
the powder formulation or granulation
3. degree of tablet compaction

Disintegrant
Tablet disintegration is usually faster than
dissolution
Can affect bioavailability if it fails

Lubricants
usually hydrophobic, water-insoluble
substances (e.g. stearic acid, magnesium
stearate, hydrogenated vegetable oil, talc)
Reduce wetting of the surface of drug
particles _______ dissolution rate,
_______ bioavailability
Mg stearate in xss, retard drug dissolution
and slow rate of absorption

Lubricants
water-soluble lubricants (e.g. L-leucine)
do not interfere with bioavailability &
dissolution

Glidants
Improve the flow properties of a dry
powder blend before it is compressed
May reduce tablet-to-tablet variability and
improve product efficacy

Surfactants
Reduce interfacial tension (surface tension)
between solid drug and liquid
Improve the wettability (contact) of solid
drug particles by the solvent
Enhance drug dissolution and bioavailability
( at low conc)
!! High concentration of surfactants
micelle formation reduced bioavailability

Coating

Sugar coat, film coat, enteric coat

Purpose:
1.
2.
3.
4.

Protects the drug from moisture, light & air

Improves appearance of the tablet
Masks the taste & odor of the drug
Affect the release rate of the drug

Enteric coating
Minimize contact between the drug and
the gastric contents or gastric mucosa
Insoluble at acidic pHs
Resist attrition and remain whole long
enough for the tablet to leave the mucosa
May decrease bioavailability

Enteric coating
Function:
1. minimize irritation of the gastric mucosa
by the drug
2. Prevent the inactivation or degradation
of the drug in the stomach
3. delay the release of the drug until the
tablet reaches the small intestine, where
conditions for absorption may be optimal

Can you still follow??

Modified-release dosage form

Drug products that alter the rate or timing
of drug release
Dose dumping (abrupt release of a large
amount of drug) is a problem
Extended-release dosage forms include
controlled-release, sustained-action and
long-acting drug delivery systems

Why are there sustainedrelease tablets?

Modified-release dosage form

1. Extended release drug products
Allow at least a two-fold reduction in dosing
frequency compared with conventional
immediate-release formulations
Ex. controlled-release, sustained-release,
and long-acting drug products
Diltiazem HCl extended release- Once-aday dosing

Modified-release dosage form

Extended, slow release of CR drug
products produces a relatively flat,
sustained plasma drug concentration that
avoids toxicity (from high drug conc.) or
lack of efficacy (from low drug conc.)

Modified-release dosage form

Provide an immediate (initial) release of a
drug followed by a slower sustained
release

Modified-release dosage form

2. Delayed-release dosage forms release the
active drug at a time other than the immediately
after the administration at a desired site in the
GI tract
Enteric-coated dosage forms
Diclofenac sodium delayed-release
Enteric-coated tablet for drug delivery into small
intestine.

Mesalamine delayed- release

Coated for drug release in terminal ileum

Transdermal DDS or patches

Controlled-release devices that contain
the drug for systemic absorption after
topical application to the skin surface
e.g. nitroglycerin, nicotine, scopolamine,
clonidine, fentanyl, 17--estradiol &
testosterone
Clonidine TTS is applied every 7 days to
intact skin on the upper arm or chest

Transdermal DDS or patches

Transdermal DDS or patches

Differ from conventional topical
preparations in the ff.
1. Impermeable occlusive backing film that
prevents insensible water loss from the
skin beneath the patch increased
hydration and skin temperature under the
patch enhanced permeation by the
drug

Transdermal DDS or patches

2. Formulation matrix of the patch
maintains the drug conc. gradient within
the device after application so that the
drug delivery to the interface between the
patch & skin is sustained
3. kept in place on the skin by an adhesive
layer ensuring drug contact with the skin
and continued drug delivery

3. Targeted (site-specific) DDS

Drug carrier systems that place the drug at or near the receptor site/
intended physiological site of rxn
Macromolecular drug carriers (protein drug carriers)
Particulate DDS (e.g. liposomes, nanoparticles)
Monoclonal antibodies
Daunorubicin citrate liposome injection
Liposomal preparation to maximize the selectivity of daunorubicin for
solid tumors in situ
Mesalamine (5-aminosalicylic acid) is a delayed-release tablet coated
with an acrylic-based resin that delays the release of mesalamine until it
reaches the terminal ileum and colon.
Mesalamine tablets could also be considered a targeted-release dosage
form

Targeted (site-specific) DDS

Drug may be delivered to:
1. capillary bed of the active site
2. special type of cell (e.g. tumor cells) but
not to normal cells
3. a specific organ or tissue by complexing
with a carrier that recognizes the target

Inserts, implants & devices

Used to control drug delivery for localized
or systemic drug effects
Drug is impregnated into a biodegradable
or nonbiodegradable material and is
released slowly
Inserted into cavities (e.g. vaginal, buccal)
or tissues (e.g. skin)
Leuprolide acetate implant (Viadur) is
inserted beneath the skin of the upper arm