CHAPTER 9

Solid Oral
Modified-Release Dosage
Form and Drug Delivery
Systems
SOLID ORAL MODIFIED-RELEASE DOSAGE FORMS
AND DRUG DELIVERY SYSTEMS
INTRODUCTION

■ Describes solid oral dosage forms and drug delivery system

that virtue of formulation and product design have modified
drug release features

■ Modified release products provide either delayed release or

extended release of drug

■ Most delayed release products are enteric-coated tablets or

capsules designed to pass through the stomach unaltered,
later to release their medication within the intestinal tract

■ Enteric coatings are used either to protect a substance from

destruction by gastric fluids or to irritating drugs
SOLID ORAL MODIFIED-RELEASE DOSAGE FORMS
AND DRUG DELIVERY SYSTEMS
Extended release products are designed to
release their medication in a controlled manner
at a predetermined rate, duration, and location
to achieve and maintain optimum therapeutic
blood levels of drug

RATIONAL FOR EXTENDED RELEASE PHARMACEUTICALS

■ Extended release tablets & capsules = take once or
twice daily
Conventional forms = 3 to 4 times daily to achieve
same TE
■ For non oral rate-controlled DDSs = 24 hours for most
transdermal patches to months to years
– Example: Lovenorgestrel subdermal implants
(Norplat System),
 MULTIPLE DAILY DOSING
■ inconvenient for the patient and can result in missed
doses, made-up doses, and noncompliance with the
regimen
■ when doses are not administered on schedule, the
resulting peaks and valleys reflect the optimum drug
therapy
ADVANTAGES OF EXTENDED-RELEASE DOSAGE
FORMS OVER CONVENTIONAL FORMS

■ Reduction in drug blood levels fluctuation

– controlling the rate of release eliminated
peaks and valleys of blood levels

■ Frequency reduction in dosing

– extended-release products frequently deliver
more than a single dose, hence may be taken often than
conventional form (Depo Foam Drug Delivery System)

■ Enhanced convenience and compliance – with less

frequency in dosing, a patient is less apt to neglect taking a
dose, also it provides greater convenience with day and
night administration
 ADVANTAGES OF EXTENDED-RELEASE DOSAGE
FORMS OVER CONVENTIONAL FORMS
■ Reduction in adverse side effects
– because of fewer blood level peaks
Outside therapeutic range and into toxic
range, adverse side effects are less
frequent

■ Reduction in overall health care costs – overall

cost of treatment may be less because of enhanced therapeutic
benefit, fewer side effects, and reduced time for health care
personnel to dispense and administer drugs and monitor
patients
DISADVANTAGE OF ETENDED-RELEASE DOSAGE
FORMS OVER CONVENTIONAL FORMS

■ loss of flexibility in adjusting the drug dose and/or

dosage regimen

■ risk of sudden and total drug release

■ dose dumping due to failure in

technology
TERMINOLOGY
1. Sustained Release (SR)
2. Sustained Action (SA)
3. Extended Release (ER)
4. Long Acting (LA)
5. Prolong Action (PA)
6. Controlled Release (CR)
7. Timed Release (TR)
 TERMS AND ABBREVIATIONS USED FOR
EXTENDED-RELEASE DOSAGE FORMS
■ SR (Sustained Release) PA (Prolonged Action)

■ SA (Sustained Action)
CR (Controlled Release)
TERMS AND ABBREVIATIONS USED FOR
EXTENDED-RELEASE DOSAGE FORMS

■ ER (Extended Release)

■ TR (Time Release)

■ LA (Long Acting)
 TERMS AND ABBREVIATIONS USED FOR
EXTENDED-RELEASE DOSAGE FORMS

■ Products bearing these descriptions differ in design

and performance and must be examined
individually to ascertain their respective features

Rate-Controlled delivery
■ applied to certain types of drug delivery systems in
which the rate of delivery is controlled by features
of service rather than by physiologic or
environmental conditions like gastrointestinal pH or
drug transit time through the gastrointestinal tract
TERMS AND ABBREVIATIONS USED FOR
EXTENDED-RELEASE DOSAGE FORMS

Modified release
■ has come into general use to describe dosage forms
having drug release features based on time course and/or
location that are designed to accomplish therapeutic or
convenience objectives not offered by conventional or
immediate-release forms

Extended-release
■ dosage forms of this type are the ones that allow a
reduction in dosing frequency form that necessitated by a
conventional dosage forms, such as solution or an
immediate-release drug dosage form
TERMS AND ABBREVIATIONS USED FOR
EXTENDED-RELEASE DOSAGE FORMS

Delayed release
■ releases the drug at a time other than promptly after
administration. The delay may be time base or base on
the influence of environmental conditions such as
gastrointestinal pH

Repeat action
■ two single doses of medication; one for immediate
release; another one for modified release

Targeted release
■ drug release directed toward isolating or concentrating a
drug in a body region, tissue or site of absorption or for
drug action
Extended Release Oral Dosage Forms (Successful ER
Product)
1. Release from dosage forms at a predetermine
rate
2. Dissolve in GT
3. Maintain sufficient Gastrointestinal residence
time
4. Be absorbed at a rate that will replace the
amount of drug being metabolized and
excreted
CHARACTERISTICS OF EXTENDED-RELEASE
PRODUCTS
1. They exhibit very slow nor very fast rates of absorption and
excretion

■ drugs with slow rates of absorption and excretion are

usually inherently long-acting, and it is not necessary to
prepare them in extended-release forms

■ drug with very short half-lives, less than 2 hours, are poor
candidates for extended release

■ drugs that act by affecting enzyme systems may be longer

acting than indicated by their quantitative half-lives
because of their residual effects and recovery of the
diminished biosystem
CHARACTERISTICS OF EXTENDED-RELEASE
PRODUCTS
2. They are uniformly absorbed from the gastrointestinal tract

■ they must have good aqueous solubility and maintain adequate

residence time in the gastrointestinal tract

■ drugs absorbed poorly or at varying and unpredictable rates

are not good candidates for extended-release products

3. They are administered in relatively small doses

■ drugs with large single doses frequently are not suitable for
extended release because the tablet or capsule needed to
maintain a sustained therapeutic blood level of the drug would
be too large for the patient to swallow easily
CHARACTERISTICS OF EXTENDED-RELEASE
PRODUCTS

4. They possess a good margin of safety

■ the most widely used measure of the margin of a

drug’s safety is its therapeutic index, that is, the
median toxic dose divided by the median affective
dose

■ the larger the therapeutic index, the safer the drug

■ drugs that are administered in very small doses or

possess very narrow therapeutic indices are poor
candidates for formulations because of technologic
limitations of precise control over release rates and
the risk of dose dumping due to a product defect
CHARACTERISTICS OF EXTENDED-RELEASE
PRODUCTS

5. They are used in the treatment of chronic rather than

acute conditions

■ drugs for acute conditions require greater adjustment of

the dosage by the physician than that provided by
extended-release products
BASIS OF DRUG RELEASE
■ modifying drug dissolution by controlling
excess of biologic fluids to the drug through
the use of barrier coatings

■ controlling drug diffusion rate from dosage

forms

■ chemical reaction or interaction between the

drug substance or its pharmaceutical barrier
and site-specific biologic fluids
COATED BEADS, GRANULES AND MICROSPHERES
■ using conventional pan coating or air suspension
coating, a solution of the drug substance is placed on
small inert nonpareil seeds or beads made of sugar and
stand or on microcrystalline cellulose spheres

Nonpareil seeds
■ 425-850μm
COATED BEADS, GRANULES AND MICROSPHERES

Microcrystalline cellulose
■ More durable during production than sugar-based cores
■ 170-600μm
Lipid materials used to coat granules

■ Beeswax

■ Carnauba wax

■ Glyceryl monostearate

■ Cetyl alcohol

■ Cellulosic material (ethyl cellulose)

Lipid materials used to coat granules
■ Aqueous coating system eliminate the hazards and
environmental concerns associated with organic based
solvent systems
■ The thicker the coat, the more resistant to penetration
and the more delayed will be the drug release and
dissolution

■ Spansule
MULTITABLET SYSTEMS
■ small spheroid compressed tablets 3 to 4 mm in
diameter may be prepared to have varying drug release
characteristics.
■ They may placed in gelatin capsule shells to provide the
desired pattern of drug release

■ each capsule contain 8 to 10 minitablets some uncoated

for immediate release and others coated for extended
drug release
MICROENCAPSULATED DRUG
Microencapsulation
■ A process by which solids, liquids or even gases may
be enclosed in microscopic particles by formation of
thin coatings of wall material around the substance

Gelatin
■ A common wall forming material and synthetic
polymers, such as polyvinyl alcohol, ethyl cellulose,
polyvinyl chloride and other materials may be used
ENCAPSULATION PROCESS
■ dissolving the wall material – ex. gelatin in water

■ encapsulated material is added and two phase mixture thoroughly stirred

■ a solution to second material is added, ex. Acacia

■ This additive material concentrates the gelatin (polymer) into the liquid
droplets.
■ These droplets (the coacervate) form a film or coat around the particles.

■ the final dry microcapsules are free-flowing discrete particles of coated

material
■ The wall material constitute into 20% of the total particle weigh
■ Different rates of drug release may be obtained by changing the (a) ratio
of core to wall; (b) polymer used for the coating; (c) the method of
microencapsulation.
 ADVANTAGE OF MICROENCAPSULATION

■ administered dose of a
drug is subdivided into
small units that are spread
over a large area of the
gastrointestinal tracts,
which may enhance
absorption by diminishing
local drug concentration

■ Micro-K ExtenCaps
(Potassium Chloride)
Encapsulation. All of the single and
combination capsules are produced
here. The empty gelatin capsules are
placed in hoppers and free-flowing to
the machine. The bottom portion of
the capsule is filled, which is
gravity-fed from a stainless steel bin
into the machine’s hopper. An
average of 6 million capsules a day
can be produced.
EMBEDDING DRUG SLOWLY ERODING OR
HYDROPHILIC MATRIX SYSTEM
■ drug substance is combined and made into granules with an
excipient material that slowly erodes in body fluids, progressively
releasing the drug for absorption
■ When these granules are mixed, the uncombined granules provide
the immediate effect, and the drug excipient granules provide
extended action.
■ The granule mix – formulated as tablets or capsules

Hydrophilic cellulose polymers

■ commonly used as the excipient base in tablet matrix
systems
EFFECTIVENESS OF THE HYDROPHILIC MATRIX
IS BASED ON:

■ successive process of hydration on the polymer’s surface

■ gel formation on the polymer’s surface

■ tablet erosion

■ subsequent and continuous release of drug

Hydroxypropyl Methyl Cellulose (HPMC)

■ a free flowing powder; commonly used to provide the

hydrophilic matrix

A successful hydrophilic matrix system must contain

the following:
polymer must form a gelatinous layer rapidly enough to protect
the inner core of the tablet from disintegrating too rapidly after
ingestion

20% of HPMC results in satisfactory rates of release for an

extended-release tablet formation

e.g Oramorph SR Tablet

manufacturers may prepare two-layer tablets

■ one layer containing the uncombined drug for immediate

release

■ the other layer having the drug embedded in a hydrophilic

matrix for extended release

they may also prepare a three-layer tablets

■ outer layers containing the drug for immediate release

■ some commercial tablets are prepared with an inner core

containing the extended-release portion of the drug and an
outer shell enclosing the core and containing drug for
immediate release
EMBEDDING DRUG IN INERT PLASTIC
MATRIX
■ Drug is granulated with an inert plastic material such as polyethylene,
polyvinyl acetate, o polymethacrylate and the granulation is compressed
into tablets

■ The drug is slowly released from the inert plastic matrix by diffusion

■ The compression creates the matrix or plastic form that retains its shape
during leaching of the drug and during its passage through the
alimentary tract

■ The immediate release portion of drug may be compressed onto the

surface of the tablet.

■ Example: Gradumet
COMPLEX FORMATION
■ form complexes that may be slowly soluble in
body fluids, depending on the pH of the
environment
■ slow dissolution rate

Example: Rynatan
■ salts of tannic acid, tannates, provide this quality
in a variety of proprietary products
 ION EXCHANGE RESINS
■ solution of a cationic drug may be passed through a
column containing an ion exchange resin, forming a
complex by the replacement of hydrogen atoms

■ release of the drug depends on the pH and electrolyte

concentration in the gastrointestinal tract

■ release is greater in the acidity of the stomach than in the

less acidic environment of the small intestine

■ hydrocodone polistirex (Tussionex) and

chlorpheniramine polistirex suspension and phentermine
resin capsules
 Mechanism of ion exchange resins:
In the stomach

1. drug resinate + HCl ↔ acidic resin + drug hydrochloride

2. resin salt + HCl ↔ resin chloride + acidic drug

In the intestine

1. drug resinate + NaCl ↔ sodium resinate + drug hydrochloride

2. resin salt + NaCl ↔ resin chloride + sodium salt of drug

■ release is extended over 12 hours by ionic exchange

OSMOTIC PUMP
■ the pioneer oral osmotic pump drug delivery system is the Oros
system developed by Alza

■ composed of a core tablet surrounded by a semipermeable

membrane coating having a 0.4mm diameter hole produced by
laser beam. Example: Acutrim

■ core tablet has two layers, one containing the drug and the
other containing a polymeric osmotic agent

■ the system is designed such that only a few drops of water are
drawn into the tablet each hour

■ function of the tablet depends on the osmotic gradient between

the contents of the two-layer core and the fluid in the
gastrointestinal tract
 Drug release rate may be altered by :
■ changing the surface area

■ thickness

■ composition of the membrane and/or diameter of the drug release

orifice
 Release rate is not affected by:
■ gastrointestinal acidity or alkalinity

■ fed conditions

■ gastrointestinal motility

Gastrointestinal therapeutic system (GIT systems)

■ is employed in the manufacture of Glucotrol XL Extended release
tablets, and Procardia XL release tablets

■ the initial drug is released 4 to 5 hours after tablet ingestion

REPEAT-ACTION TABLETS
■ the initial dose of drug is
released immediately and a
second dose follows later

■ released 4 to 6 hours after

administration

■ Example: Repetabs

■ they are best suited for

treatment of chronic
conditions requiring
repeated dosing

■ low dosage and fairly rapid

rates of absorption and
excretion
DELAYED-RELEASE ORAL DOSAGE FORMS
■ release of a drug that may be
intentionally delayed until it
reaches the intestines for
several reasons

■ protect a drug destroyed by

gastric fluids

■ reduce gastric distress caused

by drugs of particularly irritating
to the stomach

■ to facilitate gastrointestinal
transit for drugs that are
absorbed from the intestines

■ Examples: Enteric Coated

Enseals – Lilly; Ecotrin
SmithKline
PROPERTIES OF AN ENTERIC COATING
TABLETS/CAPSULES

■ pH dependent

■ breaks down in the less acidic environment of the intestine

■ time dependent

■ erodes by moisture over time during gastrointestinal transit

■ enzyme dependent

■ deteriorating as a result of hydrolysis-catalyzing action of

intestinal enzyme
AGENTS USED FOR ENTERIC COATING OF CAPSULES AND
TABLETS

■ fats

■ fatty acids

■ waxes

■ shellac

■ cellulose acetate phthalate

EXAMPLES OF MODIFIED-RELEASE TABLETS AND
CAPSULES OFFICIAL IN THE USP

Delayed release
Aspirin delayed-release tablets
Dirithromycin delayed-release tablets
Doxycycline hyclate delayed-release capsules
Erythromycin delayed-release capsules
Oxtriphylline delayed-release tablets

Extended release
Diltiazem extended-release capsules
Disopyramide phosphate extended-release capsules
Isosorbide dinitrate extended-release tablets and capsules
Propanolol hydrochloride extended-release capsules
Theophylline extended-release capsules
USP Requirements and FDA Guidelines for Modified
Release Dosage Forms
1. DRUG RELEASE

■ based on drug dissolution from the dosage unit against

elapsed test time

■ Example: Aspirin Extended-release Tablets

■ Aspirin dissolution rate:

Time (hours) Amount dissolved
1.0 15 – 40%
2.0 25 – 60%
4.0 35 – 75%
8.0 Not less than 70%
 2. UNIFORMITY OF DOSAGE UNITS
■ uniformity of dosage units may be demonstrated by either of two
methods, weight variations or content uniformity

3. IN VITRO-IN VIVO CORRELATIONS

critical to the development of oral extended-release products

important throughout product development, clinical evaluation

submission of an application for FDA approval for marketing, and
during post approval for any proposed formulation or
manufacturing changes

it provides guidance to sponsors of new drug applications and

abbreviated new drug applications and abbreviated new drug
applications for extended release of oral products
IVIVC provides methods of:
■ developing an IVIVC and evaluating its
predictability

■ using an IVIVC to establish dissolution

specifications

■ applying an IVIVC as a surrogate for in vitro-in

vivo bioequivalence during the approval process
or during post approval for certain formulation or
manufacturing changes
3 Categories of IVIVCs include in the document
Level A

■ the relationship between the entire in vitro dissolution and

release time course and the entire in vivo response time
course
■ Example: the time course of plasma drug concentration or
amount of drug absorbed

Level B

■ predictive mathematical model of the relationship between

summary parameters that characterize in vitro and in vivo time
courses
■ Example: models that relate the mean in vivo dissolution time
to the mean in vitro dissolution time
Three Categories of IVIVCs are include in the document:

Level C

■ a predictive mathematical model of the relationship between

the amount dissolved in vitro at a particular time and a
summary parameter that characterizes the time in vivo time
course or area under the curve

■ the level of IVIVCs may be useful in the early stages of

formulation development when pilot formulations are being
selected
MOST COMMON PROCESS FOR DEVELOPING
IVIVC MODEL (LEVEL A)

■ develop formulations with different release rates or

a single release rate if dissolution is independent
of condition

■ obtain in vitro dissolution profiles and in vivo

plasma concentration profiles for these
formulations

■ estimate the in vivo absorption or dissolution time

course for each formulation and subject using
appropriate mathematical approaches
CRITERIA IN DEVELOPMENT APPLICABLE TO THE
DEVELOPMENT OF IVIVCS ARE THE FOLLOWING

■ in determining in vitro dissolution, USP dissolution apparatus;

type I (basket) or type II (paddle) is preferred, although type III
(reciprocating cylinder) or type IV (flow-through cell) may be
applicable in some substances

■ aqueous medium with a pH not exceeding 6.8 is preferred as

the medium for dissolution studies. For poorly soluble drugs, a
surfactant may be added

■ the dissolution profiles of at least 12 individual dosage units

from each lot should be determined
 CRITERIA IN DEVELOPMENT APPLICABLE TO THE
DEVELOPMENT OF IVIVCS ARE THE FOLLOWING

■ for vivo studies, human subjects are used in the fasted state
unless the drug is not well tolerated, in which case the studies
may be conducted in the fed state. Acceptable data sets have
been shown to be generated with use of 6 to 36 human
subjects

■ crossover studies are preferred, but parallel studies or

cross-study analysis may be acceptable using a common
reference treatment product, such as an intravenous solution,
an aqueous oral solution, or an immediate-release product
 LABELING

■ they must be specific for the

monograph article

■ aspirin delayed-release
tablets must state that the
tablets are enteric coated

■ capsules must indicate

whether the product is
intended for dosage every 12
to 24 hours and state which
in vitro drug release test the
product complies
CLINICAL CONSIDERATIONS
■ not to be used interchangeably or concomitantly
with immediate-release forms of the same drug

■ patients using a modified release product should

not be changed into immediate release without
consideration to the blood concentration

■ patients should not be changed to another

extended-release product unless there is
assurance of equivalent bioavailability
CLINICAL CONSIDERATIONS

■ different product can result in a marketed shift in the

patient’s drug blood level because of differences in drug
release characteristics

■ modified release tablets and capsules should not be

crushed or chewed

■ patients if fed through the nasogastric tube may receive

modified-release medications

■ nonerodible plastic matrix shells and osmotic tablets remain

intact throughout gastrointestinal transit and the empty
shells or ghosts from osmotic tablets may be seen in the
stool
 Propriety Modified-Release Oral Dosage Forms

■ Delayed Release
 Propriety Modified-Release Oral Dosage Forms

■ Extended-Releas
e Coated
Particles and
Breads
Propriety Modified-Release Oral Dosage Forms

Extended-Release
Inert Matrix
 Propriety Modified-Release Oral Dosage Forms

■ Extended Release
Hydrophilic/
Eroding Matrix
 Propriety Modified-Release Oral Dosage Forms

■ Extended-Release
Microencapsulated
Drug

Extended-Release
Osmotic