CONTROLLED DRUG DELIVERY

SYSTEM
DRUG DELIVERY SYSTEMS?

• The term “drug delivery systems’’ refer to the

technology utilized to present the drug to
the desired body site for drug release and
absorption.
• An ideal dosage regimen in the drug therapy of
any disease is the one which immediately attains
the desired therapeutic concentration of drug in
plasma (or at the site of action) and maintains it
constant for the entire duration of treatment.
• This is possible through administration of a drug
delivery system in a particular dose and at a
particular frequency.
• When a drug is delivered as a conventional
dosage form such as a tablet, the dosing interval
is much shorter than the half-life of the drug
resulting in a number of limitations associated
with such a conventional dosage form
In the conventional therapy aliquot quantities of drugs are
introduced into the system at specified intervals of time with the
result that there is considerable fluctuation in drug concentration
level as indicated in the figure.

HIGH HIGH

LOW LOW
However, an ideal dosage regimen would be one, in which the
concentration of the drug, nearly coinciding with minimum
effective concentration (M.E.C.), is maintained at a constant level
throughout the treatment period. Such a situation can be graphically
represented by the following figure

CONSTANT LEVEL
 What is Sustain Release Dosage Form?
▪ “Drug Delivery system that are designed to achieve prolonged
therapeutic effect by continuously releasing medication over an
extended period of time after administration of single dose.”
▪ The basic goal of therapy is to achieve steady state blood level
that is therapeutically effective and non toxic for an extended
period of time.
▪ The design of proper dosage regimen is an important element in
accomplishing this goal.
 Repeat-action versus sustained-action drug therapy

▪ A repeat-action tablet may be distinguished from its sustained-

release product by the release of the drug in slow controlled
manner and consequently does not give a plasma concentration
time curve which resemble that of a sustained release product.
• A repeat action tablet usually contains two dose of drug; the 1st
being released immediately following oral administration in
order to provide a repeat onset of therapeutic response. The
release of second dose is delayed, usually by means of an enteric
coat.

▪ Consequently, when the enteric coat surrounding the second dose

is breached by the intestinal fluid, the second dose is release
immediately.
 V
A
L
L
P
Y
E
A
K
 figure shows that the plasma concentration time curve
obtained by the administration of one repeat- action preparation
exhibit the “PEAK & VALLY”. Profile associated with the
intermittent administration of conventional dosage forms.

The primary advantage provide by a repeat-action tablet

over a conventional one is that two (or occasionally three) doses
are administration without the need to take more than one tablet.
 Advantages
⮚Improved patient convenience and compliance due to less
frequent drug administration.

⮚Reduction in fluctuation in steady-state level and therefore better

control of disease condition.

⮚Increased safety margin of high potency drug due to better

control of plasma levels.

⮚Maximum utilization of drug enabling reduction in total amount

of dose administered.

⮚Reduction in health care cost through improved therapy, shorter

treatment period.
⮚Less frequency of dosing and reduction in personnel time to
dispense, administer monitor patients.

⮚Better control of drug absorption can be obtained, since the high

blood level peaks that may be observed after administration of a
dose of high availability drug can be reduced.
 Limitations
⮚Decreased systemic availability in comparisn to immediate
release conventional dosage forms; this may be due to incomplete
release, increased first-pass metabolism, increased instability,
insufficient residence time for complete release, site specific
absorption, pH dependent solubility etc.,

⮚Poor in-vivo, in-vitro correlation.

⮚Possibility of dose dumping due to food, physiologic or

formulation variable or chewing or grinding of oral formulation by
the patient and thus increased risk of toxicity.
⮚Retrieval of drug is difficult in case of toxicity, poisoning or
hypersensitivity reaction.

⮚The physician has less flexibility in adjusting dosage regimens.

This is fixed by the dosage form design.

⮚Sustained release forms are designed for the normal population

i.e. on the basis of average drug biologic half-life’s. Consequently
disease states that alter drug disposition, significant patient variation
and so forth are not accommodated.

⮚Economics factors must also be assessed, since more costly

processes and equipment are involved in manufacturing many
sustained release forms.
 Terminologies/Definitions
Controlled-Release Formulation: The controlled
release system maintains a constant supply of the drug at
zero-order rate by continuously releasing the drug for a
certain time period in amount equivalent to that
eliminated by the body. An ideal controlled drug delivery
system delivers the drugs either locally or systematically
at a predetermined rate for a specific time period.
Repeat Action Preparation: A drug dose, equivalent to
a single dose of the conventional drug formulation, is
initially released immediately after administration. After
a certain time period, a second single dose is released. In
some preparations, a third single dose is also released
after a certain time.
• Extended-Release Formulation: This dosage form
allows two-fold reduction in dosage frequency in
comparison to the immediate-release (conventional)
dosage form. Examples of extended-release dosage
forms include controlled-release, sustained-release, and
long-acting drug products.
• Delayed-Release Preparation: This dosage form
releases a discrete portion(s) of drug at a time or at
specific time intervals after administration, although one
portion may be released immediately after
administration. An example of delayed-release dosage
form is enteric-coated dosage form.
• Targeted-Release Drug Product: This dosage form
releases drug at or near the intended physiological site
of action. These dosage forms may have either
immediate or extended-release characteristics.
• Site-Specific Targeting System: This system targets a
drug directly to a certain biological location. The target
is adjacent to or in the diseased organ or tissue.
• Receptor Targeting System: This system targets a
drug directly to a certain biological location. The target
is the particular receptor for a drug in an organ or tissue.
Site-specific targeting and receptor targeting systems
satisfy the spatial aspect of drug delivery and are
considered as controlled drug delivery systems.
• Controlled Action System: This system provides a
prolonged duration of drug release with predictability
and reproducibility of drug release kinetics. The drug
absorption rate is equal to the drug removal rate from the
body.
• Sustained Action System: This system initially provides
a sufficient amount of drug to the body to produce the
desired pharmacological action. The remaining drug
amount is released periodically and maintains the
maximum initial pharmacological activity for a desirable
time period in excess of time expected from usual single
dose.
• Prolonged Action System: This system releases the
drug over an extended time period during which
pharmacological response is obtained, but it does not
maintain the constant blood level.
Plasma concentration v/s time curve
 Concept of sustained release
formulation
The Concept of sustained release formulation can be divided
in to two considerations i.e. release rate & dose consideration

A) Release rate consideration :-

In conventional dosage form Kr>Ka in this the release of drug

from dosage form is not rate limiting step.
 The above criteria i.e. (Kr>Ka) is in case of immediate release,
where as in non immediate (Kr<Ka) i.e. release is rate limiting step.

So that effort for developing S.R.F must be directed primarily

altering the release rate. the rate should be independent of drug
removing in the dosage form over constant time.

The release rate should follow zero order kinetics

Kr = rate in(R0) = rate out (Routput)

 Ideal Properties of a Drug Suitable for Sustained
Release Drug Delivery System (SRDDS)
• 1) It should get effectively absorbed on oral
administration and should remain stable in
gastrointestinal fluid.
• 2) It should have a short half-life (2-4 hours), e.g.,
captopril, salbutamol sulphate, etc.
• 3) Its dose should not be less than 0.5gm and its
maximum dose for designing SRDDS should be 1.0gm,
e.g., metronidazole.
• 4) It should have a wide therapeutic range so that any
variation in drug release does not result in
concentration beyond the minimum toxic levels.
Compounds that are Unsuitable for Controlled
Release Drug Delivery System (CRDDS)
• Certain drug candidates are not considered suitable to be
formulated in controlled release dosage forms owing to some of
their properties. For example, drugs with an elimination half-
life < 2 hours, or drugs having large doses to administer within
the body, or drugs having a half-life > 8 hours are not required
to be formulated as controlled release dosage form.
• Thus, drugs with the following properties are considered
inappropriate for designing CRDDS:
• 1) Drugs with a short and long half-life,
• 2) Drugs undergoing hepatic first pass metabolism,
• 3) Drugs with a low solubility, and
• 4)Drugs requiring to be administered in a large number of
doses.
 Drug properties relevant to sustained release formulation

The design of sustained release delivery system is subjected to

several variables and each of variables are inter-related.

For the purpose of discussion it is convenient to describe the

properties of the drugs as being either physico-chemical or
biological ,these may be divided in two types.

1. Physicochemical properties
2. Biological properties
 Factors to be considered In S.R.Dosage forms.

1.Biological Factors Physiological Factors:

1. Absorption. 1. Dosage size.

2. Partition coefficient and
1. Distribution.
molecular size.
1. Metabolism.
3. Aqueous Solubility.
1. Biological half 4. Drug stability.
life.(excreation)
5. Protein binding.
1. Margin of safety 6. Pka
 Biological Factors
Absorption.
▪ Rate, extent and uniformity of drug absorption are the
factors that should be taken into account for a drug to
be formulated into a sustained release dosage form.
▪ Drug release from a dosage form (and not absorption)
is the rate-limiting step in drug delivery from a
sustained release system; thus, rapid rate of drug
absorption relative to its release is essential for an
efficient system.
▪ In controlled release dosage forms, Kr <<< Ka, and this
is critical in case of oral administration.
• If a drug’s transit time through the absorption half-
life is 4 hours, a minimum absorption rate constant
(Ka) of 0.17-0.23 hour is necessary for a drug to
undergo 80-95% absorption over a transit time of 9-
12 hours.
• A drug having a rapid absorption rate (ie., Ka >> 0.23-
1 hour) has the first-order release rate constant (Kr) <
0.17-1 hour, and this results in poor bioavailability in
many patients.
• Therefore, slowly absorbed drugs are difficult to
formulate as controlled release dosage forms, in
which the drugs should essentially meet the Kr <<<
Ka criteria.
 Distribution:

▪ Drug distribution in tissues and cells lowers the

concentration of circulating drug and can also
be rate-limiting in its equilibrium with blood
and extravascular tissue, thus it majorly affects
the drug elimination kinetics.
▪ Distribution involves binding of a drug to the
tissues and blood proteins.
▪ Protein-bound drug molecules are inactive and
cannot permeate the biological membranes.
▪ Also, a high degree of protein binding results in
prolonged therapeutic action.
▪ Apparent volume of distribution (an important
parameter of the drugs) is the magnitude of
distribution and protein binding in the body.
▪ It is the proportionality constant of plasma drug
concentration to the total amount of drug in the
body.
▪ Thus, prior to designing sustained release systems,
one should gather information regarding the drug
disposition.
 Protein Binding:
• Many drugs bind to plasma proteins and show related
effects on the duration of drug action.
• Drug bound to blood proteins are mostly re-circulated
(rather than getting eliminated).
• Drug bound to plasma proteins serve as a drug depot
for a prolonged release of drug.
• The rate and extent of oral absorption of drug is also
affected by the drug interaction and the binding
period with mucin-like protein.
 Metabolism:
▪ Drug metabolism involves either inactivation of an active
drug or conversion of an inactive drug into an active
metabolite.
▪ It occurs in various tissues, containing more enzymes.
Drugs that get metabolised before absorption, either in
the lumen or in the intestinal tissues, are released at a
slower rate, and thus result in reduced bioavailability.
▪ The intestinal wall enzyme systems are mostly saturable.
▪ As the drug is released to these regions at a slower rate,
less total drug is presented to the enzymatic process
during a specific period, and thus the drug completely
converts into its metabolites. Formulating these
enzymatically-susceptible compounds as prodrugs is
another feasible solution.
•Drugs that can induce or inhibit enzyme
synthesis are considered as poor candidates
for sustained release delivery systems as they
cannot maintain uniform blood levels.
•Also drugs whose bioavailability varies due to
hepatic first-pass metabolism or intestinal
metabolism are not considered suitable
candidates for sustained release delivery
systems.
 Biological half life.
⮚The usual goal of sustained release product is to maintain
therapeutic blood level over an extended period, to this drug must
enter the circulation at approximately the same rate at which it is
eliminated. The elimination rate is quantitatively described by the
half-life (t1/2)

⮚Therapeutic compounds with short half life are excellent

candidates for sustained release preparation since these can reduce
dosing frequency.
⮚Drugs with half-life shorter than 2 hours. Such as e.g.:
Furosemide, levodopa are poor for sustained release formulation
because it requires large rates and large dose compounds with long
half-life. More than 8 hours are also generally not used in
sustaining forms, since their effect is already sustained.
E.g.; Digoxin, Warfarin, Phenytoin etc.
 e) Margin of safety:
In general the larger the volume of therapeutic index safer the
drug. Drug with very small values of therapeutic index usually are
poor candidates for SRDF due to pharmacological limitation of
control over release rate .e.g.- induced digtoxin, Phenobarbital,
phenotoin.

= TD50/ED50
Larger the TI ratio the safer is drug.
It is imperative that the drug release pattern is precise so that the
plasma drug concentration achieved in under therapeutic range.
2. Physiological Factors:

a) Dosage size.

b) Partition coefficient and molecular size.

c) Aqueous Solubility.

d)Drug stability.

e) Protein binding.

f) Pka
 1.Dosage size.

⮚In general a single dose of 0.5 - 1.0 gm is considered for a

conventional dosage form this also holds for sustained release
dosage forms.

⮚ If an oral product has a dose size greater that 500mg it is a poor

candidate for sustained release system, Since addition of sustaining
dose and possibly the sustaining mechanism will, in most cases
generates a substantial volume product that unacceptably large.
 2. Partition coefficient and molecular size.

⮚When the drug is administered to the GIT ,it must cross a variety
of biological membranes to produce therapeutic effects in another
area of the body.
⮚It is common to consider that these membranes are lipidic,
therefore the Partition coefficient of oil soluble drugs becomes
important in determining the effectiveness of membranes barrier
penetration.

⮚Partition coefficient is the fraction of drug in an oil phase to that

of an adjacent aqueous phase.
⮚High partition coefficient compound are predominantly lipid
soluble and have very low aqueous solubility and thus these
compound persist in the body for long periods.
Partition coefficient and molecular size influence not only the
penetration of drug across the membrane but also diffusion across
the rate limiting membrane

⮚The ability of drug to diffuse through membranes its so called

diffusivity & diffusion coefficient is function of molecular size (or
molecular weight).
⮚Thus high molecular weight drugs or polymeric drugs should be
expected to display very slow release kinetics in sustained release
device using diffusion through polymer membrane.
⮚Phenothiazines are representative of this type of compound
 3.Aqueous Solubility.
⮚Since drugs must be in solution before they can be absorbed,
compounds with very low aqueous solubility usually suffer oral
bioavailability Problems, because of limited GI transit time of
undissolved drug particles and limited solubility at the absorption
site.

E.g.: Tetracycline dissolves to greater extent in the stomach than in

the intestine, there fore it is best absorbed in the intestine.

⮚Most of drugs are weak acids or bases, since the unchanged form
of a drug preferentially permeates across lipid membranes drugs
aqueous solubility will generally be decreased by conversion to an
unchanged form. for drugs with low water solubility will be difficult
to incorporate into sustained release mechanism.
 4.Drug stability.
⮚The stability of drug in environment to which it is exposed, is
another physico-chemical factor to be considered in design at
sustained/ controlled release systems, drugs that are unstable in
stomach can be placed in slowly soluble forms or have their release
delayed until they reach the small intestine.

⮚Orally administered drugs can be subject to both acid, base

hydrolysis and enzymatic degradation. Degradation will proceed at
the reduced rate for drugs in the solid state, for drugs that are
unstable in stomach, systems that prolong delivery ever the entire
course of transit in GI tract are beneficial.
⮚Compounds that are unstable in the small intestine may
demonstrate decreased bioavailability when administered form a
sustaining dosage from. This is because more drug is delivered in
small intestine and hence subject to degradation.

⮚However for some drugs which are unstable in small intestine are
undergo extensive Gut –Wall metabolism have decreased the bio
availability .
⮚When these drugs are administered from a sustained dosage form
to achieve better bio availability, at different routes of the drugs
administered should be chosen
Eg. Nitroglycerine
The presence of metabolizing enzymes at the site or pathway can
be utilized.
 5.Protein binding.
⮚It is well known that many drugs bind to plasma protein with the
influence on duration of action.

⮚Drug-protein binding serve as a depot for drug producing a

prolonged release profile, especially it is high degree of drug
binding occurs.

⮚Extensive binding to plasma proteins will be evidenced by a long

half life of elimination for drugs and such drugs generally most
require a sustained release dosage form. However drugs that exhibit
high degree of binding to plasma proteins also might bind to bio-
polymers in GI tract which could have influence on sustained drug
delivery. The presence of hydrophobic moiety on drug molecule
also increases the binding potential.
⮚The binding of the drugs to plasma proteins(eg.Albumin) results
in retention of the drug into the vascular space the drug protein
complex can serves as reservoir in the vascular space for sustained
drug release to extra vascular tissue but only for those drugs that
exhibited a high degree of binding.
The main force of attraction are Wander-vals forces , hydrogen
binding, electrostatic binding.
In general charged compound have a greater tendency to bind a
protein then uncharged compound, due to electrostatic effect.

Eg amitryptline, cumarin, diazepam, digoxide, dicaumarol,

novobiocin.
 6.Pka: (dissociation constant)

The relationship between Pka of compound and absorptive

environment, Presenting drug in an unchanged form is
adventitious for drug permeation but solubility decrease as the
drug is in unchanged form.

An important assumption of the there is that unionized form of the

drug is absorbed and permeation of ionized drug is negligible, since
its rate of absorption is 3-4 times lesser than the unionized form of
the drug.

The pka range for acidic drug whose ionization is PH sensitive and
around 3.0- 7.5 and pka range for basic drug whose ionization is ph
sensitive around 7.0- 11.0 are ideal for the optimum positive
absorption
 CLASSIFICATION
1. Dissolution Controlled Release
2. Diffusion Controlled Release
3. Diffusion & Dissolution Controlled Release System
4. Ion- exchange Resins
DISSOLUTION: in chemistry, the process of dissolving a solid substance into a
solvent to make a solution

DIFFUSION: Diffusion describes the spread of particles through random motion

from regions of higher concentration to regions of lower concentration.

Dissolution Diffusion

Single bead type Reservoir

Beads containing
drug with
different Matrix
thickness
 Dissolution Controlled System
•It seems inherently obvious that a drug with a slow
dissolution rate will demonstrate sustaining
properties, since the release of drug will be limited
by the rate of dissolution.
•This being true, sustained-release pre- parations of
drugs could be made by decreasing their rate of
dissolution.
•The approaches to achieve this include preparing
appropriate salts or derivatives, coating the drug
with a slowly dissolving material, or incorporating
it into a tablet with a slowly dissolving carrier.
• Dissolution-controlled systems can be made to be
sustaining in several different ways.
• By alternating layers of drug with rate-controlling coats, as
shown in Fig., a pulsed delivery can be achieved, lf the
outer layer is a quickly releasing bolus of drug, initial
levels of drug in the body can be quickly established with
pulsed intervals following.
• Although this is not a true controlled-release system, the
biological effects can be similar.
 •
An alternative method is to administer the drug as a group of
beads that have coatings of different thicknesses.
•Since the beads have different coating thicknesses, their
release will occur in a pro- gressive manner, Those with the
thinnest layers will provide the initial dose.
•The maintenance of drug levels at later times will be
achieved from those with thicker coatings.
•This is the principle of the Spansule capsule marketed by
SmithKline Beecham.
 TWO TYPES OF DISSOLUTION CONTROLLED SYSTEMS

•
DISSOLVING COAT
SINGLE BEAD TYPE DEVICE
DRUG LAYER

BEADS CONTAINING DRUG WITH DIFFERENT THICKNESS OF DOSSOLVING COATS

VARIOUS THICKNESS OF DISSOLVING COAT

• This dissolution process can be considered to be diffusion-layer controlled. This is
best explained by considering the rate of diffusion from the solid surface to the bulk
solution through an unstirred liquid film as the rate-determining step. This
dissolution process at steady state is described by the Noyes-Whitney equation:

dc D A(c -c)
kD A(cs- c) s
dt h

dc/dt= dissolution rate

kD= dissolution rate constant
D= diffusion coefficient
Cs= saturation solubility of the solid
c=concentration of the solute in bulk solution
Equation predicts that the rate of release can be constant only if the
following parameters are constant:
•(a) surface area, (b) diffusion coefficient, (c) diffusion layer
thickness, and (d) concentration difference. These parameters,
however, are not easily maintained con- stant, especially surface area.
For spherical particles, the change in surface area can be related to the
weight of the particle; that is, under the assumption of sink conditions,
Eq. can be rewritten as the cube-root dissolution equation:

where !D is the cube-root dissolution rate constant and W and W are

the initial weight and the weight of the amount remaining at time i,
respectively
 ENCAPSULATED DISSOLUTION PRODUCTS

PRODUCT ACTIVE INGREDIENTS MANUFACTURER

ORNADE SPANSULES PHENYLPROPANOLAMINE SMITH KLINE BEECHAM
HYDROCHLORIDE
DIAMOX SEQUELS ACETAZOLAMIDE LEDERLE
NICOBID TEMPLES NICOTINIC ACID RORER
PRNTRITOL TEMPLES PENTAERYTHRIOTL RORER
POLARAMINENREPETABS DEXCHLORPHENIRAMINE SCHERING

MATRIX DISSOLUTION PRODUCTS

PRODUCT ACTIVE INGREDIENTS MANUFACTURER

DIMETANE EXTENTABS BROMPHENIRAMINE ROBINS

QUINIDEX EXTENTABS QUINIDINE SULPHATE ROBINS

MESTINON TIMESPANS PYRIDOSTIGMINE ICN

BROMIDE
TENUATE CHRONOTABS DIETHYLPROPION HCL MERREL
 DIFFUSIONAL SYSTEMS
• Diffusional systems are characterized by the release rate of a drug being
dependent on its diffusion through an inert membrane barrier.
• Usually this barrier is an insoluble polymer
• It is classified in to 2 types:
a) Reservoir devices
b) Matrix devices
 RESERVOIR DEVICES
• Reservoir devices are characterised by a core of drug, the
reservoir is surrounded by a polymeric membrane.
• The nature of the membrane determines the rate of release of
drug from the system.
• The process of diffusion is generally described by a series of
equations that were first detailed by FICKS :

J= -D dc/dx

Where D = is the diffusion coefficient of the drug.

dc/dx = is the rate of change in concentration C relative to a distance
X in the membrane.
 membrane
Cm(o)

Drug C(o) C(d)

Membrane reservo
ir
Cm(d)

d
Cm(o) & Cm(d) = represents concentrations of drug at inside surfaces of the membrane.
C(o) & C(d) = represents concentrations of drug in the adjacent regions.
d= is the thickness of the diffusion layer

It is useful to make the assumption that the drug on either side of the membrane is in
equilibrium with its respective membrane surface, so the concentration just inside
the membrane surface can be related to the concentration in the adjacent region by
the following equations:

K= Cm(o) / C(d) at x=0 K= Cm(d) /C(d) at x=d

K Is the partition coeffecient
• ADVANTAGES OF RESERVOIR DIFFUSIONAL SYSTEMS:
✔ zero order delivery is possible.
✔ release rate variable with polymer type.
• DISADVANTAGES:
✔ System must be physically removed from implant sites.
✔ Difficult to deliver high molecular weight compounds.
✔ Potentially toxic if system fails.

RESERVOIR DIFFUSIONAL PRODUCTS

Product Active ingredient Manufacturer
Nico-400 Nicotinic acid Jones
Nitro-bid Nitroglycerin Marion
Cerespan Papaverine rorer
hydrochloride
 MATRIX DEVICES
▪ In matrix devices drug is dispersed homogeneously through out
a polymer matrix.
▪ In this model drug in the outside layer exposed to the bathing
solution is dissolved first and then diffuses out of the matrix, this
process continues with the interface between the bathing
solution and the solid drug moving towards the interior.
▪ So for this system to be diffusion-controlled, the rate of
dissolution of drug particles within the matrix must be much
faster that the diffusion rate of dissolved drug leaving the matrix.

polymer
Drug dispersed in polymer
 Matrix Diffusion Types
• Rigid Matrix Diffusion
Materials used are insoluble plastics such as PVP & fatty
acids.

• Swellable Matrix Diffusion

1. Also called as Glassy hydrogels. Popular for sustaining

the release of highly water soluble drugs.
2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum,Tragacanth.
Semisynthetic -HPMC,CMC,Xanthum gum.
Synthetic -Polyacrilamides.

59
• Derivation of the mathematical model to describe this system
involves the following assumptions:
a. A pseudo-steady state is maintained during drug release.
b. The diameter of the drug particles is less than the average
distance of drug diffusion through the matrix.
c. The bathing solution provides sink conditions at all times.
d. The diffusion coefficient of drug in the matrix remains constant.
• The equation which describes the rate of release of drugs dispersed in an
inert matrix system have been derived by HIGUCHI.

dM
= Co dh - Cs /2
dh
dM= change in the amount of drug released per unit area
dh = change in the thickness of the zone of matrix that has been depleted of drug
Co = total amount of drug in a unit volume of matrix
Cs = saturated concentration of the drug within the matrix.
• From Diffusion theory,
• dM=DmCsdt/h
Where Dm is diffusion coefficient in the matrix

M=k t

Where M is amount of drug release

k is a constant
A plot of amount of drug released versus the square root of
time will be linear, if the release of drug from the matrix is
diffusion controlled.
If this is the case, then, by the Higuchi model, one may
control the release of drug from a homogeneous matrix
system by varying the following parameters: (a) initial
concentration of drug in the matrix, (b) porosity, (c)
tortuosity, (d) polymer system forming the matrix, and (e)
solubility of the drug.
ADVANTAGES:
✔ Easier to produce than reservoir devices.
✔ Can deliver high molecular weight compounds
DISADVANTAGES:
✔ Cannot obtain zero-order release
✔ Removal of remaining matrix is necessary for implanted systems.

MATRIX DIFFUSIONAL PRODUCTS

Product Active ingredient Manufacturer

Desoxyn-gradumet Methamphetamine Abbott

hydrochloride
Fero-gradumet Ferrous sulfate Abbott
 COMBINATION OF DIFFUSION AND DISSOLUTION
• It is type of swelling controlled system
• Here the drug is dissolved in the polymer, but instead of an insoluble polymer,
as in previous systems, swelling of the polymer occurs.
• This allow entrance of water, which causes dissolution of the drug and
diffusion out of the swollen matrix.
• In these systems the release rate is highly dependent on the polymer-swelling
rate, drug solubility , and the amount of soluble fraction in the matrix.
• This system usually minimizes burst effects, since polymer swelling must occur
before drug release.
• Bioerodible devices, however, constitute a group of (14

systems for which mathematical descriptions of release

characteristics can be quite complex.
• The mechanism of release from simple erodible slabs,
cylinders, and spheres has been described
• A simple expression describing release from all three of
these erodible devices is

• where n= 3 for a sphere, n = 2 for a cylinder, and n =

1 for a slab.
• The radius of a sphere, or cylinder, or the half-height of
a slab is represented by a.
• M, is the mass of a drug release at time t, and M is the
mass released at infinite time.
• As a further complication, these systems can
combine diffusion and dissolution of both the matrix
material and the drug.
• Not only can drug diffuse out of the dosage form, as
with some previously described matrix systems, but
the matrix itself undergoes a dissolution process.
• The complexity of the system arises from the fact
that, as the polymer dissolves, the diffusional path
length for the drug may change.
• This usually results in a moving-boundary diffusion
system.
• Zero-order release can occur only if surface erosion
occurs and surface area does not change with time
• The inherent advantage of such a system is that
the bioerodible property of the matrix does not
result in a ghost matrix.
• The disadvantages of these matrix systems are
that release kinetics are often hard to control,
since many factors affecting both the drug and
the polymer must be considered.
 ION EXCHANGE RESINS
• Resins are water-insoluble materials containing salt-forming
groups in repeating positions on the resin chain.
• The drug is bound to the resin and released by exchanging
with appropriately charged ions in contact with the ion-
exchange groups.
• Ion-exchange resins have been used as drug carriers for
preparing prolonged and sustained delivery by releasing the
drug from the complex over approximately 8 to 12 h into the
GI tract.
• The release rate can be further modified by coating the drug-
resin complex. Coating on the resin-drug complex can be
achieved by a microencapsulation process.
 Where X- and Y+ are ions in GI Tract

The free drug then diffuses out of the resin.

The drug—resin complex is prepared either by repeated
exposure of the resin to the drug in a chromatography
column or by prolonged contact in solution.
•The rate of drug diffusing out of the resin
is con- trolled by the area of diffusion,
diffusional path length, and rigidity of the
resin, which is a function of the amount of
cross-linking agent used to prepare the
resin.
• This system is advantageous for drugs that are highly
susceptible to degradation by enzymatic processes, since
it offers a protective mechanism by temporarily altering
the substrate.
• This approach to sustained release, however, has the
limitation that the release rate is proportional to the
concentration of the ions present in the area of
administration.
• Although the ionic concentration of the GI tract remains
rather constant with limits, the release rate of drug can be
affected by variability in diet, water intake, and in-
dividual intestinal content.
 Evaluation
• Drug release is evaluated based on drug dissolution from dosage
form at different time intervals.
• In monograph various test apparatus and procedure is specified in
USP.
• Types of evaluation
In vitro evaluation
In vivo evaluation
 EVALUATION OF SR
FORMULATIONS
In vitro Measurement of Drug Availability
• It is not possible to simulate in a single in vitro test system the
range of variables that affect drug release during the passage of
sustained release medication through the GI tract.
• Properly designed in vitro tests for drug release serve two
important functions.
• First, data from such tests are required as a guide to formulation
during the development stage, prior to clinical testing.
• Second, in vitro testing is necessary to ensure batch-to-batch
uniformity in the production of a proven dosage form.
• Tests developed for the purpose of quality control are generally
limited to USP dissolution testing methods, using either the
rotating basket (apparatus 1), the paddle (apparatus 2)
 Data is analysed to see
• Does the product “dump” maintenance dose before the
maintenance period is complete?
• What fraction of the dose remains unavailable, i.e. what
fraction will not be released in the projected time of transit in
the GI tract?
• What is the effect of physiologic variables on drug release?
• Is the loading dose (if present) released immediately?
• What is the unit-to-unit variation? How predictable is the
release profile?
• What is the sensitivity of the drug release profile to process
variables?
• What is the stability of the formulation with respect to its
drug release profile?
• In short, does the observed release profile fit expectations?
 Methods used to measure drug release profiles should
have the following characteristics
• The analytic technique should be automated so that the
complete drug release profile can be directly recorded.
• Allowance should be made for changing the release
media from simulated gastric to simulated intestinal fluid
at variable programmed time intervals, to establish the
effect of retention of the dosage form in gastric fluid as
well as to approximate more closely the pH shifts that
the dosage form is likely to encounter in vivo.
• In addition, the hydrodynamic state in the dissolution
vessel should be controllable and capable of variation.
• The apparatus should be calibrated using a non
disintegrating dissolution standard (e.g. salicylic acid
compacts).
Other apparatus specific for SR
Formulations
• Rotating Bottle
• Stationary basket/ Rotating Filter
• Sartorious absorption and solubility simulator
• Column type flow through assembly
Rotating Bottle method:
Sample are tested in 90ml of bottle containing 60ml of
fluid which are rotated end over end in 370 Water bath at
40 RPM.

Sartorius Device:
Includes an artificial lipid membrane which separates the
dissolution chamber from simulated plasma compartment
in which the drug concentrations are measured or dialysis
membrane may be used.

Advantages
Measure release profile of disintegrating dosage unit such
as powder materials, suspensions, granular materials, if
permeability is properly defined.
Column Flow through Apparatus
• Drug is confined to a relatively small chamber in a highly
permeable membrane filters.
• Dissolution fluid might be recirculated continuously
from the reservoir allowing measurement of cumulative
release profile.
• Duration of testing 6 to 12 hr.
• Media used
Simulated gastric fluid pH 1.2
Simulated intestinal fluid pH 7.2
Temperature 37 0C
If required bile salt, Pancreatin and pepsin can be added.
 In vivo Measurement of Drug
Availability
• Validation of sustained release product designs can be
achieved only by in vivo testing.
• The basic objective is to establish the bioequivalence
of the product for which a controlled release claim is to
be made with conventional dosage forms of the
formulated drug.
• Since no unnecessary human testing should be done,
animal models, such as dogs, should be used initially
during the product development stage to tune the
formulation to the desired specifications.
• It is necessary to verify that dumping or insufficient
drug availability are not observed in vivo.
• Tests in both animal and subsequent human trials
should include periodic blood level determinations,
comparison of urinary excretion patterns, serial
radiophotographs (in humans) to follow the course of
the dosage form in the GI tract, and sequential
observations of pharmacologic activity.
• In some instances (e.g. with insoluble core tablets),
ingested dosage forms should be recovered and
assayed for drug content.
• If drug level cannot be measured in biologic fluids,
then the pharmacologic effect must be observed as a
function of time, or clinical trials must be designed, to
establish the effectiveness of the drug product.
 IVIVC
• Attempts to correlate in vivo performance with in vitro
availability tests generally have been based on “single-point”
measurements.
• For example, AUC-values, peak blood levels or peak times
might be correlated with the time required for 50% of drug to
be released in vitro.
• The best that can be expected from this approach is a rank-
order correlation.
• Significant bioavailability difference between formulations
might be masked by improper in vitro methods, or drug
release studies might indicate a greater difference than is
actually seen in vivo.
• Two general approaches to interrelating in vivo and in vitro
measurements of drug release have been suggested.
• In one approach, an in vitro release profile is
transformed into a predicted in vivo response.
• A weighting function characterizing a reference
product is determined between the release profile and
the average in vivo response, which is measured in a
panel of human subjects by the mathematical
operation of deconvolution.
• The in vivo response, predicted in vitro, of the dosage
form undergoing testing is obtained by convolution of
the observed release profile and the weighting
function.
• In the second approach, the apparent in vivo drug
release profile is computed from smoothed blood level
or urinary excretion data.
• This technique requires knowledge of the
pharmacokinetic model of the drug.
• The in vivo data are used as input to a computer
simulation of the pharmacokinetic model; the output
represents the amount of drug released at the
absorption site as a function of time.