Sustain Release Drug Delivery System Seminar

A
SEMINAR
ON

SUSTAINED RELEASE
DRUG DELIVERY
SYSTEM
presented by
SONAM M. GANDHI
M.Pharm (1st year)
.

Sustain Release
Drug Delivery
System

contents
INTRODUCTION
RATIONALATY IN DESIGNING S.R.D.F.
CONCEPT OF S.R.D.F.
DIFFERENCE BETWEEN C .R. AND S. R.
REPEAT-ACTION Vs SUSTAINED-ACTION DRUG THERAPY.
DIFFICULTIES ARISE IN MAINTAINING THE DRUG CONCENTRATION
IN THERAPEUTIC RANGE .
OVERCOME OF THESE DIFFICULTIES.
MERITS.
DE-MERITS.
FACTORS TO BE CONSIDERD IN S.R.D.F.
METHOD OF FORMULATION OF S.R.D.F
EVALUATION OF S.R.F.
 PROBLEMS DURING FORMULATION.
MARKETED PRODUCT OF SRDF.
REFERENCES.

INTRODUCTION

WHAT IS 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.

INTRODUCTION

The history of controlled release technology is divided into three
time periods

From 1950 to 1970 was the period of sustain drug release

From 1970 to 1990 was involved in the determination of the
needs of the control drug delivery

Post 1990 modern era of controlled release technology

INTRODUCTION
Before initiating a discussion of sustained release dosage forms, it is
necessary to provide a short explanation of terminology used
because there is considerable confusion in this area. The general
consensus is that controlled release denotes systems, which can
provide some control, whether this is of a temporal or spatial nature,
or both, of drug release in the body. In other words, the systems
attempts to control drug concentration in the target tissue or cells.
Thus, prolonged release or sustained release systems, which only
prolong therapeutic blood or tissue levels of the drug for an
extended period of time, cannot be considered as controlled release
systems by this definition. They are distinguished from rate-
controlled drug delivery systems, which are able to specify the
release rate and duration in vivo precisely, on the basis of simple in
vitro tests. Drug targeting, on the other hand, can be considered as a
form of controlled release in that it exercises spatial control of drug
release within the body.

INTRODUCTION
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

INTRODUCTION
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

INTRODUCTION

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.

The difference between controlled release and sustained release,

Controlled drug delivery- which delivers the drug at a pre
determined rate for a specified period of time

Controlled release is perfectly zero order release that is the
drug release over time irrespective of concentration.
Sustain release dosage form- is defined as the type of dosage
form in which a portion i.e. (initial dose) of the drug is released
immediately, in order to achieve desired therapeutic response more
promptly, and the remaining(maintanance dose) is then released
slowly there by achieving a therapeutic level which is prolonged,
but not maintained constant.

Sustained release implies slow release of the drug over a time
period. It may or may not be controlled release.

Rationality in designing S.R.Dosage form.

The basic objective in dosage form design is to optimize the
delivery of medication to achieve the control of therapeutic effect in
the face of uncertain fluctuation in the vivo environment in which
drug release take place.

This is usually concerned with maximum drug availability by
attempting to attain a maximum rate and extent of drug absorption
however, control of drug action through formulation also implies
controlling bioavailability to reduce drug absorption rates.

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 = rate out = KeVd.Cd

Where
Ke = overall elimination (first order kinetics).
Vd = total volume of distribution.
Cd = desired drug concentration.

B) Dose consideration :-
To achieve the therapeutic level & sustain for a given period of time
for the dosage form generally consist of 2 part

a) Initial (primary) dose b) maintenance dose

there for the total dose „W‟ can be.

W = Di + Dm

In a system, the therapeutic dose release follows zero order
process for specified time period then,

W= Di + K0 r. Td

Td = time desired for sustained release from one dose.

If maintenance dose begins to release the drug during
dosing t=O then,

W = Di + K0 r Td – K0 r Tp

Tp = time of peak drug level.

However a constant drug can be obtained by suitable
combination of Di & Dm that release the drug by first order
process, then

W = Di + ( Ke Cd /Kr ) Vd

Sustained release, sustained action, prolonged action,
controlled release, extended action, time release dosage formed are
terms used to identify drug delivery system that are designed to
achieve a prolonged therapeutic effect by continuously releasing
medication over an extended period of time after administration of
single dose .

In case of injectable dosage form, this period may vary
from days to month, in case of orally administrated
forms, however, this period is measured in hours & critically
depends on the residence time of the dosage form in GI tract.

In some case, control of drug therapy can be achieved by
taking advantage of beneficial drug interaction that affect drug
disposition and elimination. E.g.:- the action of probenicid, which
inhibit the excretion of penicillin, thus prolonging it‟s blood level.

Mixture of drug might be utilized to attend, synergize, or
antagonize given drug action.

Sustained release dosage form design embodies this
approach to the control of action i.e. through a process of either
drug modification, the absorption process, and subsequently drug
action can be controlled.

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.

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.

Difficulties arise in maintaining the drug concentration in the
therapeutic range.

Patient incompliance due to increase frequency of dosing,
therefore chances of missing the dose of the drugs with short half
life.

Difficulty to attain steady state drug concentration.

Fluctuation may lead to under medication or over medication.

These difficulties may be overcome by:

Developing the new better and safer drug with long half life &
large therapeutic indices.

Effective and safer use of existing drugs through concept and
techniques of controlled and targeted drug delivery.

Merits.
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.

Demerits..
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.

CHARACTERITICS OF DRUG FOR FORMULATION AS
SUSTAINED RELEASE DOSAGE FORM:-

•Drug should exhibit neither very fast rate of absorption nor
excretions

Drug with higher rate of absorption and excretion are usually
inherently long acting and their formulation in SRDF is not
necessary, as they remain longer time in the body.
e.g.- Diazepam and Phenytoin

Drug with slow rate of absorption and elimination i.e. short half life
less then 2 hr are difficult to formulate as system requires a larger
unit dose size and may contribute to patient complains problem and
also difficult to control the release rate of drug.

•Drug should be uniformly absorbed throughout GI tract.

Drug that are absorbed poorly and at unpredictable rate are not good
candidate for SRDF because there release rate and absorption are
depending on the position of drug in the GI tract and rate movement
of drug.
e.g.- Riboflovin is not absorbed in GI tract.

They should require relatively small doses.

Some drug like sulfonamide require larger dose for therapeutic
activity so this kind of drug are difficult to form in SRDF as unit
dose increases to an extent where it is difficult to swallow by
patient.

•They should have good margin of safety i.e. that their therapeutic
index should be relative range.

•The drug should not show any cumulative action, any undesired
side effect as in case of dose dumping it might produce toxicity.

Some drug does not have any clear advantage for SRDF like
Cqiseuilin.

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
2. Distribution.
molecular size.
3. Metabolism.
3. Aqueous Solubility.
4. Biological half 4. Drug stability.
life.(excreation)
5. Protein binding.
5. Margin of safety 6. Pka

Biological Factors
Absorption.
Absorption of drug need dissolution in fluid before it reaches to
systemic circulation. The rate, extent and uniformity in absorption
of drug are important factor when considering its formulation in to
controlled release system. Absorption= dissolution

The characteristics of absorption of a drug can be greatly effects
its suitability of sustained release product. The rate of release is
much slower than rate of absorption. The maximum half-life for
absorption should be approximately 3-4 hr otherwise, the device
will pass out of potential absorptive region before drug release is
complete.

Compounds that demonstrate true lower absorption rate constants
will probably be poor candidates for sustaining systems.

The rate, extent and uniformity of absorption of a drug are
important factors considered while formulation of sustained
release formulation. As the rate limiting step in drug delivery from a
sustained-release system is its release from a dosage form, rather
than absorption.
It we assume that transit time of drug must in the absorptive
areas of the GI tract is about 8-12 hrs.

If the rate of absorption is below 0.17/hr and above the
0.23/hr then it is difficult to prepare sustained release formulation.
an another important criteria is the through absorption of drug in
GIT tract, drug like Kanamycine and gentamycine shows absorption
are different sites, Riboflavin like drug absorbed effectively by
carrier transport and at upper part of GIT that make it preparation
in SRDF difficult.

As the rate limiting step in drug delivery from a sustained-release
system is its release from a dosage form, rather than absorption.
Rapid rate of absorption of drug, relative to its release is essential if
the system is to be successful.

Distribution:
The distribution of drugs into tissues can be important factor in
the overall drug elimination kinetics.

Since it not only lowers the concentration of drug but it also can
be rate limiting in its equilibrium with blood and extra vascular
tissue, consequently apparent volume of distribution assumes
different values depending on time course of drug disposition.

For design of sustained/ controlled release products, one must
have information of disposition of drug.

Two parameters that are used to describe distribution
characteristics are its apperent volume of distribution and the ratio
of drug concentration in tissue that in plasma at the steady state the
so- colled T/P ratio.

The apparent volume of distribution Vd is nearly a proportional
constant that release drug concentration in the blood or plasma to
the amount of drug in the body. In case of one compartment model

Vd = dose/C0

Where:

C0= initial drug concentration immediately after an IV bolus
injection
In case of two compartment model.

Vss = (1+K12/K21)/V1

Where:
V1= volume of central compartment
K12= rate constant for distribution of drug from central to
peripheral
K21= rate constant for distribution of drug from peripheral to
central
Vss= estimation of extent of distribution in the body
Vss results concentration in the blood or plasma at steady state
to the total mount of the drug present in the body during respective
dosing or constant rate of infusion. Equation 2 is limited to those
instance where steady state drug concentration in both the
compartment has been reached. At any other time it tends to
overestimate or underestimate.

To avoid ambiguity inherent in the apparent volume of
distribution as an estimation of the amount of drug in the body. The
T/P ratio is used.

The amount of drug in the body can be calculated by T/P ratio as
given bellow.

T/P = K12 (K21-β)

Where:

β = slow deposition constant

T= amount of drug in peripheral

Metabolism:
There are two areas of concern relative to metabolism that
significantly restrict sustained release formulation.

1.If drug upon chronic administration is capable of either inducing
or inhibition enzyme synthesis it will be poor candidate for
sustained release formulation because of difficulty of maintaining
uniform blood levels of drugs.

2. If there is a variable blood level of drug through a first-pass
effect, this also will make preparation of sustained release product
difficult.

Drug that are significantly metabolized before absorption, either in
lumen of intestine, can show decreased bio-availability from
slower-releasing dosage forms.

Most intestinal wall enzymes systems are saturable. As drug is
released at a slower rate to these regions less total drug is presented
to the enzymatic. Process device a specific period, allowing more
complete conversion of the drug to its metabolite.

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).

Generally, values of diffusion coefficient for intermediate
molecular weight drugs, through flexible polymer range from 10-8
to 10-9 cm2 / sec. with values on the order of 10-8 being most
common for drugs with molecular weight greater than 500.

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.

Aqueous solubility and pKa
These are the most important to influence its absorptive behavior
and its aqueous solubility ( if it‟s a weak acid or base) and its
pKa
The aqueous solubility of the drug influences its dissolution rate
which in turn establishes its concentration in solution and hence
the driving force for diffusion across the membranes as shown by
Noye‟s Whitney‟s equation which under sink condition that is
dc/dt= Kd.A.Cs
Where dc/dt = dissolution rate
Kd= dissolution rate constant
A = total surface area of the drug particles
Cs= aqueous solubility of the drug

Dissolution rate (dc/dt) is constant only when Surface Area A is
the initial rate is directly proportional to the Aqueous solubility
(Cs) hence Drug with low aqueous solubility have low dissolution
rate and its suffer low bioavailability problem.
The aqueous solubility of weak acid and bases are controlled by
pKa of the compound and pH the medium.
For weak acids
St= So(1+Ka/H+) = So (1+10pH-pKa )
Where St = total solubility of weak acid.
So = solubility of unionized form
Ka= Acid dissociation constant
H+= H ion concentration

Similarly for Weak Bases
St = So (1+H+/Ka) = So (1+10pKa-pH )
if a poorly soluble drug was consider as a suitable candidate for
formulation into sustained release system.
Since weakly acidic drugs will exist in the stomach pH 1-2
, primarily in the unionized form their absorption will be favored
from this acidic environment on the other hands weakly basic drugs
will be exist primarily in the ionized form (Conjugate Acids) at the
same site, their absorption will be poor.
in the upper portion of the small intestine the pH is more alkaline
pH 5-7 and the reverse will be expected for weak acids

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
under go 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 of polymers

Natural polymers Semi synthetic Synthetic polymers
eg. Xanthan gum, polymers eg. Polyesters,
polyurethanes, eg. Celluloses such as polyamides,
Guar gum, HPMC, NaCMC, polyolefins etc
polycarbonates, Ethyl
Karaya gum cellulose etc.
etc

Classification Of Polymers Used In Sustained Release Drug Delivery Systems
According To Their Characteristics:
Sr.no Polymer characteristics Material

1. Insoluble, inert Polyethylene, polyvinyl chloride, methyl acrylates-
methacrylate copolymer, ethyl cellulose.
2. Insoluble, erodable Carnauba wax
Stearyl alcohol,
Stearic acid,
Polyethylene glycol.
Castor wax
Polyethylene glycol monostearate
Trigycerides
3. Hydrophilic Methylcellulose, Hydroxyethylcellulose, HPMC,
Sodium CMC, Sodium alginate, Galactomannose
Carboxypolymethylene.

1. Oral forms
2. Parenteral forms
3. Common sustained action dosage forms
a. Spansules
b. Slow core release tablets
c. Multilayer tablets
d. Repeat action tablets
e. Liquid products
f. Transdermal system

DESIGN OF ORAL SUSTAINED ACTION PRODUCTS

Formulation methods used to obtain the desired drug
availability rate from sustained action dosage form include…….

• Increasing the particle size of the drug.

• Embedding the drug in matrix.

• Coating the drug or dosage form containing
drug(microencapsulation).

• Forming complexes of the drug with material such as ion
exchange resins.

1) Increasing the particle size of the drug:-
The purpose of increasing particle size is to decrease the
surface to volume ratio slow the rate of drug availability. This
method is a single means for obtaining the desired drug availability
rate is limited to poorly soluble drug.

2) Embedding the drug in matrix:-
Matrix may be defined as uniform dispersion of drug in
solid which is less soluble than a drug in the dispersion fluid, &
which for the continuous external phase of the dispersion effectively
impeder the passage of the drug from the matrix to the dispersion
fluid.

One of the least complicated approaches to the
manufacture of sustained release dosage form involves the direct
compression of drug, materials & additives to form a tablet in
which drug is embedded in a matrix core of the retardant.

Polymers:-

• Insoluble, inert - polyethylene, polyvinyl chloride, methyl acrilate,
ethylcellulose.

•Insoluble, erodible – carnauba wax, stearyl alcohol, castor wax.

•Hydrophilic – methyl cellulose, hydroxyl ethyl cellulose, sodium
carboxymethyl cellulose, sodium alginate.

In a matrix system the drug is dispersed as solid particle within
a porous matrix formed of a water insoluble polymer, such as poly-
vinyl chloride.

Initially, drug particle located at the surface of the release unit
will be dissolved and the drug released rapidly. Thereafter, drug
partical at successively increasing distance from the surface of the
release unit will be dissolved and release by diffusion in the pores to
the exterior of the release unit.
The main formulation factor by which the release rate from
matrix system can be controlled are; the amount of the drug in the
matrix, the porosity of the release unit & the solubility of the drug.

Types of matrix systems
Two types of matrix systems
1. Slowly eroding matrix
2. Inert plastic matrix
1.Slowly eroding matrix
Consists of using materials or polymers which erode over a period
of time such as waxes, glycerides, stearic acid, cellulosic materials
etc.
Principle:
• Portion of drug intended to have sustained action is combined with
lipid or cellulosic material and then granulated.
• Untreated drug granulated
• Both mixed

2. Embedding drug in Inert plastic matrix

Principle:
Drug granulated with an inert, insoluble matrix such as
polyethylene, polyvinyl acetate, polystyrene, polyamide or
polymethacrylate.
Granulation is compressed results in MATRIX
Drug is slowly released from the inert plastic matrix by leaching
of body fluids
Release of drug is by diffusion.

Methods of preparation

Preparation of matrix tablets:

Solidify Granulate

Grind

Powder
Suspension of
drug in wax

Granulate
Drug
Tablets

3) Coating the drug or a dosage form containing the
drug (microencapsulation)
The method for retarding drug release
from the dosage form is to coat its
surface with a material(polymers) that
retards penetration by the dispersion
fluid. Drug release depends upon the
physiochemical nature of coating
material.

Microencapsulation is rapidly
expanding technique as a process; it is a
means of applying relatively thin coating
to small particles of solid or droplets of
liquids and dispersion.

The application of microencapsulation might will include,
sustained release or prolonged action medication, taste masked,
chewable tablet, powder and suspension, single layer tablets.
Containing chemically incompatible ingredient & new formulation
concepts for creams, ointments, aerosols, dressing, plasters,
suppositories & injectables.

Polymers: - polyvinyl alcohol, polyacrylic acid, ethyl
cellulose, polyethylene, polymethacrlate, poly (ethylene-vinyl
acetate), cellulose nitrite, silicones, poly (lactide-co-glcolide)

4) Chemically reacting the drug with material such as an
ion-exchange resin:-

Sustained delivery of ionizing acidic & basic drug can be
obtained by complexing them with insoluble non-toxic anion
exchanger and cation exchanger resin respectively.

Here the drug is released slowly by diffusing through the resin
particle structure.

The complex can be prepared by incubating the drug-resin
solution or passing the drug solution through a column containing
ion exchange resin.

Principle:

Is based on preparation of totally insoluble ionic material
• Resins are insoluble in acidic and alkaline media
•They contain ionizable groups which can be exchanged for drug
molecules
IER are capable of exchanging positively or negatively charged
drug molecules to form insoluble poly salt resinates.
Types:
There are two types of IER
Resins functional groups
Cationic Exchange resins - RSO3-H+
Anionic Exchange resins – RNH3+ OH-

Structurally made up of a stable acrylic polymer of
styrene-divinyl benzene copolymer.
Mechanism of action
IER combine with drug to form insoluble ion complexes
1. R-SO3 – H+ + H2N – A
R-SO3 – NH3+ - A
-
+
2. R-NH3 OH + HOOC – B RNH3+ -OOC-B + H2O

Where A- NH2 is basic drug
B-COOH is acidic drug

These resinates are administered orally

2 hrs in stomach in contact with acidic fluid at pH 1.2

Intestinal fluid, remain in contact with slightly basic pH for
6hrs.
Drug can be slowly liberated by exchange with ions present in
G.I.T.

In the stomach
-
®- SO3- NH3+ - A + HCl ®-SO3 H+ + A-NH3+ Cl-

®-NH3+ -OOC –B + HCl ®-NH3+Cl- + HOOC-B
Un dissociated

Thus carboxylic acid will be poorly dissociated in stomach and thus
absorbed.

In the Intestine

-
®- SO3- NH3+ - A + NaCl ®- -SO3 Na+ + A-NH3+ Cl
-

Basic pH un dissociated

®-NH3+ -OOC – B + NaCl ®-NH3+Cl- + Na+-OOCB
Sodium salt of acid
(dissociation of acid salt
unabsorbed)

Amine salt will be poorly dissociated in intestine and thus absorbed.

Parenteral forms
The following parameters are generally manipulated in the design of
parenteral forms:
A) Route of administration

Route of administration of drugs are very many and all of them do
not afford same rate of absorption. A drug given by intravenous
injection may attain a certain blood concentration almost
instantaneously, while the same drug administered intramuscularly
may take considerable time to build up that level since it takes time
to diffuse from muscular tissues into the blood stream. Further a
drug, placed under the skin in the form of an implant, may remain
active over extended period of time giving a sustained action lasting
for mouths. Hence, rate of administration may sometime be
fruitfully employed to obtain sustained action of a medicament.

B)Vehicles

Vehicles significantly alter the bioavailability profile and may be
employed to obtain sustained action. If a drug is suspended in a
lipophilic vehicle and injected in tissues like muscles it gives a
longer action than when it is given in aqueous media.
C)Vaso-constrication

The rate of passage of drugs, administered intradermally or
intramuscularly, depends to a considerable extent upon their area of
contact with blood vessels. Hence, constriction of blood vessels
may be employed to prolonged action. Adrenaline is sometime
administered with local anesthetics to delay absorption of drugs and
to prolong duration of their action,

D) Particle size

The particle size governs the dissolution rate and hence the
bioavailability of drug. Consequently this parameter may be
exploited to prolong its action. This principle is used in the
formulation of the hypodermic tablets which retain their size over
long period of time releasing the drug slowly.

E)Chemical modification of the drug

The structure of the drug molecules can sometime be chemically
modified such that their action is intact while ADME characteristics
get altered. In some cases an analog is synthesized which gives it
the desired capacity of prolonged action. Sometime pro-drug
approach is possible whereby a derivative of the drug is evolved
which is slowly regenerated into the original drug in the presence of
body fluids.

Lidocaine, where two hydrogen atoms are replaced by methyl
groups enabling it to give prolonged effect, is an example of analog
approach, while chlorphenactin palmitate is an example of pro-drug
since the palmitate has to hydrolyse in the g.i.t. to produce
chloromycetin which is the therapeutic agent.
Pro-drug which consist of reservoir of drug whose flow into the
body is calculated either by some body indicator like insulin or by
condition of body is calling for specified inputs of drugs. Such
systems are popularly refered to as “triggered system”, “pulsed
system”. The principles made use of there designs are briefly
discussed below.

Portable pumps
Zyklomat pump, marketed by a german firm has a drug reservoir
and a timing device linked to a computer. It can administer
hormones like LHRH every one and a half hours for 20 days. Yet
another example is a four channel porgrameable portable syringe
pump having four 30 ml. syringes programmed to deliver drug at
any predetermined rate. A personal computer transfer the
programme to a control cartridge which is plugged in the pump
system. Such devices have been used in antibiotic as well.

Implantable devices

Implantable devices marketed in USA and designed for
implantation in the body, consist of peristaltic pump, drug reservoir,
battery and a control unit. The drug administration programme is
entered on a personal computer and is transmitted by a control unit
to the pump system through skin. Such unit have been employed for
administration of drug in cancerous and neurological disorders.
Gradually their use may extended to other conditions requiring
specified drug administration programmes.

Infusor devices
These devices are light weight, portable, disposable and elastomeric
infusion systems. They generally have a small reservoir of drug
sufficient for half day, a day or 5day needs and carry command
modules operable by patients. For control of pain, patients
themselves can operate the system every 5-6 min. such systems
have few side effects and allow optimal pain control.

Osmotic pumps

Osmotic pumps are specifically beneficial in veterinary medicine
and enable zero order drug delivery. The pumping device are linked
with programmable catheter to permit patterned drug delivery and
have largely used for LHRH hormone delivery in animals to induce
ovulation.

Implantable magnetically triggered systems

These system have a porous matrix with drug embedded in it along
with a few magnetic pellets. In the normal course very little drug is
released. However, by an oscillating magnetic field the drug diffuse
out in pulses to the system.

Biodegradable system

In biodegradable system the drug is incapsulated in a polymer
whose erosion is pH dependent. The outer core of the coat is a
hydrogel with immobilized enzymes like glucose oxidase which
convert glucose into gluconic acid everytime its level rises in blood
decreasing pH and thereby causing erosion of polymer and release
of drug.

Antibody coated particles
In these dosage form the drug is convalently linked to a hapten and
coated with corresponding antibodies. When the drug is to be
released more haptens are introduced which displace the antibody
coating enabling release of drug. Naltrexone has been thus linked
with a hapten moiety and coated with antibodies.

Common sustained action dosage form
•Spansules:

Spansules are hard gelatin capsules filled with coated granules or
beads. They are marketed by manufacturer under variety of trade
names.

•Slow core released tablets:

These tablets consist of a core of drug mixed up with substances
from which drug can be slowely leached out by GIT fluid. On to the
core is compressed another layer consisting of drug and other
excipients. The upper layer generally disintegrates rapidly releasing
the drug which builds up blood level. Thereafter the drug is slowly
leached out from the core.

•Multilayer tablets:

Multilayer tablets consist of 2-3 separate layers which release drug
at different rates. In two layers tablets one of the layers is designed
for immediate disintegration while the other remains firm and intact
throughout its sojourn in the intestines. In three layers tablets, one
layer may be for immediate disintegration, the other is designed to
disintegration after sometime and the third may remain intact
releasing drug at a slow pace.

•Repeat action tablets:
Repeat action tablets are regarded to be prototypes of sustained
action products but in fact they are not. In these tablets a second
dose is released only after the first is practically worn off and there
is no continuous release. These tablets usually consist of a core and
a coat. The initial dose is in the coat and the following one in the
core.

•Liquid products:
It is possible to formulate liquid product, having sustained action,
by suspending coated granules or particles in a suitable liquid media
which has no action on the coats of the granules. These formulation
are similar to suspensions.

Evaluation

Drug release is evaluated based on drug dissolution from

dosage form at different time intervals.

Specified in monograph.

Various test apparatus and procedures – USP, Chapter <724>.

Two types
1. In vitro evaluation
2. In vivo evaluation
In vitro evaluation :
• Acquire guidelines for formulation of dosage form during
development stage before clinical trials.
Kinetics or rate of drug release from the dosage form can be
measured in simulated gastric and intestinal fluids.
• Necessary to ensure batch to batch uniformity in production of a
proven dosage form.
Obtain in vitro / in vivo correlation

In vitro quality control tests include:
1. Rotating basket (apparatus 1)
2. Paddle (apparatus 2)
3. Modified disintegration testing apparatus (apparatus 3)
At a specified time intervals measurement of drug is made in
simulated gastric fluid / intestinal fluid.
- 2 hrs in gastric fluid and 6 hrs in intestinal fluid

Data is analysed to see

 Dose dumping i.e., Maintenenance dose is released before the
period is completed.
 Dose that is unavailable is not released in G.I.T.
 Release of loading dose.
 Unit to unit variation, predictability of release properties.
 Sensitivity of the drug to the process variables
Composition of the simulated fluid
 Rate of agitation

Stability of the formulation
Ultimately does the observed profile fit expectations.

Other apparatus specific for SR evaluations

Rotating bottle

Stationary basket / rotating filter

Sartorius absorption and solubility simulator

Column-type flow through assembly

Rotating bottle method:

Samples are tested in 90 ml bottles containing 60 ml of fluid which
are rotated end over end in a 370 C bath at 40 rpm.

Sartorius device

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

Advantages:

Measure release profile of disintegrating dosage units 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 re-circulated continuously from the
reservoir allowing measurement of cumulative release profile.
Duration of testing 6-12hrs.
Media used:
•Simulated gastric fluid or pH 1.2
•Simulated intestinal fluid pH 7.2
•Temperature 37oC
•If required bile salts, pancreatin and pepsin can be added.

Example-

Specifications for Aspirin Extended- release Tablets
Time (hr) Amount Dissolved
1.0 Between 15% and 40%
8.0 Not less than 70 %

In vivo evaluation
A clinical trial, testing the availability of the drug being used in
the form prepared by noting its effect versus time.
Preliminary in vivo testing of formulation carried out in a limited
number of carefully selected subjects based on
- Similar body built, size, occupation, diet, activity
and sex.
- A single dose administered and effect measured over
time (24hrs)
- Test may or may not be blind and cross over design.

Evaluation and testing:
•During formulation

•Precompression granular properties

•Post compression test

During formulation development, testing method should be
designed to provide answer of the following question.

 Does the product “dump” maintenance dose before the
maintenance period is complete? Sustained release product is
subjected to either of two modes of failure, insufficient dose is
release or too much drug is made available too quickly.

 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 effect of physiologic variables on drug release? For
e.g.: delayed gastric empting, interaction between drug and GI
constituent‟s composition and volume of GI fluid.

 is the loading dose released immediately? Is release of the
maintenance dose delayed? If so, is the delay time within the
desired range?

 What is the stability of the formulation with respect to its drug
release profile?

 What is the sensitivity of drug release profile to process
variables?

Precompression granular properties:
Hausner ratio a similar index has been defined by hausner (1967):
Hausner ratio = tapped density/ poured density×100.

Value less than 1.25 indicate good flow (=20% Carr), where as
greater than 1.25 indicates poor flow (=33%Carr), between1.25 and
1.5, added glident normally improve flow.

Angle of repose
It is simple practical technique for measuring resistance to
partical movement.

It is the maximum angle that can be obtained between the
surface of the powder pile and the horizontal plane.

Bulk density

It is great importance when one the size of a high dose
formulation in which there are large difference in drug and
excipients densities.

Bulk density is determined by pouring presived (40-mesh) bulk
drug into a graduated cylinder via a large funnel and measuring the
volume and weight “as is”

Tapped density:
Tapped density is determined by placing a graduated cylinder
containing a known mass of drug and taps (1000) for mechanical
tapper until the powder bed volume has reached a minimum. Using
the weight of drug in the cylinder and this minimum volume, the
tapped density may be computed.

Carr`s index:
a simple test to evaluate the flowability of a powder by
comparing the poured density and tapped density of a powder and
the rate at which it packed down.
Carr‟s index (%) = tapped – poured density/tapped density×100

Post compression test:
Hardness: the force required to break a tablet in a diametric
compression test (Monsanto hardness tester).

Wt variation: mean of 10 tablets.

Friability: loss of drug during handling, manufacturing, packaging,
and shipping.

General appearance: visual identity and overall “elegance,” lot to
lot & tablet to tablet uniformity.
Size, shape, color, presence or absence of an odor, taste, surface
texture, physical flows and consistency.

Unique identification marking:

the type of informational marking placed on a tablet usually
include the company name or symbol, a product code such as that
from the National Drug Coad number, the product name or the
product potency.

Organoleptic properties:

colour, odor, taste.

Drug content of formulated tablets

Five tablets from each batch were randomly chosen,
pulverized and weight equivalent to 50mg of Drug was extracted
with 100ml phosphate buffer (pH 7.4). Aliquot from subsequent
filtered solution was further diluted in phosphate buffer (pH 7.4) in
such a way that theoretical concentration was same as that of
standard concentration. Resultant solutions were analyzed by using
a UV spectrophotometer and the average results taken.

Disintegration:

the first important step toward solution is breakdown of the
tablet into smaller particle or granules for rapidly available to the
body.

The USP device- 6 glass tube – 3 inch long open at top, 10-
mesh screen.temp 370c ± 2 in simulated intestinal fluid.

28-32 cycle per minute.

Dissolution:

The dissolution studies were performed in triplicate for all the
batches in a USP dissolution rate test apparatus.

The release studies were performed at 50 rpm in 900 ml of
phosphate buffer pH 7.4 at 37 ± 0.2οC. Five milliliters sample were
withdrawn at predefined intervals, and the volume of the dissolution
medium was maintained by adding the same volume of fresh buffer
in dissolution medium.

The absorbance of the withdrawn samples was measured
spectrophotometrically at ………… nm.

Problems during formulation of SR dosage form
Film Coating Challenges
One of the main challenges in film coating is developing a process
that is easily controlled and able to generate reproducible and
reliable films. It is important to consider the Minimum Film
Formation Temperature (MFT) for a given polymeric coating
product. It has been shown that it is only possible to form a
continuous polymer film above the MFT; the dispersed particles
will not fully coalesce below the MFT, and, as a result, no film
formation will occur.

Ethyl cellulose and other methacrylate polymers have MFTs that are
higher than room temperature, making film formation much more
difficult.

Prevent Drug Dumping

A further challenge in sustained release film coating is to prevent
drug dumping. One of the recent trends in oral sustained release is
multi-particulates, a formulation in which the drug dose is divided
over a multiple-unit system made up of many small, discrete
particles. Multi-particulates have several advantages over single-
unit systems, including less local irritation due to better distribution
and less variability in gastrointestinal transit time due to their small
size. More importantly, even if failures occur in a few multi-
particulate units, drug dumping is not as severe as it is when failures
occur in a single-unit system.

Release and Compression Force

When investigating the degree of drug release from compressed
tablets, it is important to consider the relationship between drug
release and compression force. Drug release from compressed
pellets coated with Aquacoat is significantly faster than it is from
un-compressed pellets. The higher the compression force, the faster
the release rate, which indicates the existence of damaged film
coatings after compression.

There is no doubt that the importance of sustained release drug
delivery has increased during the last 20 years. This growth is
reflected in the proliferation of sustained release drugs that have
been commercialized largely due to the availability of effective
sustained release coating products. Process improvements and the
role of plasticizers and other protective excipients have helped
provide cost and performance benefits. Many of the challenges
caused by sustained release coatings can now be overcome.

MARKETED CONTROLLED RELEASE PRODUCT

Composition Product Name Manufacturer
Tablet
Carbamazepine Zen Retard Intas
Diazepam Calmrelease – TR Natco

Diclofenac sodium Dic – SR Dee Pharma
Limited
Diclofenac sodium Nac – SR Systopic

Diclofenac sodium Agile – SR Swift

Diclofenac sodium Dicloram SR Unique

Diclofenac sodium Doflex SR Nicholas Piramal

Diclofenac sodium Mobinase – SR Crosland

Diclofenac sodium Monovac – SR Boehringer –
Mannheim
Diclofenac sodium Relaxyl - SR Franco – Indian

Diclofenac sodium Voveran – SR Ciba – Geigy

Diltiazem Dilzem SR Torrent

Diltiazem Hcl Diltime SR Alidac

Lithium carbonate Lithosun – SR Sunpharma

Nifedipine Nyogard LA Searle (I) Ltd

Nifedipine Calcigard Torrent
Retard
Nifedipine Depin Retard Cadila Health
Care
Salbutamol TheoAsthalin Cipla
Theophylline SR
Terbutaline Sulphate, Theobric – SR Remidex
Theophylline
Anhydrous

Theophylline Theo PA Welcome

Theophylline Theo Stan – CR Stancare
Anhydrous

Verapamil Calpatin SR Boehringer –
hydrochloride Mannheim

Verapamil Calapatin 240 SR Boehringer –
hydrochloride Mannheim

Capsules
Chlorpheniramine Coldvir – SR Dee Pharma
maleate, Phenylepinephrine Ltd
hydrochloride

Diazepam Elcoin Ranbaxy
Diclofenac sodium Diclotal CR Blue Cross
Diclofenac sodium Nalco TR Natco
Dried Ferrous Sulphate, Feron SR Dee Pharma
Folic acid Ltd

Dried Ferrous Sulphate, Fefol Eskayef
Folic acid Spansules

Dried Ferrous Sulphate, Ultiron – TR Stancare
Folic acid, Ascorbic acid
Dried Ferrous Sulphate, Convinon TR Ranbaxy
Folic acid, Vit. B12, Vit.
C, Vit. B2
Ferrous Fummarate, Ziberrin – TR Recon
Zinc Sulphate
Monohydrate

Flurbiprofen Arflur SR FDC
Indomethacin Indoflam TR Recon
Isosorbide Dinnitrate Cardicap TR Natco
Ketoprofen Profenid CR Rhone–
Poulenc

Nifedipine Nicardia J. B. Chemicals &
Pharmaceuticals

Nifedipine Indocap SR J. B. Chemicals &
Pharmaceuticals

Nifedipine Cardules Retard Nicohlas Piramal

Nitroglycerin Angispan TR Lyka

Vitamin C, B2, B1, Pesovit Eskayef
Nicotinamide, Spansules
Pantothenic acid,
Dried Ferrous
Sulphate

Transdermal
Estrogen Estraderm TTS Ciba – Geigy

Nitroglycerine Nitorderm TTS Ciba – Geigy

Nicotine Nicotine Patch Ciba – Geigy

References

 Leon lachman – The theory and practic of industrial pharmacy.
 Michael E Alton - Pharmaceutics
The science of dosage form design.
 N.K. Jain – Controlled & novel drug delivery.
 S.P. Vyas & Khar – Controlled Drug delivery,
 Brahmankar – Text Book of Biopharmaceutics &
Pharmacokinetics.
 Yie.W.Chein- Controlled & Novel Drug Delivery, CBS
publishers.
 Painter,P & Coleman ,M – “ Fundamental of Polymer science”.
 IUPAC. Glossary of Basic terms in polymer science”. Pure
application -1996.
 www.goggle.com
• FORMULATION | Sustained Release Coatings By Nigel Langley, PHD,
MBA, and Yidan Lan, Issue Date: June 2009

Sustain Release Drug Delivery System Seminar

Sustain Release Drug Delivery System Seminar

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