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THE PHARMA INNOVATION

Sustained Release Drug Delivery System Potential

K.P. Sampath kumar*, Debjit Bhowmik, Shweta Srivastava, Shravan Paswan and A.S. Dutta

1. Karpagam University, Coimbatore, Tamil Nadu, India

2. Department of Pharmaceutical sciences, Coimbatore medical college, Coimbatore,Tamil Nadu, India
3. R. K. Pharmacy college, Azamgarh, Uttar Pradesh, India
Pharmaceutical invention and research are increasingly focusing on delivery systems which
enhance desirable therapeutic objectives while minimizing side effects. Oral drug delivery
system represents one of the frontier areas of controlled drug delivery system. Such a dosage
forms having a major advantage of patient compliance. Sustained release dosage forms are
designed to release a drug at a predetermined rate in order to maintain a constant drug
concentration for a specific period of time with minimum side effects. Now a days as very few
drugs are coming out of research and development and already existing drugs are suffering the
problem of resistance due to their irrational use specifically in case of drugs like antibiotics.
Hence, change in the operation is a suitable and optimized way to make the some drug more
effective by slight alteration in the drug delivery. Sustained Release is also providing promising
way to decrease the side effect of drug by preventing the fluctuation of the therapeutic
concentration of the drug in the body.
Keyword: Sustained Release Drug Delivery System, Controlled Drug Delivery

INTRODUCTION: Oral drug delivery has The design of oral sustain drug delivery system
been known for decades as the most widely (DDS) should be primarily aimed to achieve the
utilized route of administration among all the more predictability and reproducibility to control
routes that has been explored for the systemic the drug release, drug concentration in the target
delivery of drugs via various pharmaceutical tissue and optimization of the therapeutic effect
products of different dosage form. Nowadays of a drug by controlling its release in the body
most of the pharmaceutical scientists are involved with lower and less frequent dose. Conventional
in developing an ideal DDS. This ideal system drug therapy typically involves the periodic
should have advantage of single dose for whole dosing of a therapeutic agent that has been
duration of the treatment and it should deliver the formulated in a manner to ensure its stability,
drug directly at specific site. Scientists have activity and bioavailability. For most of the
succeeded to develop a system that can be as drugs, conventional methods of formulation are
near to an ideal system and it encourages the quite effective. However some drugs are unstable
scientists to develop controlled release system. and toxic and have a narrow therapeutic range,
exhibit extreme solubility problems, require
Corresponding Author’s Contact information: localization to a particular site in the body or
K.P. Sampath Kumar* require strict compliance or long-term use. In
Karpagam University, Coimbatore, Tamil Nadu, India such cases a method of continuous administration
E-mail: [email protected]
of drug is desirable to maintain fixed plasma drug

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

levels. The goal in designing sustained or existing international patents, discovery of new
sustained delivery systems is to reduce the polymeric materials suitable for prolonging the
frequency of the dosing or to increase drug release, and the improvement in therapeutic
effectiveness of the drug by localization at the efficiency and safety achieved by these delivery
site of action, reducing the dose required or systems. Now-a-days the technology of sustained
providing uniform drug delivery. So, sustained release is also being applied to veterinary
release dosage form is a dosage form that release products.
one or more drugs continuously in a
predetermined pattern for a fixed period of time, These systems also provide a slow release of drug
either systemically or to a specified target organ. over an extended period of time and also can
sustained release dosage forms provide a better provide some control, whether this be of a
control of plasma drug levels, less dosage temporal or spatial nature, or both, of drug release
frequency, less side effect, increased efficacy and in the body, or in other words, the system is
constant delivery. successful at maintaining constant drug levels in
the target tissue or cells.
1) Controlled Release:
Terminology: 1,2
These systems include any drug delivery system
Modified release delivery systems may be that achieves slow release of drug over an
divided conveniently in to four categories. extended period of time.

A) Delayed release 2) Extended Release:

B) Sustained release Pharmaceutical dosage forms that release the

drug slower than normal manner at predetermined
i) Controlled release rate & necessarily reduce the dosage frequency
by two folds.
ii) Extended release
C) Site specific targeting:
C) Site specific targeting These systems refer to targeting of a drug directly
D) Receptor targeting to a certain biological location. In this case the
target is adjacent to or in the diseased organ or
tissue.

A) Delayed Release: D) Receptor targeting:

These systems are those that use repetitive, These systems refer to targeting of a drug directly
intermittent dosing of a drug from one or more to a certain biological location. In this case the
immediate release units incorporated into a single target is the particular receptor for a drug within
dosage form. Examples of delayed release an organ or tissue.
systems include repeat action tablets and capsules Site specific targeting and receptor targeting
and enteric-coated tablets where timed release is systems satisfy the spatial aspect of drug delivery
achieved by a barrier coating. and are also considered to be sustained drug
delivery systems.
B) Sustained release:
During the last two decades there has been
remarkable increase in interest in sustained Potential advantages and disadvantages of
release drug delivery system. This has been due sustained release dosage forms
to various factor viz. the prohibitive cost of
developing new drug entities, expiration of Advantages: 2,3,4,5

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

i] Patient Compliance: those required in the cells have to be administered

Lack of compliance is generally observed with in order to achieve the necessary therapeutically
long term treatment of chronic disease, as success effective concentration. This unfortunately may
of drug therapy depends upon the ability of lead to undesirable, toxicological and
patient to comply with the regimen. Patient immunological effects in non-target tissue. A
compliance is affected by a combination of sustained release dosage forms leads to better
several factors, like awareness of disease process, management of the acute or chronic disease
patient faith in therapy, his understanding of the condition.
need to adhere to a strict treatment schedule.
Also the complexity of therapeutic regimens, the
cost of therapy and magnitude of local and or
systemic side effect of the dosage form. The Challenges: 3,4,5
problem of lack of patient compliance can be
resolved to some extent by administering i) Dose dumping:
sustained release drug delivery system.
Dose dumping is a phenomenon where by
ii] Reduced 'see- saw' fluctuation: relatively large quantities of drug in a sustained
release formulation is rapidly released,
Administration of a drug in a conventional introducing potential toxic quantities of the drug
dosage form [except via intravenous infusion at a into the systemic circulation. Dose dumping can
constant rate] often results in 'see – saw' pattern lead to fatalities in case of potent drug, which
of drug concentration in the systemic circulation have a narrow therapeutic index e.g.
and tissue compartments. The magnitudes of Phenobarbital.
these fluctuations depend on drug kinetics such as
the rate of absorption, distribution, elimination ii) limited choice of selecting desired dose in the
and dosing intervals. The 'see-saw' or 'peak and unit:
valley' pattern is more striking in case of drugs
In conventional dosage forms, dose adjustments
with biological half lives of less than four hours,
are much simpler e.g. tablet can be divided into
since prescribed dosing intervals are rarely less
two fractions. In case of sustained release dosage
than four hours. A well-designed sustained
forms, this appears to be much more complicated.
release drug delivery system can significantly
Sustained release property may get lost, if dosage
reduce the frequency of drug dosing and also
form is fractured.
maintain a more steady drug concentration in
blood circulation and target tissue cells. iii) Poor In Vitro – In Vivo correlation:
iii] Reduced total dose: In sustained release dosage form, the rate of drug
release is deliberately reduced to achieve drug
Sustained release drug delivery systems have
release possibly over a large region of
repeatedly been shown to use less amount of total
gastrointestinal tract. Here the so called
drug to treat a diseased condition. By reducing
‘Absorption window’ becomes important and may
the total amount of drug, decrease in systemic or
give rise to unsatisfactory drug absorption in vivo
local side effects are observed. This would also
despite excellent in-vitro release characteristics.
lead to greater economy.
iv) Patient variation:
iv] Improved efficiency in treatment:
The time period required for absorption of drug
Optimal therapy of a disease requires an efficient
released from the dosage form may vary among
delivery of active drugs to the tissues, organs that
individuals. Co-administration of other drugs,
need treatment. Very often doses far in excess to

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

presence or absence of food and residence time in that have poor bioavailability because their
gastrointestinal tract is different among patients. absorption is limited to upper GI tract can be
This also gives rise to variation in clinical delivered efficiently thereby maximizing their
response among the patient. absorption and improving their absolute
bioavailability.
Floating dosage forms with SR characteristics can
Other advantages are: also be expected to reduce the variability in
Sustained drug delivery: transit performance. In addition, it might provide
As mentioned earlier, drug absorption from oral a beneficial strategy for gastric and duodenal
controlled release (CR) dosage forms is often cancer treatment.
limited by the short GRT available for absorption. The concept of FDDS has also been utilized in
However, HBS type dosage forms can retain in the development of various anti- reflux
the stomach for several hours and therefore, formulations. Floating systems are particularly
significantly prolong the GRT of numerous useful for acid soluble drugs, drugs poorly
drugs. soluble or unstable in intestinal fluids, and those
These special dosage forms are light, relatively which may undergo abrupt changes in their pH
large in size, and do not easily pass through dependent solubility due to food, age and disease
pylorus, which has an opening of approx. 0.1– 1.9 states.
cms.
LIMITATIONS
Site specific drug delivery 1. The major disadvantage of floating
A floating dosage form is a feasible approach system is requirement of a sufficient high
especially for drugs which have limited level of fluids in the stomach for the drug
absorption sites in upper small intestine. The delivery to float. However this limitation
controlled, slow delivery of drug to the stomach can be overcome by coating the dosage
provides sufficient local therapeutic levels and form with the help of Bioadhesive
limits the systemic exposure to the drug. This polymers that easily adhere to the mucosal
reduces side effects that are caused by the drug in lining of the stomach.
the blood circulation. In addition the prolonged 2. Floating system is not feasible for those
gastric availability from a site directed delivery drugs that have solubility or stability
system may also reduce the dosing frequency. problem in gastric fluids.
3. The dosage form should be administered
The eradication of Helicobacter pylori requires with a minimum of glass full of water
the administration of various medicaments (200-250 ml).
several times a day, which often results in poor 4. The drugs, which are absorbed throughout
patient compliance. More reliable therapy can be gastro-intestinal tract, which undergo first
achieved by using GRDDS. Floating alginate pass metabolism (nifedipine, propranolol
beads have been used for the sustained release of etc.), are not desirable candidate.
Amoxycillin trihydrate. Thus, it can be expected 5. Some drugs present in the floating system
that the topical delivery of antibiotic through a causes irritation to gastric mucosa.
FDDS may result in complete removal of the
organisms in the fundal area due to bactericidal
drug levels being reached in this area, and might Criteria to be met by drug proposed to be
lead to better treatment of peptic ulcer. formulated in sustained release dosage forms.
3,4.

Pharmacokinetic advantages a) Desirable half-life.

As sustained release systems, floating dosage
forms offer various potential advantages. Drugs b) High therapeutic index

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

c) Small dose compounds into sustained release formulations is

therefore unrealistic and may reduce overall
d) Desirable absorption and solubility absorption efficiency.
characteristics.
e) Desirable absorption window:
e) Desirable absorption window.
Certain drugs when administered orally are
f) First past clearance. absorbed only from a specific part of
gastrointestinal tract. This part is referred to as
the ‘absorption window’. Drugs exhibiting an
absorption window like fluorouracil, thiazide
a) Desirable half-life: diuretics, if formulated as sustained release
dosage form are unsuitable.
The half-life of a drug is an index of its residence
time in the body. If the drug has a short half life f) First pass clearance:
(less than 2 hours), the dosage form may contain
a prohibitively large quantity of the drug. On the As discussed earlier in disadvantages of sustained
other hand, drug with elimination half-life of delivery system, delivery of the drug to the body
eight hours or more are sufficiently sustained in in desired concentrations is seriously hampered in
the body, when administered in conventional case of drugs undergoing extensive hepatic first
dosage from, and sustained release drug delivery pass metabolism, when administered in sustained
system is generally not necessary in such cases. release forms.
Ideally, the drug should have half-life of three to
four hours.
DESIGN AND FORMULATION OF ORAL
SUSTAINED RELEASE DRUG DELIVERY
SYSTEM AND THE FACTORS AFFECTING
b) High therapeutic index: THERE OF: 5,6,7,8
The oral route of administration is the most
Drugs with low therapeutic index are unsuitable
preferred route due to flexibility in dosage form,
for incorporation in sustained release
design and patient compliance. But here one has
formulations. If the system fails in the body, dose
to take into consideration, the various pH that the
dumping may occur, leading to fatalities eg.
dosage form would encounter during its transit,
Digitoxin.
the gastrointestinal motility, the enzyme system
c) Small dose: and its influence on the drug and the dosage form.
The majority of oral sustained release systems
If the dose of a drug in the conventional dosage rely on dissolution, diffusion or a combination of
form is high, its suitability as a candidate for both mechanisms, to generate slow release of
sustained release is seriously undetermined. This drug to the gastrointestinal milieu.
is chiefly because the size of a unit dose sustained
release formulation would become too big, to Theoretically and desirably a sustained
administer without difficulty. release delivery device, should release the drug
by a zero-order process which would result in a
d) Desirable absorption and solubility blood-level time profile similar to that after
characteristics: intravenous constant rate infusion.

Absorption of poorly water soluble drug is often Plasma drug concentration-profiles for
dissolution rate limited. Incorporating such conventional tablet or capsule formulation, a

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

sustained release formulation, and a zero order c= concentration difference across the
sustained release formulation. membrane.
1] Reservoir type:
Sustained (zero-order) drug release has been
attempted to be achieved, by following classes of
sustained drug delivery system.

A) Diffusion sustained system.

i) Reservoir type.
ii) Matrix type
B) Dissolution sustained system.
i) Reservoir type.
ii) Matrix type
C) Methods using Ion-exchange.
D) Methods using osmotic pressure.
E) pH independent formulations.
F) Altered density formulations.

Figure No-1
6,7,8
A] Diffusion sustained system:
Schematic representation of diffusion sustained
Basically diffusion process shows the movement drug release: reservoir system.
of drug molecules from a region of a higher
concentration to one of lower concentration. The In the system, a water insoluble polymeric
flux of the drug J (in amount / area -time), across material encases a core of drug. Drug will
a membrane in the direction of decreasing partition into the membrane and exchange with
concentration is given by Fick’s law. the fluid surrounding the particle or tablet.
Additional drug will enter the polymer, diffuse to
J= - D dc/dx. the periphery and exchange with the surrounding
media.
D = diffusion coefficient in area/ time
Characterization
dc/dx = change of concentration 'c' with
distance 'x' Description:
Drug core surrounded by polymer membrane
In common form, when a water insoluble which controls release rate.
membrane encloses a core of drug, it must diffuse
through the membrane, the drug release rate dm/ Advantages:
dt is given by, Zero order delivery is possible, release rates
variable with polymer type.
dm/ dt= ADK C/L

Where A = area Disadvantages:

K = Partition coefficient of drug between System must be physically removed from implant
the membrane and drug core sites. Difficult to deliver high molecular weight
L= diffusion path length [i.e. thickness compound, generally increased cost per dosage
of coat] unit, potential toxicity if system fails.

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

ii] Matrix type: Schematic representation of diffusion sustained

drug release: matrix system.
A solid drug is dispersed in an insoluble
matrix and the rate of release of drug is A third possible diffusional mechanism is the
dependent on the rate of drug diffusion and not system where a partially soluble membrane
on the rate of solid dissolution. encloses a drug core. Dissolution of part of
membrane allows for diffusion of the constrained
Higuchi has derived the appropriate drug through pores in the polymer coat.
equation for drug release for this system,
Q = D/ T [2 A –Cs] Cst ½ The release rate can be given by following
equation:-
Where; Release rate = AD / L = [ C 1- C2 ]
Q = weight in gms of drug released per Where,
unit area of surface at time t A = Area
D = Diffusion coefficient of drug in the D = diffusion coefficient
release medium C1 = Drug concentration in the core
 = porosity of the matrix C2 = Drug concentration in the
Cs = solubility of drug in release medium surrounding medium
T= Tortuosity of the matrix L = diffusional path length
A = concentration of drug in the tablet, as
gm/ ml Thus diffusion sustained products are based on
two approaches the first approach entails
Characterization placement of the drug in an insoluble matrix of
some sort. The eluting medium penetrates the
Description: Homogenous dispersion of solid matrix and drug diffuses out of the matrix to the
drug in a polymer mixture. surrounding pool for ultimate absorption. The
Advantages: Easier to produce than reservoir or second approach involves enclosing the drug
encapsulated devices, can deliver high molecular particle with a polymer coat. In this case the
weight compounds. portion of the drug which has dissolved in the
Disadvantages: Cannot provide zero order polymer coat diffuses through an unstirred film of
release, removal of remaining matrix is necessary liquid into the surrounding fluid.
for implanted system.

B] Dissolution sustained systems:7,8

A drug with a slow dissolution rate is inherently

sustained and for those drugs with high water
solubility, one can decrease dissolution through
appropriate salt or derivative formation. These
systems are most commonly employed in the
production of enteric coated dosage forms. To
protect the stomach from the effects of drugs such
as Aspirin, a coating that dissolves in natural or
alkaline media is used. This inhibits release of
Figure No-2 drug from the device until it reaches the higher
pH of the intestine. In most cases, enteric coated
dosage forms are not truly sustaining in nature,
but serve as a useful function in directing release

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

of the drug to a special site. The same approach

can be employed for compounds that are
degraded by the harsh conditions found in the C] Methods using lon Exchange:6,7
gastric region. It is based on the formation of drug resin complex
formed when a ionic solution is kept in contact
with ionic resins. The drug from these complex
gets exchanged in gastrointestinal tract and
i) Reservoir type: released with excess of Na+ and Cl- present in
gastrointestinal tract
Drug is coated with a given thickness coating,
which is slowly dissolved in the contents of Resin + - Drug - + Cl- goes to resin + Cl- +
gastrointestinal tract. By alternating layers of Drug-
drug with the rate controlling coats as shown in
figure, a pulsed delivery can be achieved. If the Where x- is cl- conversely
outer layer is quickly releasing bolus dose of the
drug, initial levels of the drug in the body can be Resin - - drug+ + Na +goes resin –
Na+ +
quickly established with pulsed intervals. Drug
Although this is not a true sustained release
system, the biological effects can be similar. An These systems generally utilize resin compounds
alternative method is to administer the drug as of water insoluble cross – linked polymer. They
group of beads that have coating of different contain salt – forming functional group in
thickness. This is shown in figure. Since the repeating positions on the polymer chain. The
beads have different coating thickness, their rate of drug diffusion out of the resin is sustained
release occurs in a progressive manner. by the area of diffusion, diffusional path length
and rigidity of the resin which is function of the
Those with the thinnest layers will provide the amount of cross linking agent used to prepare
initial dose. The maintenance of drug levels at resins .The release rate can be further sustained
late times will be achieved from those with by coating the drug resin complex by
thicker coating. This is the principle of the microencapsulation process.15 The resins used
spansule capsule. Cellulose nitrate phthalate was include Amberlite, Indion, polysterol resins
synthesized and used as an enteric coating agent and others.
for acetyl salicylic acid tablets.

ii) Matrix type:

D] Methods using osmotic pressure:7
The more common type of dissolution sustained
dosage form as shown in figure. It can be either a A semi permeable membrane is placed around a
drug impregnated sphere or a drug impregnated tablet, particle or drug solution that allows
tablet, which will be subjected to slow erosion. transport of water into the tablet with eventual
pumping of drug solution out of the tablet
Two types of dissolution- sustained pulsed through a small delivery aperture in tablet
delivery systems: coating.

a] Single bead– type device with Two types of osmotically sustained systems are:-
alternating drug and rate-controlling layer. Type A contains an osmotic core with drug
b] Beads containing drug with differing Type B contains the drug in flexible bag with
thickness of dissolving coats. osmotic core surrounding.

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

Low density approach:

E] pH– Independent formulations:6,9 Globular shells which have an apparent density

lower than that of gastric fluid can be used as a
The gastrointestinal tract present some unusual carrier of drug for sustained release purpose.
features for the oral route of drug administration
with relatively brief transit time through the
gastrointestinal tract, which constraint the length
of prolongation, further the chemical environment Factors Influencing Design of sustained
throughout the length of gastrointestinal tract is Release Dosage Forms:7,1,4
constraint on dosage form design. Since most The therapeutic efficacy of drug under clinical
drugs are either weak acids or weak bases, the conditions is not simply a function of its intrinsic
release from sustained release formulations is pH pharmacological activity but also depends upon
dependent. However, buffers such as salts of the path of the drug molecule from the site of
amino acids, citric acid, phthalic acid phosphoric administration to the target site. Different
acid or tartaric acid can be added to the conditions encountered by the drug molecule
formulation, to help to maintain a constant pH while traversing the path of distribution may alter
thereby rendering pH independent drug release. A either the effectiveness of the drug or affect the
buffered sustained release formulation is prepared amount of the drug reaching the receptor site.
by mixing a basic or acidic drug with one or more
buffering agent, granulating with appropriate A] Pharmaceutics:
pharmaceutical excipients and coating with
gastrointestinal fluid permeable film forming This refers to the development/manufacturing of
polymer. When gastrointestinal fluid permeates an efficient delivery system in which the drug has
through the membrane, the buffering agents maximum physiological stability and optimum
adjust the fluid inside to suitable constant pH bioavailability.
thereby rendering a constant rate of drug release
B] Biopharmaceutics / pharmacokinetics:
e.g. propoxyphene in a buffered sustained release
formulation, which significantly increase This involves the study of absorption,
reproducibility. distribution, metabolism and excretion of the
drug, before and after reaching the target site and
evaluation of the relationship between delivery
F] Altered density formulations:1 system and therapeutic response.
It is reasonable to expect that unless a delivery
C] Pharmacodynamics/ Clinical Pharmacology:
system remains in the vicinity of the absorption
site until most, if not all of its drug contents is It is the study of the mechanism of action and
released, it would have limited utility. To this clinical efficacy of a drug administered in dosage
end, several approaches have been developed to form in terms of onset, intensity and duration of
prolong the residence time of drug delivery pharmacological activity.
system in the gastrointestinal tract.

High density approach

Drug properties influencing the design of
In this approach the density of the pellets must sustained or sustained release drug delivery
exceed that of normal stomach content and system are classified as:
should therefore be at least 1-4gm/cm3. 1] Physicochemical properties of the drug

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

These include dose size, aqueous solubility, 1. They must be completely inert and non-
protein binding, molecular size, drug stability and reactive with the drug and additives in the
partition coefficients. tablet.
2. They must be able to form a stable and strong
2] Biological factors matrices when compressed either directly or
more often as granules prepared by the
These include absorption, distribution, addition of a binding agent.
metabolism, duration of action, margin of safety, 3. They must be non-toxic.
side effects of drug, disease state and circadian
rhythm.

Methods to achieve oral sustained drug Hydrophilic matrix system:

delivery:6
There are various methods employed for the Carboxymethylcellulose sodium, hydroxymethyl
fabrication of oral sustained release delivery cellulose, polyethylene oxide, polyvinyl-107,
systems. Ritschel has given a detailed report of molidones and natural gums can be used as
these techniques. These are as follows. matrix materials. The matrix may be tableted by
direct compression of the blend of active
a. Hydrophilic matrix ingredient and certain hydrophilic carriers or
b. Plastic matrix from a wet granulation containing the drug and
c. Barrier resin beads hydrophilic matrix material.
d. Fat embedment
e. Repeat action Upon immersion in water the hydrophilic matrix
f. Ion exchange resin quickly forms a gel layer around the tablet. Drug
g. Soft gelatin depot capsules release is sustained by a gel diffusional barrier
h. Drug complexes and /or tablet erosion.
In the following discussion, sustained release
dosage form using method of matrix is
discussed. EVALUATION OF SUSTAINED RELEASE
TABLETS:10,11

Matrix devices: Before marketing a sustained release product, it is

must to assure the strength, safety, stability and
Historically, the most popular drug delivery reliability of a product by forming in-vitro and in-
system has been the matrix because of its low vivo analysis and correlation between the two.
cost and ease of fabrication. Methods of altering Various authors have discussed the evaluating
the kinetics of drug release from the inherent first parameters and procedures for sustained release
order behavior especially to achieve a constant formulations.
rate of drug release from matrix devices have
involved several factors.
1. In – Vitro Methods
These are:-
Requirements of matrix materials:
a. Beaker method
The matrix materials must comply with the b. Rotating disc method
following conditions, c. Rotating Bottle method
d. Rotating Basket method
e. Stationary Basket Method

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

f. Oscillating tube method sustained release drug delivery system but also
g. Dialysis method the biopharmaceutics and pharmacokinetics of
h. USP dissolution method. the therapeutic agent in the body after its release
from the drug delivery system and also the
2. In–Vivo Methods pharmacodynamics of therapeutic agent at the site
of drug action.
Once the satisfactory in-vitro profile is achieved,
it becomes necessary to conduct in-vivo A simple in vitro-in vitro relationship can
evaluation and establish in-vitro in-vivo be established by conducting in-vitro and in-vivo
correlation. The various in-vivo evaluation evaluations of a potential drug delivery system
methods are:- simultaneously to study and compare the
mechanism and rate profiles of sustained drug
a. Clinical response release. When the in-vivo drug release
b. Blood level data mechanism is proven to be in good agreement
c. Urinary excretion studies with that observed in the in-vitro drug release
d. Nutritional studies. studies, then in-vitro in-vivo correlation factor is
e. Toxicity studies derived. For capsule type drug delivery system
f. Radioactive tracer techniques the factor can be represented as:
3. Stability Studies : (Q/t) in-vivo
Q=
Adequate stability data of the drug and its dosage
(Q/t) in-vitro
form is essential to ensure the strength, safety,
Where Q/t = Rate of release
identity, quality, purity and in-vitro in-vivo
release rates, that they claim to have at the time ‘Q’ values are dependent profiles of drug
of use. A sustained release product should release delivery systems. upon the sites of administration
a predetermined amount of the drug at specified and environmental conditions to which the
time intervals, which should not change on animals are exposed during treatment (study).
storage. Any considerable deviation from the The above relationship can be used for
appropriate release would render the sustained optimization of sustained release Levy has
release product useless. The in-vitro and in-vivo classified in-vivo – in-vitro correlation in to:
release rates of sustained release product may be
altered by atmospheric or accelerated conditions a] Pharmacological correlations based on clinical
such as temperature & humidity. observations;
The stability programmes of a sustained release b] Semi-quantitative correlations based on blood
product include storage at both nominal and levels or urinary excretion data;
accelerated conditions such as temperature & c] Quantitative correlation arising from
humidity to ensure that the product will withstand absorption kinetics. While most of the published
these conditions. correlations are of semi-quantitative nature, the
most valuable are those based on absorption
kinetics.
In vitro- In vivo Correlations:4,10

The requirement of establishing good in-vitro in- Bioavailability Testing:

vivo correlation in the development of sustained Bioavailability is generally defined as the rate
release delivery systems is self-evident. To make and extent of absorption of unchanged drug from
a meaningful in-vitro in-vivo correlation one has its site of application to the general circulation.
to consider not only the pharmaceutical aspect of Bioavailability is defined in terms of a specific

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K.P. Sampath kumar*, Debjit Bhowmik, Sweta Srivastava, Shravan Paswan and A.S. Dutta

drug moiety, usually active therapeutic entity,

which may be the unchanged drug or as with
prodrug, for instance, a metabolite. In contrast,
the term "absorption" often refers to net transport
CONCLUSION
of drug related mass from its site of application Sustained release systems include any drug
into the body. Hence, a compound may be
delivery system that achieves slow release of
completely absorbed but only partially drug over an extended period of time. If the
bioavailable as would occur, when low
system is successful in maintaining constant drug
bioavailability is caused by incomplete levels in the blood or target tissue it is considered
absorption. Pharmaceutical optimization of the
as controlled release system. If it is unsuccessful
dosage form may be warranted to improve at this but nevertheless extends the duration of
absorption characteristics of the drug and thereby
action over that achieved by conventional
also its bioavailability. Bioavailability studies are
delivery, it is considered a prolonged release
ordinarily single dose comparisons of tested drug
system. The oral route of administration for
product in normal adults in a fasting state. A
sustained release systems has received greater
crossover design, in which all subjects receive
attention because of more flexibility in dosage
both, the product and reference material on
form design. The design of oral sustained release
different days is preferred. Guidelines for clinical
delivery systems is subject to several inter related
testing have been published for multiple dose
variables of considerable importance such as the
studies. Correlation of pharmacological activity
type of delivery system, the disease being treated,
or clinical evidence of therapeutic effectiveness
the patient, the length of therapy and the
with bioavailability may be necessary to validate
properties of the drug.
the single significance of sustained release
claims. While single dose studies are usually
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