Vol 8, Issue 5, 2015 ISSN - 0974-2441

Review Article

FORMULATION APPROACHES FOR SUSTAINED RELEASE DOSAGE FORMS: A REVIEW

SUDHIR KARNA*, SHASHANK CHATURVEDI, VIPIN AGRAWAL, MOHAMMAD ALIM

Department of Pharmaceutics, Invertis Institute of Pharmacy, Invertis University, Bareilly, Uttar Pradesh, India.
Email: [email protected]
Received: 30 May 2015, Revised and Accepted: 14 July 2015

ABSTRACT

Over the past 30 years, as the expense and complications involved in marketing new drug entities have increased, with concomitant recognition of
the therapeutic advantages of controlled drug delivery, greater attention has been focused on development of sustained or controlled release drug
delivery systems (DDS). For many disease states, a substantial number of therapeutically effective compounds already exist. The effectiveness of these
drugs is often limited by side effects or necessity to administer the compound in an ethical setting. The goal in designing sustained drug delivery
is to reduce the frequency of dosing or to increase the effectiveness of the drug by localization at the site of action, reducing the dose required or
providing uniform drug delivery. The design of oral sustained release DDS depends on various factors such as, physicochemical properties of drug,
type of delivery system, disease being treated, and patient condition, and treatment duration, presence of food, gastrointestinal motility, and co-
administration of other drugs.

Keywords: Sustained release drug delivery system, Dose frequency, Biological half-life, Physicochemical properties of drugs.

INTRODUCTION therapeutically effective concentration can be achieved in the systemic

circulation over an extended period of time, thus achieving better
Oral drug delivery has been known for decades as the most widely compliance of patients. In many instances, the conventional method
utilized route of administration among all the routes that has been is more preferred to deliver the drug, but some drugs are unstable
explored for the systemic delivery of drugs via various pharmaceutical and toxic by frequently dosing. These kinds of the drug have the
products of the different dosage form. Traditional drug delivery system narrow therapeutic range and face solubility difficulties. In such cases,
(DDS) has been characterized by immediate release and repeated sustained DDS is used, which maintain the drug plasma level in the
dosing of the drug which might lead to the risk of dose fluctuation, this therapeutic index [2,9].
arises the need of a formulation with control release that maintain a
near-constant or uniform blood level. Therefore, nowadays the most If one were to imagine the ideal DDS, two prerequisites would be
of the pharmaceutical scientists are involved in developing an ideal required. First, it would be a single-dose for the duration of treatment,
DDS. This ideal system should have the advantage of single-dose for whether it is for days of weeks, as with infection, or for a lifetime of
the whole duration of the treatment, and it should deliver the drug the patient, as in hypertension or diabetes. Second, it should deliver the
directly at a specific site at a controlled manner [1,2]. The design drug directly to the site of action, thereby minimizing or eliminating
of oral sustain DDS should be primarily aimed to achieve the more side effects [10]. SR has received most of the attention because of the
predictability and reproducibility to control the drug release, drug fact that there is more feasibility in dosage form [11].
concentration in the target tissue and optimization of the therapeutic
effect of a drug by controlling its release in the body with lower and The infrared DDS lacks some features such as dose maintenance, SR
less frequent dose [3]. rate, and site targeting. The oral sustained drug delivery has some
potential advantage such as SR rate and dose maintenance in plasma.
The goal in designing sustained or sustained delivery systems is to The SR formulations have some swelling polymer or waxes or both
reduce the frequency of the dosing or to increase effectiveness of the which controls the release rate. The use of reservoir system is also well-
drug by localization at the site of action, reducing the dose required known for controlling release rate [12].
or providing uniform drug delivery. So, sustained release (SR) dosage
form is a dosage form that release one or more drugs continuously in a The goal of an SR dosage form is to maintain therapeutic blood
predetermined pattern for a fixed period of time, either systemically or or tissue levels of the drug for an extended period. This is usually
to a specified target organ [4,5]. accomplished by attempting to obtained zero-order release from the
dosage form. Zero-order release constitutes drug release from the
DEMERITS OF CONVENTIONAL RELEASE DOSAGE FORM [6,7] dosage form that is independent of the amount of drug in the delivery
system (i.e., a constant release rate). SR systems generally do not
1. If the drug has a short half-life, it has to be administered frequently,
attain this type of release and usually try to mimic zero-order release
so there are chances of missing the dose.
by providing the drug in a slow first-order fashion (i.e., concentration
2. If the drug is not taken at a periodic interval, peak-valley plasma
dependent). Fig. 1 shows the relation between plasma concentration
concentration-time profile obtained is not steady.
verses time [13].
3. The fluctuations of drug plasma level that occurs during conventional
release may produce under medication or overmedication. RATIONALE OF DEVELOPING SR DDS [13]
4. Poor patient compliance.
• To extend the duration of action of the drug
The therapy of many chronic diseases requires a repeated dosing of • To reduce the frequency of dosing
a drug. Drugs having a short half-life have to administer up to several • To minimize the fluctuations in plasma level
times daily within short intervals. To reduce the application frequently • Improved drug utilization
sustained formulations have been developed [8]. By the SR method • Less adverse effects.
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Controlled-release dosage forms

They are the class of pharmaceuticals or other biologically active
products from which a drug is released from the delivery system in a
planned, predictable, and slower-than-normal manner for a longer
period of time [26].

Extended release
Pharmaceutical dosage forms that release the drug slower-than-normal
manner at a predetermined rate and necessarily reduces the dosage
frequency by two folds [27].
Fig. 1: Plasma drug concentration profile for conventional release, a
sustained release and zero order controlled release formulation [13] Delayed release
Delayed release systems are those systems that use repetitive,
ADVANTAGES OF SR DDS OVER THE CONVENTIONAL DOSAGE intermittent dosing of a drug from one or more immediate release units
FORM [6-13] incorporated into a single dosage form [28].

• Reduced dosing frequency Repeat action DDS

• Dose reduction These are the alternative system of SR which multiple contains doses of
• Improved patient compliance the drug within the dosage form, and each dose is released at regular
• A constant level of drug concentration in blood plasma intervals [29].
• Reduced toxicity due to overdose
• Reduces the fluctuation of peak-valley concentration Prolonged release system
• Night time dosing can be avoided They are designed to release the drug slowly and to provide a
• Economic continuous supply of drug over an extended period. They prevent very
• The total amount of drug administered can be reduced, thus: rapid absorption of the drug, which could result in extremely high peak
• Maximizing availability with minimum dose plasma drug concentration [30].
• Minimize or eliminate local side effects
• Minimize or eliminate systemic side effects Timed release DDS
• Minimize drug accumulation with chronic dosing. Timed release DDS are used to obtain the drug release after a lag time of
about 4-5 hrs. Enteric coated dosage forms of cellulose acetate phthalate
DISADVANTAGES OF SR DDS [1] are designed to provide protection in the stomach. Application of a thick
• Probability of dose dumping coat causes a delay in the drug release in the small intestine and delays
• Reduced potential for dose adjustment the drug release. This time controlled drug release may be retarded
• Cost of single unit higher than conventional dosage forms upto 5 hrs this targets the drug to the colon [31].
• Increase potential for first-pass metabolism
• The requirement for additional patient education for proper Site-specific and receptor release
medication They are designed to target the drug directly to a certain biological
• Decreased systemic availability in comparison to immediate release location. In the case of site-specific release, the drug directly target to
conventional dosage forms a certain organ or tissue, while in receptor release, the target on the
• Poor in vitro and in vivo correlations. particular receptor within an organ or tissue [28].

DRUG SELECTION FOR ORAL SR DDS FACTORS AFFECTING THE FORMULATION OF ORAL SR DDS

The biopharmaceutical evaluation of a drug for potential use in SR DDS There are two major factors that affect the release rate from the DDS.
requires knowledge on the absorption mechanism of the drug form They are:
the gastrointestinal (GI) tract, the general absorbability, the drug’s 1. Physicochemical factors
molecular weight, pKa, solubility at different pH, and apparent partition 2. Biological factors.
coefficient as shown in Table 2 [1,10,24].
PHYSICOCHEMICAL FACTORS
Similarly, there are some pharmacokinetic parameters for drug a. Aqueous solubility
selection which includes drug’s elimination half-life, total clearance, b. Partition coefficient (P [O/W])
absolute bioavailability, possible first-pass effect, and the desired steady c. Drug pKa and ionization at physiological pH
concentrations for peak and trough as shown in Table 3 [1,10,24]. d. Drug stability
e. Molecular weight and diffusivity
CHARACTERISTIC THAT MAKES A DRUG UNSUITABLE FOR SR
f. Protein binding
FORMULATION [24]
g. Dose size.
• Short elimination half-life, i.e., t1/2 <2 hrs
• Long elimination half-life, i.e., t1/2 >8 hrs AQUEOUS SOLUBILITY
• Narrow therapeutic index
Most of the drugs are weak acids or weak bases. Drugs with low water
• Large doses
solubility will be difficult to incorporate into SR mechanism. For a
• Poor absorption
drug with high solubility and rapid dissolution rate, it is often quite
• Low or slow solubility
difficult to retard its dissolution rate. A drug of high water solubility
• Extensive first-pass clearance.
can dissolve in water or GI fluid readily and tends to release its
dosage form in a burst and thus is absorbed quickly leading to a sharp
TERMINOLOGY
increase in the blood drug concentration compared to less soluble
SR drug. It is often difficult to incorporate a highly water-soluble drug in
These are DDS that are designed to achieve a prolonged therapeutic the dosage form and retard the drug release, especially when the dose
effect by continuously releasing medication over an extended period of is high. The pH-dependent solubility, particularly in the physiological
time after administration of single-dose of drug [25]. pH range, would be another problem for SR formulation because of

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Table 1: List of some marketed sustained release formulations

Technology Brand name Drugs References

Reservoir system tablet Kadian® Morphine sulfate 14
Matrix system tablet Oramorph® Morphine sulfate
Imdura® Isosorbite mononitrate 15
K‑TAB® Potassium chloride 16
Glucomet® SR Metformin HCl 17
BIAXIN® XL Clarithromycin 18
Ambien CR Zolpidem tartarate 12
Diffusion controlled release Welbutrin XL Bupropion
Elementary osmotic pump system Efidac 24® Chlorpheniramine meleate
Acutrim Phenylpropanolamine 20
Minipress XL Prazosin
Push pull osmotic system Cardura XL Doxazosin
Covera HS Verapamil
Glucotrol XL Glipizide 12, 19
Ion‑exchange system Tussionex Hydrocodon 12
Pennkinetic ER suspension Polystirex and clorpheniramine polistirex
Delsym Dextromethorphan 20
Phentuss Codeine and chlorpheniramine
pH‑dependent system Hifenac SR Aceclofenac 21
Inac TR Diclofenac sodium 22
Asacol 5‑amino salicylic acid 23
pH‑independent system Avinza® Capsule Morphine sulfate 14
Inderal® LA Propanolol HCl 12
Alter density formulation Modapar Levodopa and benserazide

Table 2: Physicochemical parameters for drug selection solubilization obstacles and often compounds with solubility
10 mg/ml present difficulties to solubilization dosing formulation. In
Parameter Preferred value general, highly soluble drugs are undesirable for formulation into an
Molecular weight/size <1000 Daltons SR product [12].
Solubility >0.1 mg/ml for pH 1‑7.8
Apparent partition coefficient High PARTITION COEFFICIENT
Absorption mechanism Diffusion
General absorbability From all GI segments The partition coefficient is defined as the fraction of drug in an oil phase
Release Should not be influenced to that of an adjacent aqueous phase. Partition coefficient influences not
by pH and enzymes only the permeation of the drug across the biological membranes but
also diffusion across the rate controlling membrane or matrix between
GI: Gastrointestinal
the time when a drug is administered, and when it is eliminated from
the body, it must diffuse through a variety of biological membranes that
Table 3: Pharmacokinetic parameters for drug selection act primarily as lipid-like barriers. A major criterion in evaluation of the
ability of a drug to penetrate these lipid membranes (i.e., its membrane
Parameter Comment permeability) in its apparent oil or water partition coefficient defined
Elimination half‑life Preferably between 2 and 8 hrs as,
Total clearance Should not be dose dependent
Elimination rate constant Required for design Co
Apparent volume of The larger Vd and MEC, the larger K=
Cw
distribution (Vd) will be the required dose size
Absolute bioavailability Should be 75% or more
Intrinsic absorption rate Must be greater than release rate Where,
Therapeutic The lower Css and smaller Vd, the
concentration Css loss among of drug required Co = Equilibrium concentration of all forms of the drug in an organic
Toxic concentration Apart the values of MTC and MEC, phase at equilibrium,
safer the dosage form. Also suitable Cw = Equilibrium concentration of all forms in an aqueous phase.
for drugs with very short half‑life
In general, drugs with an extremely large value of K are very oil soluble
and will partition into membranes quite readily. The relationship
the variation in the pH throughout the GI tract and variation in the between tissue permeation and partition coefficient for the drug is
dissolution rate [6,32]. generally defined by the Hansch correlation, which describe a parabolic
relationship between the logarithm of its partition coefficient as shown
The biopharmaceutical classification system allows estimation of in Fig. 2 [6,33].
the likely contribution of three major factors which affect the oral
absorption. DRUG PKA AND IONIZATION AT PHYSIOLOGICAL PH
• Solubility
• Dissolution and Drugs existing largely in an ionized form are poor candidates for oral
• Intestinal permeability. SR DDS. Absorption of the unionized drugs is well whereas permeation
of ionized drug is negligible because the absorption rate of the ionized
Class  III (high solubility-low permeability) and Class  IV (low drug is 3-4 times less than that of the unionized drug. The pKa range
solubility-low permeability) drugs are poor candidates for SR for an acidic drug whose ionization is pH sensitive is around 3.0-7.5
dosage form compound with solubility <0.1 mg/ml face significant and pKa range for a basic drug whose ionization is pH sensitive is

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e. Margin of safety/therapeutic index

f. Side effect
g. Disease state.

ABSORPTION

The constant blood or tissue concentration of drug can be obtained

from the oral SR systems through uniform and consistent release as
well as absorption of the drug. The desirable quality of the sustaining
system is that it should release completely absorbed. Apparently the
release of the drug from the system is the rate limiting step, where
rapid absorption relative to the drug release is always expected,
i.e., Kr << Ka [4].

If we assume the transit time of dosage forms in the absorptive areas of

Fig. 2: A relationship between drug action and partition GI tract is about 8-12 hrs, the maximum half-life for absorption should
coefficient be approximately 3-4 hrs. Otherwise, the dosage form will pass out
of absorptive regions before drug release is complete. Therefore, the
compounds with lower absorption rate constants are poor candidates.
around 7.0-11.0 are ideal for optimum positive absorption. Drug shall Some possible reasons for the low extent of absorption are poor water
be unionized at the site to an extent 0.1-5.0% [32,34]. solubility, small partition co-efficient, protein binding, acid hydrolysis
and metabolism or site specific or dose-dependent absorption. Drugs
DRUG STABILITY with the high apparent volume of distribution, which influence the
rate of elimination of the drugs, are a poor candidate for oral SR DDS.
Drugs undergo both acid/base hydrolysis and enzymatic degradation
A drug which extensively metabolizes is not suitable for SR DDS. A drug
when administered oral route. Drugs that are unstable in gastric
capable of inducing metabolism, inhibiting metabolism, metabolized
pH can be developed as slow release dosage form and drug release
at the site of absorption or first-pass effect is the poor candidate for
can be delayed until the dosage form reaches the intestine. Drugs
SR delivery, as it could be difficult to maintain constant blood level.
that undergo gut wall metabolism and show instability in the small
Drugs that are metabolized before absorption, either in the lumen or
intestine are not suitable for SR system. In such case, the drug can be
the tissues of the intestine, can show decreased bioavailability from the
modified chemically to form prodrugs, which may possess different
physicochemical properties or a different route of administration sustained releasing systems [12].
should be chosen [4,35].
DISTRIBUTION
MOLECULAR WEIGHT AND DIFFUSIVITY The distribution of drug molecules into the tissue and cells can be the
Diffusivity is defined as the ability of a drug to diffuse through the primary factor in particularly drug elimination kinetics. Since it not
membrane. Diffusivity depends on size and shape of the cavities only lowers the concentration of circulating drug, but it also can be
of the membrane. The diffusion co-efficient of intermediate drug rate limiting in its equilibrium with blood and extravascular tissue. The
molecular weight is 100-400 Daltons; through flexible polymer distribution includes the binding of the drug to the tissues and blood
range is 10−6-10−9 cm2/seconds. Molecular size or weight is indirectly proteins. Protein-bound drugs molecules are considered as inactive
proportional to the diffusibility. Drugs with larger molecular size are a and unable to permeate biological membranes, and a high degree of
poor candidate for oral SR system [32]. protein binding provides prolonged therapeutic action. The apparent
volume of distribution is one of the important parameters of the
PROTEIN BINDING drugs that describes the magnitude of distribution as well as protein
binding within the body. The apparent volume of distribution is the
It is well-known that many drugs bind to plasma proteins with proportionality constant of the plasma concentration of the drug to the
concomitant influence on the duration of drug action. Since blood total drug amount in the body. Thus for the design of sustain release
proteins are four the most part re-circulated and not eliminated, drug products, one must have information of the disposition of drug [4,37].
protein binding can serve as the depot for drug producing a prolonged
release profile, especially if a high degree of drug binding occurs. The METABOLISM
drug interaction and the period of binding with mucin-like protein also
influence the rate and extent of oral absorption [4,36,37]. Metabolism of the drug is either an inactivation of an active drug or
conversion of an inactive drug to an active metabolite. Metabolism
DOSE SIZE of the drug occurs in a variety of tissues, which are containing more
enzymes. Drugs that are significantly metabolized before absorption,
For orally administered systems, there is an upper limit to the bulk size
either in the lumen or tissue of the intestine, can show decreased
of the dose to be administered. In general, a single dose of 0.5-1.0 g is
bioavailability from slower-releasing dosage forms. Most intestinal wall
considered maximal for a conventional dosage form. This also holds for
enzyme systems are saturable. As the drug is released at a slower rate
sustained-release dosage forms. Those compounds that require large
to these regions, less total drug is presented to the enzymatic process
dosing size can sometimes be given in multiple amounts or formulated
during a specific period, allowing more complete conversion of the drug
into liquid system. Another consideration is the margin of safety
to its metabolites. The formulation of these enzymatically susceptible
involved in the administration of large amounts of a drug with narrow
compounds as prodrugs is another viable solution.
therapeutic range [13].
Drugs that are capable of either inducing or inhibiting enzyme synthesis,
BIOLOGICAL FACTORS
they are the poor candidate for SR delivery system due to difficulty in
a. Absorption maintaining uniform blood levels.
b. Distribution
c. Metabolism Drugs possessing variation in bioavailability due to the first-pass effect
d. Biological half-life/duration of action or intestinal metabolism are not suitable for SR DDS [4,36].

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BIOLOGICAL HALF-LIFE/DURATION OF ACTION D. Methods using osmotic pressure

E. pH-independent formulation
The usual goal of an oral sustained-release product is to maintain
F. Altered density formulation
therapeutic blood levels over an extended period. The duration of
action significantly influences the design of oral SR delivery system DIFFUSION SUSTAINED SYSTEM [27,30,38]
and it is dependent on the biological half-life. Factors influencing the
biological half-life of a drug include its elimination, metabolism and Diffusion systems are characterized by the release rate of a drug being
distribution patterns. Drugs with short half-lives required frequent dependent on its diffusion through an inert membrane barrier. Basically,
dosing to minimize fluctuations in the blood levels. SR dosage forms diffusion process shows the movement of drug molecules from a region
would appear very desirable for such drugs. For a given steady state of a higher concentration to one of the lower concentration. The flux of
drug concentration, the zero-order rate of release of a drug from its the drug J (in amount/area−time), across a membrane in the direction
dosage form is directly proportional to its rate of elimination. Thus of decreasing concentration is given by Fick’s law.
drug with very short half-lives require faster rate of release, for a
modest duration of time while dosage form requires large dosage. In −Ddc
J=
general, drugs with half-lives shorter than 2 hrs are poor candidates for dxL
sustained-release preparations. Compounds with long half-lives, more
than 8 hrs, are also generally not used in sustaining forms, since there
D = diffusion coefficient in area/time
effect is already sustained [4,35,36].
dc/dx = change of concentration “c” with distance “x”
MARGIN OF SAFETY/THERAPEUTIC INDEX
In common form, when a water-insoluble membrane encloses a core of
Margin of safety of a drug can be described by considering therapeutic drug, it must diffuse through the membrane, the drug release rate dm/
index, which is the ration of median toxic dose and median effective dt is given by,
dose.
dm ADK∆C
=
Therapeutic index = TD50/ED50 dt L

A drug is considered to be relatively safe with therapeutic index more Where,

than 10 i.e., larger the ratio the more safely is the drug. Margin of the A = area
safety of the drugs determined on the basis of therapeutic index is the K = Partition coefficient of drug between the membrane and drug core
range of plasma concentration in which the drug is considered to the L = diffusion path length [i.e. thickness of coat]
safe and therapeutically effective. The drugs with narrow therapeutic
Δc= concentration difference across the membrane.
indices the release pattern should be more precise to maintain the
plasma concentration within the narrow therapeutic and safety range. In general, two types or subclasses of diffusional systems are recognized:
The unfavorable therapeutic index of a drug can be overcome by
suitable employment of the SR mechanisms [4,35]. Reservoir types
In the system, water insoluble polymeric material encases a core of
SIDE EFFECT drug. The drug will partition into the membrane and exchange with
The side effects of the some drugs are mainly developed due to fluctuation the fluid surrounding the particle or tablet. The additional drug will
in the plasma concentrations. The incidences of side effects can be enter the polymer, diffuse to the periphery and exchange with the
minimized by controlling the concentration within therapeutic range at surrounding media [27] (Fig. 3).
any given time. The SR drug delivery is the most widely used to incidences
of the GI (local) side effects rather than a systemic side effect of the drug. Description
The drug properties which induce local or systemic side effect can be • Drug core surrounded by polymer membrane that controls release
circumvented or modified by their incorporation in a suitable oral SR rate [30].
delivery system that employs a specific controlled release mechanism [4].

DISEASE STATE Advantages [30]

• Zero-order delivery is possible.
Disease state and circadian rhythm are not drug properties, but they • Release rate variable with polymer type.
are equally important as drug properties in considering a drug for SR.
For example:-
Disadvantages [30]
• Aspirin is a drug of choice for rheumatoid arthritis though it is not
suitable for SR dosage form. Still, aspirin SR dosage form could be • System must be physically removed from implants site.
advantageous to maintain therapeutic concentrations, particularly • Difficult to deliver high molecular weight compound.
throughout the night, thus alleviating morning stiffness.
• Asthma attacks are commonly occurring before bedtime, due to a
low cortisol level. The highest cortisol level occurred between 12
midnight and 4 a.m. These variations entail for the design an oral
SR delivery in accordance to circadian rhythm [4,35].

CLASSIFICATION OF SR DDS [27]

A. Diffusion sustained system

a. Reservoir type
b. Matrix type
B. Dissolution sustained system
a. Reservoir type
b. Matrix type Fig. 3: Schematic representation of diffusion sustained drug
C. Methods using Ion-exchange release: Reservoir system

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• Generally increased cost per dosages unit. groups in repeating positions on the polymer chain. The drug is bound
• Potential toxicity, if the system fails. to the resin and released by exchanging with appropriately charged
ions in contact with the ion-exchange groups.
Matrix types
In a matrix system, the drug is dispersed as solid particles within a Resin+ - drug− + X− →→ Resin+ - X− + drug-
porous matrix formed of a water-insoluble polymer. The drug particles
located at the surface of the release unit will be dissolved first and drug Resin− - drug+ + Y+ →→ Resin− - X+ + drug+
release rapidly. Thereafter, drug particles at a successively increasing
distance from the surface of the release unit will be dissolved and Where, X− and Y+ are ions the GI tract.
release by the diffusion in the pores to the exterior of the release unit.
Thus, the diffusion distance of dissolve drug will increase as the release The rate of drug diffusing out of the resin is controlled by the area of
process proceeds [25] (Fig. 4). diffusion, diffusion path length, and rigidity of the resin, which is the
function of the amount of cross-linking agent used to prepare the resin.
For the better release in this system is to coat the ion-exchange resin
Description [30]
with hydrophobic rate-limiting polymer.
• Homogeneous dispersion of solid drug in a polymer mix.
Advantages
Advantages [30] • Suitable for the drugs that are highly susceptible to degradation by
• Easier to produce than reservoir devices enzymatic processes.
• Can deliver high molecular weight compounds.
Disadvantages
• The release rate is proportional to the concentration of the ions
Disadvantages [30]
present in the area of administration, and the release rate of a drug
• Cannot obtain zero-order release can be affected by variability in diet, water intake, and individual
• Removal of remaining matrix is necessary for implanted system. intestinal content.

DISSOLUTION SUSTAINED SYSTEM SR FORMULATION BASED ON OSMOTIC PRESSURE [25]

A drug with a slow dissolution rate will demonstrate sustaining In this system, the flow of liquid into the release unit driven by a
properties, since the release of the drug will be limited by the rate of difference in osmotic pressure between the inside and the outside of
dissolution. SR preparation of drugs could be made by decreasing their the release unit is used as the release-controlling process. In osmosis
rate of dissolution. The approaches to achieve this include preparing SR system, the following sequences of steps are involved in the release
appropriate salts or derivatives, coating the drugs with slowly dissolving process:
materials or incorporating it into a tablet with a slowly dissolving carrier. • Osmotic transport of liquid into the release unit.
Dissolution sustained system can be made by different ways [30]. • Dissolution of the drug within the release unit.
• Convection transport of a saturated drug solution by pumping
Reservoir type of the solution through a single orifice or through pores in the
The drug is coated with a given thickness coating, which is slowly semi-permeable membrane (Fig. 6).
dissolved in the contents of GI tract. By alternating layers of the drug
with the rate controlling coats, a pulsed delivery can be achieved. If the Description [30]
outer layer is quickly releasing bolus dose of the drug, initial levels of • Drug surrounded by semi-permeable membrane and release
the drug in the body can be quickly established with pulsed intervals. governed by osmotic pressure.

An alternative method is to administer the drug as a group of beads Advantages [30]

that have coating of different thickness. Since the beads have different • Zero-order release obtainable.
coating thickness, their release occurs in a progressive manner [27] • Reformulation not required for different drugs.
(Fig. 5). • The release of a drug independent of the environment of the system.

Matrix type Disadvantages [30]

The more common type of dissolution sustained dosage form as it can • The system can be much more expensive than the conventional
be either a drug impregnated sphere or a drug impregnated tablet, counterpart.
which will be subjected to slow erosion [27]. • Quality control more extensive than most conventional tablets.

METHODS USING ION-EXCHANGE [30] pH-INDEPENDENT FORMULATION

Ion-exchange systems generally use resins composed of water-insoluble Since most drugs are either weak acids or weak bases, the release
cross-linked polymers. These polymers contain salt-forming functional from SR formulations is pH-dependent. However, buffers such as salts
of amino acids, citric acid, phthalic acid, phosphoric acid or tartaric
acid can be added to the formulation, to help to maintain a constant
pH thereby rendering pH-independent drug release. A  buffered SR
formulation is prepared by mixing a basic or acidic drug with one or
more buffering agent, granulating with appropriate pharmaceutical
excipients and coating with GI fluid permeable film forming a polymer.
When GI fluid permeates through the membrane, the buffering agents
adjust the fluid inside to suitable constant pH thereby rendering a
constant rate of drug release [27].

ALTERED DENSITY FORMULATIONS [27,38]

Fig. 4: Schematic representation of diffusion sustained drug It is reasonable to expect that unless a delivery system remains in the
release: Matrix system vicinity of the absorption site until most, if not all of its drug contents is

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a b
Fig. 5: (a) Single bead-type device with alternating drug and rate-controlling layers; (b) beads containing drug with differing thickness of
dissolving coats

Fig. 6: Schematic illustration of drug release from osmosis sustaining system

released, it would have limited utility. To this end, several approaches 5. Longer MA, Robinson JR. Sustained release drug delivery system. In:
have been developed to prolong the residence time of DDS in the GI Remington JP, editor. The Science and Practice of Pharmacy. 18th ed.
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1990. p. 1677-9.
6. Wani MS, Controlled release system-A. Rev 2008;6(1): www.
High-density approach
pharmainfo.net/review. Available from: http://www.pharmainfo.net/
In this approach, the density of the pellets must exceed that of normal
reviews/controlled-released-system-review.
stomach content and should therefore, be at least 1-4 g/cm3. 7. Bechgaard H, Nielson GH. Controlled release multiple units and single
unit dosage. Drug Dev Ind Pharm 1978;4(1):53-67.
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