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Controlled Released System - A Review

M. S. Wani

Manish Shivadas Wani

Over past 30 year as the expanse and complication 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. There are several reasons for the attractiveness of these dosage forms. It is generally recognized that for many disease states, a substantial number of therapeutically effective compounds already exist.

The effectiveness of these drugs, however, is often limited by side effects or the necessity to administer the compound in a clinical setting, the goal in designing sustained or controlled delivery system is to reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required, or providing uniform drug delivery. Sustained release constitutes any dosage form that provides medication over and extended time. Controlled release, however, denotes that the system is able to provide some actual therapeutic control, whether this is of a temporal nature, spatial nature or both.

This correctly suggests that there are sustain release system that can not be considered controlled release system. In general, the goal of a sustained release dosage from is to maintain therapeutic blood or tissue levels of drug for an extended period this is usually accomplished by attempting to obtain zero-order release from the dosage form; zero-order release constitutes drug release from the dosage form. Sustained release systems generally do not attain this type of release and provides drug is a slow first order fashion. In recent year sustained release dosage forms continue to draw attention in the search for improved patient compliance and decreased incidence of adverse drug reactions. Sustained release technology is relatively cow field and as a consequence, research in the field has been extremely fertile and has produced many discoveries. New and more sophisticated controlled release, sustained release delivery systems are constantly being developed and tested.

Sustained release, sustained action, prolonged action controlled release, extended action, timed release, depot and repository dosage forms are terms used to identify drug delivery system that are designed to achieve or prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.2


Fig.1: Drug level verses time profile showing differences between zero order, controlled release, slow first order sustained release and release from conventional tablet.2

Systems that are designed as prolonged release can also be considered as attempts at achieving sustained-release delivery. Repeat action tablets are an alternative method of sustained release in which multiple doses of drug are contained within a dosage form, and each dosage is related to a periodic interval. Delayed release systems, in contrast may not be sustaining, science often function of these dosage forms is to maintain the drug within the dosage form for some time before release. Commonly the release rate of drug is not altered and does not result in sustained delivery once drug release has begun.

Successful fabrication of sustained release products is usually difficult & and involves consideration of physicochemical properties of drug, pharmacokinetic behavior of drug, route of administration, disease state to be treated and, most importantly, placement of the drug in dosage form total will provide the desired temporal and spatial delivery pattern for the drug3

The slow first order release obtained by a sustained release pre parathion is generally achieved by the release of the drug from a dosage form. In some cases in some cases, this achieved by making slow the release of drug from a dosage form. In some cases, this is accomplished by a continuous release process4

2. Potential advantages of Controlled drug therapy 21

  1. Patient compliance due to reduction in the frequency of designing.
  2. Employ minimum drug.
  3. Minimize or eliminates local and systemic side effects.
  4. Obtain less protentiation or deduction in drug activity with chronic use.
  5. Minimize drug accumulation with chromic dosing.
  6. Improves efficacy in treatment.
  7. Cure or control confirm more promptly.
  8. Improve control of condition i.e. reduce fluctuation in drug level.
  9. Improve bioavailability of same drugs.
  10. Make use of special effects, e.g. sustained release aspect for morning relief of arthritis by dosing before bedtime.

3. Disadvantages of controlled release dosage forms 22

  1. They are costly.
  2. Unpredictable and often poor in-vitro in-vivo correlations, dose dumping, reduced potential for dosage adjustment and increased potential first pass clearance.
  3. Poor systemic availability in general.
  4. Effective drug release period is influenced and limited by GI residence time.

4. Rationale of Controlled –Drug Delivery:23

The basic rationale for controlled drug delivery is to alter the pharmacokinetic and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and/or physiological parameters inherent in a selected route of administration. It is desirable that the duration of drug action become more to design properly. Rate controlled dosage form, and less, or not at all, a property of the drug molecules inherent kinetic properties.

As mentioned earlier, primary objectives of controlled drug delivery are to ensure safety and to improve efficiency of drugs as well as patient compliance. This achieved by better control of plasma drug levels and frequent dosing. For conventional dosage forms, only the dose (D) and dosing interval (C) can vary and, for each drug, there exists a therapeutic window of plasma concentration, below which therapeutic effect is insufficient, and above which toxic side effects are elicited. This is often defined as the ratio of median lethal dose (LD 50) to median effective dose (ED50) 23

5. Controlled Release Systems:18

Diffusion controlled



·Reservoir and monolithic

Dissolution controlled



Water penetration controlled

·Osmotically controlled

·Swelling controlled

Chemically controlled

·Erodible systems

·Drug covalently linked with polymer


·Chemically controlled

·Swelling controlled

·Diffusion controlled

·Environment responsive

Ion-exchange resins

·Cationic exchange

·Anionic exchange

Diffusion controlled systems:-

The basic mechanism of drug release from these two systems is fundamentally different besides these simple systems, combination of reservoir and monolithic systems also exist in practice18.      

Diffusion systems are characterized by release rate of drug is dependant on its diffusion through inert water insoluble membrane barrier.

There are basically two types of diffusion devices.

(I)Reservoir devices  

(II)Matrix devices

Reservoir Devices :

Reservoir Devices are those in which a core of drug is surrounded by polymeric membrane. The nature of membrane determines the rate of release of drug from system.

The process of diffusion is generally described by a series of equations governed by Fick’s first law of diffusion.

J = -D (DC/ DX)…….(1)

Where J :  is the flux of drug across the membrane given in units of amount / area time.

D : is diffusion coefficient of drug in membrane in units of area / time. This is reflecting to drug molecule’s ability to diffuse through the solvent and is dependent on the factors as molecular size and charge.

dc/ dt : represents rate of change in concentration C relative to a distance X in the membrane.

The law states that amount of drug passing across a unit area, is proportional to the concentration difference across that plane.

Schematic representation of reservoir diffusion device Cm (o), and Cm (d) represent concentration of drug inside surfaces of membrane and C (o) & C(d) represents concentration in adjacent  regions.

Fig 2


If it is assumed that the drug on the both side of membrane is in equilibrium with its respective membrane surface which in equilibrium between the membrane surfaces and their bathing solutions as shown in Figure.

Therefore the concentration just inside the membrane surface can be related to the concentration in the adjacent region by following expression.

K  = Cm (o) /C(d)      at  X = o                                  (2)

K  = Cm (d) / C(d)     at  X = d                                  (3)

Where K  = partition coefficient.

If we consider K & D are constants then equation (1) becomes,

J  = D KimageC/d                                                           (4)

Where imagec is the concentration difference across the membrane and d is path length of diffusion.

The simplest system to consider is that of slab, where drug release is from only one surface as shown Figure  in this case equation (4) becomes

dMt/ dt  =    ADKimageC/ d                                              (5)

Figure 3 Diagrammatic representation of slab configuration of reservoir diffusion system.



Non permeable polymer shell

Where Mt  = Mass of drug released after time t, dMt/dt. Steady state drug release rate of time‘t’.

A :  surface area of device.

In equation (7) if variables of right side of equation remain constant, then left side of equation represents release rate of system, a true controlled release system with a zero-order release rate.

A constant effective area of diffusion, diffusional path length, concentration difference, and diffusion coefficient are required to obtain a release rate that is constant. Reservoir diffusional systems have several advantages over conventional dosage forms. They can after zero order release of drug, kinetics of which can be controlled by changing the characteristics of the polymer to meet the particular drug and therapy conditions.

Pot showing approach to steady state for reservoir device that has been stored for an extended period (the burst effect curve) and for device that has been freshly made (the time lag curve)

Fig 4


Common methods used to develop reservoir type of devices include micro encapsulation of drug particles and press coating of tablets containing drug cores. In most cases particles coated by microencapsulation form a system where the drug is contained in the coating film as well as in the core of micro capsule. The drug release generally involves combination of dissolution and diffusion with dissolution being process that controls the release rate. If encapsulating material is selected properly will be the controlling process. Some materials such as membrane barrier coat alone or in combination, are hardened gelatin, methyl or methylcellulose, polyhydroxymethacrylate hydroxypropylmethylcellulose, polydroxymethacrylate, polyvinyl acetate & various waxes.

Matrix devices:

A matrix device, as the name implies, consists of drug dispersed homogenously throughout a polymer.

Matrix diffusion system before release (time =0) & after partial drug release (time = t)



Time= 0                                                        Time=t                                   

In this model drug in out side layer exposed to the bathing solution is dissolved first and diffused out of the matrix.  This process continues with the interface between  bathing solution and the solid drug moving controlled, the rate of dissolution of drug particles within the matrix must be faster that the diffusion rate of dissolved drug leaving matrix.

Following assumptions are made in retrieving the mathematical models are.

i.A pseudo steady state is maintained during drug release.

ii.The diameter of drug particles is less than the average distance of drug Diffusion through the matrix.

iii.The bathing solution provides sink conditions.

iv.The diffusion coefficient of drug in the matrix remains constant.

The next equation that describes the rate of release drugs dispersed in an inert matrix system has been derived by Higuchi.


Figure 6 : Schematic representation of the physical model used for a planer slab matrix diffusion device.

The change in amount of drug released per unit area dM and change in the thickness of the zone of the matrix that has been depleted of the drug,

dM/dh = Co dh – Cs /2                                               (6)

by Fick’s first law,

dm = (DmCs/h) dt.                                                     (7)

where Dm is diffusion coefficient in matrix if equation (6)  & (7) are equated & solved for D that value of h sustituted back into the integrated form of equation (7) An equation for M is obtained.

M= [ Cs Dm (2Co – Cs) t] ½                          (8)

Similarly, a drug released from porous or granular matrix is described.

M= [ Ds Ca (є/τ)( 2Co – єCa) t           ] ½   (9)

Where    e = Porosity of matrix

              τ = tortuosity.

Ca = Solubility of drug in release medium

Ds = diffusion coefficient of drug in release medium.

In this system drug is leached from matrix through channels or pores.

For purpose of data treatment equation (8) & (9) are reduced to

M = Kt½

image          (10)

Where K is constantan so, that plot amount of drug released verses square root of time should be linear if the release of drug from the matrix is diffusion controlled.  The release rate of drug from such a device is not zero order, since if decreases with time but as previously mentioned, this may be clinically equivalent to constant drugs. 5

Water Penetration Controlled Systems:41

In water penetration controlled delivery systems, rate control is obtained by the penetration of water into the system. Two general types of these systems include, swelling controlled release systems and osmotically controlled delivery systems.

Swelling Controlled Systems:

Swelling controlled release systems are initially dry and when placed in the body absorb water or other body fluids and swell. Swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. Figure 1-18 (A and B> illustrates swelling reservoir and matrix systems, respectively. Most of the materials used in swelling controlled release systems that will swell without dissolving, when exposed to water or other biological fluids. These hydrogels can absorb a great deal of fluid and at equilibrium, typically comprise 60-90% fluid and only 10-30% polymer In case of polymer hyfrogel containing dispersed water-soluble agent, initiall3ç the diffusion coefficient of agent in the dehydrated hydrogel is very 10% however a significant increase is noticed as the gel imbibes water. Thus the release of active agent from the system is a function of rate of uptake of water from the vicinity nd the rate of drug diffusion.28

6. Factors Affecting Sustained Release Dosage Forms:-

Physicochemical properties of drug

a) Dose Size:

If an oral product has a dose size greater that 0.5gm 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.

b) Aqueous Solubility :

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. The lower limit on solubility for such product has been reported 0.1mg/ml. drugs with great water solubility are equally difficult to incorporate in to sustained release system. pH dependent solubility, particularly in the physiological pH range, would be another problem because of the variation in pH throughout the GI tract and hence variation in dissolution rate

c) Partition Coefficient:

Partition coefficient is generally defined as the fraction of drug in an oil phase to that of an adjacent aqueous phase. Accordingly compounds with relatively high partition coefficient are predominantly lipid soluble and consequently have very law aqueous solubility. Compounds with very law partition coefficients will have difficulty in penetrating membranes resulting poor bioavailability. 

Typical relationship between drug activity and partition

 Coefficient K, generally known as Hansch Correlation.    


d) Pka :

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

e) Drug Stability :

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

f) Molecular size and diffusivity:

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, the diffusion coefficient  in many polymers frequently are so small that they are difficult to quantify i.e. less than 16-12 cm2/sec.  Thus high molecular weight drugs and / or polymeric drugs should be expected to display very slow release kinetics in sustained release device using diffusion through polymer membrane.

g) Protein binding:

It is well known that many drugs bind to plasma proteins with a concomitant influence on the duration of drug action. Since blood proteins are for the most part re-circulated and not eliminated, drug Protein binding can serve as a depot for drug producing a prolonged release profile, especially if a 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.

Biological factors:

a) Biological Half Life:

The usual goal of an oral sustained release product is to maintain therapeutic blood levels over an extended period. To action this, drug must enter in the circulation of approximately the same rate of which it is eliminated. The elimination rate is quantitatively described by half-life (t1/2). Therapeutic compounds with short half lives are excellent candidates for sustained release preparations. Since this can reduce dosing frequency. In general drugs with half-lives shorter than 3hrs are poor candidates of sustained release dosage forms of dose size will increase as well as compounds with long half lives, more than 8 hrs are also not used in sustained release forms because their effect is already sustained.

b) Absorption:

The rate, extent and uniformity of absorption of a drug are important factors when considered its formulation into a sustained release system. 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.6 It we assume that transit time of drug  must in the absorptive areas of the GI tract is about 8-12 hrs. The maximum half life for absorption should be approximately 3-4 hrs. Otherwise device will pass out of potential absorption regions before drug release is complete.

c) 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 circulating 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.

d) Metabolism:

Drugs that are significantly metabolized before absorption, either in lumen or the tissue of the intestine, can show decreased bioavailability 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.6

7. Compounds Those Are Unsuitable For Controlled Release22

For drugs with elimination half life less than two hrs, as well as those that are administered in large doses, a controlled release dosage from may contain in prohibiting large quantity of drug, on the other hand, drugs with elimination half lives of 3 hrs or more are sufficiently sustained in the bldg from conventional doses, and controlled release is generally not necessary.

Administering drugs like warfarin, whose pharmacological effect is delayed relative to its blood profile, offers no clinical advantage, similarly, incorporating drugs like fluorouracil, and perhaps some beta lactum antibiotics and thiamine diuretics that appears to exhibit an “absorption window” may reduce absorption efficiency. Problems of first pass clearance of sustained release drugs.

About Authors

M. S. Wani

Prof.Manish S. Wani

Working as Senior Lecturer at MAEER’s Maharashtra Institute of Pharmacy, MIT campus, Pune. He has done his M.Pharm in Pharmaceutics from PuneUniversity. He has also done his MBA from PuneUniversity. He has nearly 13 years of Professional experience in the field of Pharmacy out of which he has worked for 5 years as Factory Manager.
Email : manishswani@yahoo.co.in

Dr. M.H.Dehghan

Dr. M.H.Dehghan

Working as Principal and Professor in Pharmaceutics at Y.B.ChavanCollege of Pharmacy, Dr.Rafiq Zakaria Campus, Aurangabad-431001
Email : mhdehghan@hotmail.com

Prof.Satish A. Polshettiwar

Prof.Satish A. Polshettiwar

Working as Lecturer at MAEER’s, Maharashtra Institute of Pharmacy, MIT Campus, Pune. He has done his M.Pharm in Quality Assurance from NagpurUniversity. He is a Life member of APTI. He has published and presented several research articles in national level and International level
E.Mail:contact_psatish@yahoo.co.in, Cell No. 09422842838

Prof. Amol A. Gadkari

Prof. Amol A. Gadkari

Working as Lecturer in Pharmaceutics at SiddhantCollege of Pharmacy, Pune.
Email id: aamolgadkari@gmail.com,



Working as Lecturer at Siddhant college of Pharmacy,Sadumbare, Pune. He has done his M.Pharm in Quality Assurance from NagpurUniversity

Mr. S. B. Chepurwar

Mr. S. B. Chepurwar

Working as Research Associate at Emcure Pharmaceuticals Limited, Pune. He has done his M.Pharm in Pharmaceutical Chemistry from North MaharashtraUniversity, Jalgaon.
E-mail: suyogvaibhav53@yahoo.com

Mrs. Richa N.Joshi

Mrs. Richa N.Joshi.

Senior Lecture in Pharmaceutics,MAEER’S Maharashtra Institute Of Pharmacy,Pune-411038.
E.mail ID:richanjoshi@yahoo.com

Ms. Vaishali M. Mute

Ms. Vaishali M. Mute

Lecture in Pharmaceutics, MAEER’S Maharashtra Institute of Pharmacy, Pune-411038. She has done her M. Pharm from The Tamilnadu Dr. M.G.R. Medical University, Chennai, Tamilnadu

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