CONTROLLED RELEASE SYSTEMS Daulat Haleem Khan

CONTROLLED RELEASE SYSTEMS

Controlled release (CR) may be defined as a technique or approach by which active
chemicals are made available to a specified target at a rate and duration to accomplish an
intended effect. More specifically, an oral controlled release drug delivery system is a device
or dosage form that control drug release into the absorption site in the GIT. It controls the
drug absorption rate to achieve the desired plasma profiles defined by the steady-state
pharmacology.

Table 1: Classification of polymers on the basis of characteristics

POLYMER TYPES POLYMERS

INSOLUBLE, INERT Polyethylene, PVC, EC, Acrylates

INSOLUBLE, ERODIDABLE Carnuaba Wax, Stearic Acid, PEG, PEO

HYDROPHILIC MC, HPMC, HEC, Alginates, Na cmc

Table 2: Classification on the basis of origin

POLYMER TYPES POLYMERS

NATURAL Xanthan, Guar gum, Karaya gum

SEMISYNTHETIC HPMC, Na cmc, EC, MC, HEC, HPC

SYNTHETIC Polyesters, Polyamides

ADVANTAGES OF CONTROLLED RELEASE SYSTEMS

 Total dose is decreased
 Reduced GIT side effect
 Better patient compliance
 Less fluctuation of plasma levels
 Improved efficacy
 Decrease healthcare cost
 Decrease frequency

DISADVANTAGES OF CONTROLLED RELEASE SYSTEMS

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CONTROLLED RELEASE SYSTEMS Daulat Haleem Khan

 Chance of dose dumping is increasing by the collapse of system

 Additional patient education problem
 Stability concerns are increased
 Decrease retrieval of drug

CLASSIFICATION OF CONTROLLED RELEASE SYSTEMS

Oral controlled delivery systems can be broadly divided into following categories, based on
their mechanism of drug release

1. Dissolution controlled release

a) Encapsulated system
b) Matrix systems
2. Diffusion controlled release
a) Encapsulated systems
b) Matrix system
3. Osmotic controlled release
4. pH dependant system
5. Gastroretentive systems

1. DISSOLUTION CONTROLLED RELEASE SYSTEMS

Dissolution controlled release can be obtained by slowing the dissolution rate of a drug in the
GI medium, incorporating the drug in an insoluble polymer or coating drug particles or
granules with polymeric materials of varying thickness. The rate limiting step for these
systems is diffusion of the drug across an aqueous boundary. The solubility of the drug
provides the source of energy for drug release which is countered by the stagnant-fluid
diffusion boundary layer. The rate of dissolution can be calculated as (Noyes Whitney
Equatio);

dc/dt = ADS/h or dc/dt = AD(Cs-C)/h

Where

A= surface area of dissolving particles

D= diffusivity of drug

S/ (Cs-C)= aqueous solubility of drug

h= thickness of boundary

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CONTROLLED RELEASE SYSTEMS Daulat Haleem Khan

Drug delivery using this mechanism can be achieved by encanpsulation of drug-polymer

matrix with a relatively insoluble polymeric system and or by just forming drug-polymer
matrices.

The mechanism of drug release from hydrophilic matrix tablets is based on the dissolution of
the drug, diffusion of the drug through the hydrated layer of the matrix and erosion of the
outer hydrated polymer present on the surface of the matrix. In general, when the matrix
tablet gets contact with an aqueous media, the surface of the tablet becomes wetted and the
polymer hydrates to form a jelly-like mass usually referred to as the 'gel layer'. This process
is also termed as the glassy-to-rubbery state transition of the polymer. The core of the tablet
remains essentially dry at this stage. In the case of a highly soluble, large dose drug, this
incident may lead to preliminary burst release because of the presence of drug on the surface
of the matrix tablet. As more water penetrates, the gel layer (rubbery state) grows with time
into the core of the matrix, increasing the thickness of the gel layer and providing a diffusion
barrier to drug release. Altogether, as the outer layer gets completely hydrated, the polymer
chains become fully relaxed and remain unable to maintain the integrity of the gel layer,
leading to disentanglement and erosion from the surface of the matrix. Water continues to
penetrate into the tablet core through the gel layer, until it has been entirely eroded. Erosion is
the major release mechanism for insoluble drugs, apart from their dose. Quick hydration of
polymer and rapid gel layer formation on tablet surface are essential characteristics of an
extended release system to prevent premature drug release. Small sized particles of
hydrophilic matrices ensure rapid hydration and consistent gel layer formation on the surface
of tablets.

Water Penetration And Uptake Study

Water penetration into the matrix is the first step which leads to the polymer swelling and
polymer and drug dissolution. In general, drug release from swelling matrix tablet is based on
glassy-rubbery transition of polymer as a result of water penetration into the matrix. The
presence of water decrease the glass-rubbery temperature, giving rise to the transformation of
glassy polymer in rubbery phase (gel layer). Whereas interaction between water, polymer and
drug are the primary factors for release control, various formulations variables, polymer
grade, drug/ polymer ratio, drug solubility, filler solubility, drug and polymer particle size
and compression pressure.

Water penetration in the matrix is studied by different workers. At regular intervals, the pre-
weighed matrix system was withdrawn from the dissolution vessel, lightly blotted with a
tissue paper to remove excess test liquid and re-weighed. The percent water uptake i.e. degree
of swelling due to absorbed test liquid, was estimated at each time point using Eq.

Where Ws is the weight of the swollen matrix at time, t, Wi is the initial weight of the matrix
and Wp is the weight of polymer in the matrix.

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CONTROLLED RELEASE SYSTEMS Daulat Haleem Khan

Boundaries Of Gel Layer And Relevant Fronts

When water penetrates the matrix system, it causes the polymer swelling forming the gel
around the matrix (Figure 1.). As a result of this there are present different layers around the
tablet. These are;

a) The swelling front, the boundary between the still glassy-polymer and its
rubbery phase
b) The diffusion front, the boundary between the solid as yet undissolved drug
and the dissolved drug in gel layer
c) The erosion front, the boundary between the matrix and the dissolution
medium

Fig. 1: Boundaries of gel layer and relevant fronts

DIFFUSION CONTROLLED RELEASE SYSTEMS

Diffusion of a drug molecule through a polymeric membrane forms the basis of these
controlled drug delivery systems. Similar to the dissolution controlled systems; the diffusion
controlled devices are manufactured either by matrix systems or by encapsulated
technologies. Unlike the dissolution controlled systems the drug is made available as a result
of partitioning through the polymeric system. In the case of a matrix or reservoir type
diffusion controlled devices the rate of drug release can be calculated as;

dm/dt = ADK ∆C/l

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CONTROLLED RELEASE SYSTEMS Daulat Haleem Khan

Where

A= surface area of dissolving particles

D= diffusivity of drug

K= partition coefficient

∆C= concentration difference

l= diffusional pathlength

It is very common for diffusion controlled release devices to exhibit a non-zero release rate
due to an increase in diffusional resistance and a decrease in effective diffusion area as the
release proceeds.

In case of matrix diffusion controlled systems a number of release pattern are being followed
depending upon the nature of drug and polymer and formulation variables.

2. OSMOTICALLY CONTROLLED RELEASE SYSTEMS

Osmosis refers to the process of movement of solvent molecules from lower solute
concentration to higher solute concentration across a semi permeable membrane. Osmosis is
the phenomenon that makes controlled drug delivery a reality. Osmotic pressure created due
to imbibitions of fluid from external environment into the dosage form regulates the delivery
of drug from osmotic device. Rate of drug delivery from osmotic pump is directly
proportional to the osmotic pressure developed due to imbibitions of fluids by solute.
Osmotic pressure is a colligative property of a solution in which the magnitude of osmotic
pressure of the solution is independent on the number of discrete entities of solute present in
the solution. Hence the release rate of drugs from osmotic dispensing devices is dependent on
the solubility and molecular weight and activity coefficient of the solute (osmogent).

Osmotic drug delivery technology is primarily based on semipermeable membrane. These

membranes are permeable to water but impermeable to ionic or high molecular weight
compounds. The permeability of membrane is controlled by number of factors, including the
polymer chemistry and processing variables. For example, the hydraulic permeability varies
exponentially with acetyl content.

Drugs can be delivered in a controlled pattern over a long period of time by the process of
osmosis. Drug delivery from this system is not influenced by the different physiological
factors within the gut lumen and the release characteristics can be predicted easily from the
known properties of the drug and the dosage form.

These systems are of two main types;

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CONTROLLED RELEASE SYSTEMS Daulat Haleem Khan

Elementary Osmotic Pump (EOP)

In its simplest form, the system is constructed by coating an osmotically active agent with the
rate controlling semipermeable membrane. This membrane contains an orifice of critical size
through which agent is delivered. The dosage form after coming into contact with aqueous
fluids, imbibes water at a rate determined by the fluid permeability of the membrane and
osmotic pressure of the core formulation. This osmotic imbibitions of water result in
formation of a saturated solution of drug within the core, which is dispensed at controlled rate
from the delivery orifice in the membrane.

Push Pull Osmotic Pump (PPOP)

Push pull osmotic pump is a modified EOP through, which it is possible to deliver highly
water soluble drugs at a constant rate. This system resembles a standard bilayer coated tablet.
One layer (depict as the upper layer) contains drug in a formulation of polymeric, osmotic
agent and other tablet excipients. This polymeric osmotic agent has the ability to form a
suspension of drug when this tablet later imbibes water. The other layer contains osmotic and
agents, polymer and tablet excipients. These layers are formed and bonded together by tablet
compression to form a single bilayer core. The tablet core is then coated with semi permeable
membrane. After the coating has been applied, a small hole is drilled through the membrane
by a laser or mechanical drill on the drug layer side of the tablet. When the system is placed
in aqueous environment water is attracted into the tablet by an osmotic agent in both the
layers. The osmotic attraction in the drug layer pulls water into the compartment to form in
situ a suspension of drug. The osmotic agent in the non-drug layer simultaneously attract
water into that compartment, causing it to expand volumetrically and the expansion of non
drug layer pushes the drug suspension out of the delivery orifice.

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CONTROLLED RELEASE SYSTEMS Daulat Haleem Khan

Fig. 2: Schematic diagram of EOP (a) and PPOP (b)

PROPERTIES OF POLYMERS USED IN CONTROLLED RELEASE

PREPARATIONS
1. POLYMER DIFFUSIVITY

Diffusivity is the component of permeability. Some of the factors that affect the diffusivity of
polymeric systems are given as below;

Table 3: Factors affecting diffusivity

INCREASE IN FACTOR EFFECT ON DIFFUSIVITY

Interchain force −
Molecular weight −
Polymer crystallinity −
Plasticizer +
Temperature +
Segmental mobility +

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2. SOLUBILITY

The active ingredient is either suspended or dissolved in a polymeric matrix. One or another
type of solvent is used for the fabrication of these systems. The choice of an ideal solvent to
dissolve a polymer for any further study can be made by comparing the solubility parameters
of both polymers and solvent. For example, solvent and polymer with similar solubility
parameters will most likely be compatible and soluble in each other. A polymer will
precipitate from a solvent with a significant different solubility.

3. STRUCTURAL CONSIDERATIONS

The structure of the polymer used in the drug delivery system is a very important parameter
determining the mechanism of drug release. The diffusivity of drug molecule dispersed in
hydrophobic polymer is dependent on the porous structure of the polymer. The solute diffuses
through solvent filled pores, indirectly affected by partition coefficient of solute. As porosity
increases the diffusion of the drug from the system increases. For nonporous polymeric
systems, it will therefore be necessary to consider the polymeric system properties like degree
of crystallinity, size of crystallites and molecular weight to formulate the dosage form.
Porosity of the system may be increased by addition of some agents like starch, povidone,
alginates etc. Many controlled release tablets and granules utilize hydrophilic polymers for
retarding drug release. The mechanism of drug release is dependent on swelling and
dissolution process. Examples of such polymers are HPMC and HPC. In this case, when
water concentration at the polymeric surface exceeds a critical concentration of
macromolecular disentanglement, dissolution occurs.

4. COMPACTNESS

Compactness of the polymer along with compactness of the device is important controlling
the release rate. More the compactness of polymer and final dosage form more the time is
required to release the drug from the device. Hardness of matrix tablet is so adjusted at more
values (≥ 8Kg) as compared to conventional one (5Kg).

5. POLYMER-DRUG RATIO

The effect of polymer concentrations on drug release from different devices has been studied
extensively and it is seen that by increasing the polymer concentration the rate of drug release
from these decreases dramatically. The formulations containing relatively higher polymer
content shows less initial drug release due to the unavailability of drug molecules at the
surface of dosage form then a point is reached at which pores/ channels are formed or erosion
of particular layer occurs and diffusion is started.

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CONTROLLED RELEASE SYSTEMS Daulat Haleem Khan

FEASIBILITY ASSESSMENT OF DRUGS

1. SOLUBILITY

Different sort of mechanisms are present for the absorption of drug through membranes of
GIT. These range from passive to carrier mediated transport mechanism. Non-polar drugs
(most of drugs are weak acids or bases, since their unchanged form) are preferentially
permeated across lipid membranes. But we well know that GIT fluids are aqueous base in
nature so there is a question mark for the partition of such non-polar or unionized drugs
between the polymeric systems in aqueous medium. Therefore these kinds of drugs are
having self sustained effect for absorption; controlled by partitioning. More soluble drugs are
best candidate for controlled release or modified release preparations. The lower limit on
solubility for such product has been reported 0.1mg/ml.

Table 4: Effect of solubility on feasibility of controlled release

Sr. No. Solubility Comments

1. < 1mg/1ml Good candidate
2. 1mg/1-100ml Average degree of difficulty
3. 1mg/100-1000ml Challenging

2. DOSE/ FREQUENCY

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. Along
with this drugs having less frequencies of administration are poor candidate for modified
release preparations.

Table 5: Effect of dose on feasibility of controlled release

Sr. No. Dose Comments

1. < 1mg Complexity of development
2. 1-10mg Suitable
3. 10-250mg Average degree of difficulty

3. 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 in the form of sustaining dosage
from. This is because more drug is delivered in small intestine and hence subject to
degradation.

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4. PLASMA 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 2hrs are poor candidates of sustained release dosage where as
compounds with long half lives, more than 6 hrs are also not used in sustained release forms
because their effect is already sustained.

5. THERAPEUTIC WINDOW/ INDEX

The main goal for a formulation to be formulated as controlled release or modified release is
to maintain the drug plasma level within acceptable range of therapeutic window. This is
serious concern especially in case of drugs having shorter therapeutic index. This can be
shown in the form of Figure 3.
Concentration
Plasma

MSC

MEC

Time

Fig. 3: Plasma drug concentration profiles for conventional formulation (– –) and

controlled-release formulation ( ___ ). MEC = Minimum Effective
Concentration; MSC = Maximum Safe Concentration

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