Controlled release dosage forms

Introduction
Controlled release dosage form:
• Controlled drug delivery is one which delivers the
drug at a predetermined rate, for locally or
systemically, for a specified period of time.
• Continuous oral delivery of drugs at predictable &
reproducible kinetics for predetermined period
throughout the course of GIT.
Sustained release dosage form:
• Sustained drug delivery may provide an immediate
dose required for the normal therapeutic response,
followed by the gradual release of drug in amounts
sufficient to maintain the therapeutic response for a
specific extended period of time usually 8-12 hours.
Differences between sustained and controlled
drug delivery system:
Sustained release dosage form Controlled release dosage form
1. Constitutes dosage form that 1. Constitutes dosage form that
provides medication over maintains constant drug
extended period of time levels in blood or tissue
2. SRDF generally do not attain 2. Maintains constant drug
zero order release kinetics levels in the blood target
tissue usually by releasing
the drug in a zero order
pattern.
3. Usually do not contain 3. Controlled dosage forms
mechanisms to promote contain methods to promote
localization of the drug at localization of the drug at
active site. active site.
Comparison of Drug release profile
Advantages of Control Release Dosage Forms
• Reduction in frequency of drug administration
• Improved patient compliance
• Reduction in drug level fluctuation in blood
• Reduction in total drug usage when compared with
conventional therapy
• Reduction in drug accumulation with chronic
therapy
• Reduction in drug toxicity (local/systemic)
• Stabilization of medical condition (because of more
uniform drug levels)
• Improvement in bioavailability of some drugs
because of spatial control
• Economical to the health care providers and the
patient
Disadvantages of Control Release Dosage Forms
• Delay in onset of drug action
• Possibility of dose dumping in the case of a poor
formulation strategy
• Increased potential for first pass metabolism
• Greater dependence on GI residence time of dosage
form
• Possibility of less accurate dose adjustment in some
cases
• Cost per unit dose is higher when compared with
conventional doses
• Not all drugs are suitable for formulating into ER
dosage form
Selection of drug candidates or characteristics
that may make a drug unsuitable for Control
release dosage form
• Short elimination half-life
• Long elimination half-life
• Narrow therapeutic index
• Poor absorption
• Active absorption
• Low or slow absorption
• Extensive first pass effect .
Parameters for drug selection
Parameter Preferred value
Molecular weight/ size < 1000
Solubility > 0.1 mg/ml for pH 1 to pH 7.8

Pka Non ionized moiety > 0.1% at pH 1 to pH 7.8

Apparent partition coefficient High

Absorption mechanism: Diffusion

General absorbability From all GI segments

Release Should not be influenced by pH

and enzymes
Approaches to design controlled release formulations
Based on the mechanism of drug release and carrier used, the
modified release dosage form can be classified into the
following categories
1. Dissolution controlled system
I. Encapsulation Dissolution control
II. Matrix Dissolution control
2. Diffusion controlled system
I. Reservoir type devices
II. Matrix type devices
3. Ion exchange resins
4. Osmotically controlled release
5. pH- independent formulations
6. Altered density formulations
1. Dissolution controlled release
In dissolution controlled drug-release, the drug is release is controlled by
dissolution of either polymeric membrane surrounding the drug core or
polymeric matrix containing the drug. The simple preparation of this category is
sustained-release oral products, where dissolution is the rate-limiting step.
When the rate of dissolution of a drug is high, the drug is mixed with a carrier
having a slow rate of dissolution, and a tablet is prepared to sustain or control
the release of the drug.
When the dissolution process is diffusion layer controlled, the rate of diffusion of
the drug is the rate-limiting step. In such case, the dissolution process at steady-
state would be described by
Noyes Whitney Equation
dc/dt = kD.A (Cs – C)
dc/dt = D/h A. (Cs – C)
Where, dc/dt = Dissolution rate,
k= Dissolution rate constant (1st order),
D = Diffusion coefficient/diffusivity,
Cs = Saturation/maximum drug solubility,
C =Conc. of drug in bulk solution,
Cs-C=concentration gradient, h =Thickness of diffusion layer.
There are two ways to prepare dissolution-controlled preparations:
i. Encapsulated dissolution system
ii. Matrix dissolution system
i. Encapsulated dissolution system
This is also known as Coating dissolution controlled system. In this
method, the particles or granules of the drug are coated individually
with slowly dissolving coating material. The coated particles are
compressed into tablet directly, such as space tabs or spansules.
Dissolution rate of coat depends upon stability & thickness of
coating. In this system release of drug is controlled by decreasing the
dissolution rate. It masks color, odor, taste and minimize GI
irritation.
Examples: Ornade spansules, Chlortrimeto Repetabs.
ii. Matrix dissolution system
It is also known as monolithic dissolution controlled system. The
drug release can be determined by dissolution rate of polymer. In
this method, the drug is mixed with a slowly dissolving carrier to
prepare a matrix material, which is then compressed,. The rate of
bioavailability of the drug is controlled by the rate of penetration of
the dissolution fluid into the matrix, the presence of hydrophilic
material, the wettability of the tablet and the particle surface.
Poorly water soluble drugs (BCS class II
and IV) inherently show sustain release. In
case of water soluble drugs, a water
insoluble carrier in incorporated in the
formulation to reduce the rate of
dissolution of the drug particles, which are
pre-coated with this type of materials,
such as polyethylene glycol.
Examples:Demeaned extencaps, Dimetapp extentabs.
2. Diffusion controlled system
In diffusion controlled formulations, drug molecules
diffuse through a polymer membrane or a
polymer matrix and are released. Depending on
whether a polymer membrane surrounds a drug
or distributed within the polymer matrix,
diffusion-controlled formulation can be divided
into following categories:
– Reservoir diffusion system
– Matrix diffusion system
In non porous reservoir system, drug molecules
diffuse through the polymer membrane, but in
microporous reservoir systems, the drug
molecules are released by diffusion through
micropores. The micropores are usually filled
with either water or oil.
i. Reservoir diffusion system
It is also called as laminated matrix device. In this system,
a water insoluble polymeric material encloses a core
of drug, which controls release rate.
The drug will partition into the membrane and exchange
with the fluid surrounding the particle or tablet. The
additional drug will enter the polymer, diffuse to the
periphery and exchange with the surrounding media.
. Commonly used polymers are Ethyl cellulose &
polyvinyl acetate.
 The rate of drug released (dm/dt) can be
calculated using following equation

Where, A=Area,
D=Diffusion coefficient
K=Partition coefficient of the drug between the drug core and
the membrane
l=Diffusion path length and
∆c=Concentration difference across the membrane
Advantages
• Zero-order delivery is possible with this method
• Release rate variable with polymer type.
Disadvantages
• The system must be physically removed from
implant sites.
• Difficult to deliver high molecular weight
compound,
• Generally increased cost per dosage unit,
• Potential toxicity may occur if the system fails.
ii. Matrix diffusion system
A solid drug powder is homogenously dispersed within a
rate controlling insoluble matrix. The waxes such as
beewax, carnauba wax, hydrogenated castor oil, etc.
are used to prepare the matrix. These waxes control
drug dissolution by controlling the rate of dissolution
in fluid and subsequent penetration into the matrix.
The drug release from such matrices follows the first
order kinetics. The wax embedded drug is generally
prepared by dispersing the drug in molten wax and
solidifying and granulating the same. The rate of drug
release is subject to the rate of drug diffusion, not on
the rate of dissolution of the drug.
Advantages
• Production of this system is more accessible
than reservoir type
• High molecular weight compounds can be
delivered.
Disadvantages
• Cannot provide zero order release
• Removal of the remaining matrix is necessary
for the implanted system.
3. Osmotically controlled release:
Osmosis is the movement of solvent (water)
from its higher concentration to its lower
concentration through a semi permeable
membrane. While diffusion is the movement
of solute from its higher concentration to
lower concentration. This principle of osmosis
has been used for the development of zero-
order release drug delivery systems.
These system are made-up by encapsulating an osmotic drug
core comprising an osmotically active drug (or blend of an
osmotically inactive drug with osmotically active salt such as
NaCl) within a semi-permeable membrane made from
biocompatible polymers, such as cellulose acetate. Once a
difference (gradient) in osmotic pressure is created, the drug
(solute) is continuously pumped out of tablet through small
delivery orifice present in tablet coating. This continues for a
prolonged period, about 24 hrs. This type of drug system
provides drug solutes continuously at zero-order rate and
release of the drug is independent of the environment of
gastrointestinal tract but depends on the osmotic pressure of
the release medium.
4. Ion exchange resins controlled release
system
Ion-exchange resins are also used to control the
release of the drugs. Ion exchange resins are
cross-linked water insoluble polymers carrying
ionizable functional groups. Through
electrostatic interaction, the drug molecules
attach onto the oppositely charged ionic groups
of the resin. The drug molecules can be
exchanged with other ions having the same
charge and accordingly, the drug molecules are
released from the ion-exchange resin.
The method of preparation is –
• The ionized drug is absorbed onto the ion-exchange resin granules;
for example, codeine base (drug) is absorbed onto amberlite (resin)
• The resins are filtered from the alcoholic medium
• The filtered drug-resin compplex granules are coated with a water
permeable polymer, such as a modified copolymer of polyacrylic and
methacrylic ester, by spray drying method
The drug is released by replacing with appropriately charged ion in the
GIT, and then the drug diffuses out of the resin. The release of the
drug depends on;
a) The strength and type of ionic environment (pH, electrolyte conc.)
b) The properties of the resin.
The rate of diffusion is controlled by:
a) The area of diffusion
b) Diffusion path length and
c) The rigidity of resin
Advantages
• It offers a protective mechanism by temporarily
changing the substrate.
• Suitable for the drug which are highly susceptible
to degradation by enzymatic process.
Disadvantages
• The release rate s proportional to the concentraton
of the ions present in the proximity of the
granules in the site of administration.
• The rate of release varies with diet, water intake,
and intestinal contents.
5. pH-Independent formulation
Since most drugs are either weak acids or weak bases, the
release 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.
Factors influencing the design and action of
controlled release dosage form
1. Physiochemicalcal properties
i. Aqueous Solubility’s: Most of the active
pharmaceutical moiety (API) are weakly acidic or
basic in nature that affect the water solubility of
API. Weak water soluble drugs are difficult to
design the controlled release formulations. High
aqueous solubility drug show burst release
followed by a rapid increment in plasma drug
concentration. The pH dependent solubility also
creates a problem in formulating CRDDS.
BCS class-III & IV drugs are not a suitable
candidate for this type of formulations.
ii. Partition coefficient (P-value):
P-value denotes the fraction of the drug into oil &
aqueous phase that is a significant factor that affects the
passive diffusion of the drug across the biological
membrane. The drugs are having high or low P
value not suitable for CR, it should be appropriate to
dissolve in both phases.
iii. Drug pKa:
pKa is the factor that determined the ionization of drug at
physiological pH in GIT. Generally, the high ionized
drugs are poor candidates for CRDDS. The absorption of
the unionized drug occurs rapidly as compared to ionized
drugs from the biological membranes. The pKa range for
an acidic drug that ionization depends on the pH is 3.0 to
7.5 and for a basic drug it lay between 7 and 11
iv. Drug stability:
Drugs that are stable in acid/base, enzymatic degradation, and
other gastric fluids are good candidates for CRDDS. If drug
degraded in the stomach and small intestine, it not suitable for
controlled release formulations because it will decrease in
bioavailability of concern drug.
iv. Molecular size & molecular weight:
The molecular size & molecular weight are two important
factors which affect the molecular diffusibility across a
biological membrane. The molecular size less than 400D is
easily diffuse but greater than 400D create a problem in drug
diffusion.
iv. Protein binding: The drug-protein complex act as a reservoir in
plasma for the drug. Drug showing high plasma protein
binding are not a good candidate for CRDDS because
Protein binding increases the biological half-life. So there is no
need to sustain the drug release.
2. Biological factors
i. Absorption:
Uniformity in rate and extent of absorption is an
important factor in formulating the CRDDS. However,
the rate limiting step is drug release from the
dosage form. The absorption rate should rapid then
release rate to prevent the dose dumping. The various
factors like aqueous solubility, log P, acid hydrolysis,
affect the absorption of drugs.
ii. Biological half-life (t1/2): In general the drug is
having short half-life required frequent dosing and
suitable candidate for controlled release system. A drug
with long half-life required dosing after a long time
interval. Ideally, the drugs having t1/2 2-3 hrs are a
suitable candidate for CRDDS. Drugs have t1/2 more
than 7-8 hrs not used for controlled release system.
iii. Dose size:
The CRDDS formulated to eliminate the repetitive
dosing, so it must contain the large dose than
conventional dosage form. But the dose used in
conventional dosage form give an indication of the dose
to be used in CRDDS. The volume of sustained dose
should be within acceptance criteria.
iv. Therapeutic window:
The drugs with narrow therapeutic index are not suitable
for CRDDS. If the delivery system failed to control
release, it would cause dose dumping and ultimately
toxicity.
v. Absorption window:
The drugs which show absorption from the specific
segment in GIT, are a poor candidate for CRDDS. Drugs
which absorbed throughout the GIT are good candidates
for controlled release.
3. Patient physiology:
The Physiological condition of the patient like gastric emptying
rate, residential time, and GI diseases influence the release of the
drug from the dosage form directly or indirectly.
Pharmacokinetic parameters consider during the drug selection listed
as follow.
 Examples of controlled and sustained release dosage forms
Transdermal patches
A transdermal patch is a medicated adhesive patch that is
placed on the skin to deliver a specific dose of medication
through the skin and into the bloodstream. Often, this
promotes healing to an injured area of the body.
Advantages Disadvantages
Topical patches are a painless way to It cannot achive high drug levels in
deliver substance directly into the body. blood/plasma.
Topical patches are cost effective , and It cannot deliver ionic drugs, and
preferable with fewer side effect cannot develop for drugs of large
molecular size
They are controlled, steady delivary of It cannot deliver drugs in a
medication over long periods of time pulsatile fashion.
Implants
An implant is a medical device manufactured to
replace a missing biological structure, support a
damaged biological structure, or enhance an
existing biological structure.
Advantages Disadvantages
Convenience- effective concentration of Invasive- to initiate therapy either a
drug in the blood can be maintained for minor or a major surical procedure is
longer period of time. required to initiate therapy.
Improved drug delivery- Drug is distributed Danger of device failure- If
in systemic circulation with least device may for some reason
interference by metabolic or biological fails to work, it requires surgical
barrier. involvement to correct.
Compliance- By allowing complete Limited to potent drug- The
elimination, of patientinvolved dosing size of implant is small, therefore
compliance is increased. implants have potent medicine like
hormones in limited loading capacity .
Liposomes
Liposomes is an artificial vesicle composed of one or more
concentric phospholipid bilayers and used especially to
deliver microscopic substances to body cells.
Advantages Disadvantages
Liposomes are biocompatible, The production cost is high, they
completely biodegradable, nontoxic have short half-life
and non-imunogenic for systemic and
non-systemic
administrations.
Liposomes are increased efficacy and Liposomes have low solublity,
therapeutic index of drug. leakage and fusion of encapsulated
drug molecules.
Liposomes helps to reduce Sometimes phospholipid undergoes
exposure of sensitive tissue to oxidation and hydrolysis like
toxic drugs. reaction.
Mechanism aspects of controlled and Sustained release
1. Diffusion
• Major process for absorption.
• No energy required.
• Drug molecules diffuse from a region of higher
concentration to lower concentration until equilibrium
is attained.
• They are of 2 types:
Matrix diffusion system Reservoir diffusion system
The drug is released either by passing The drug is contained in a core,
through the pores or between polymer which is surrounded by a polymer
chains. membrane, and it is released by
diffusion through rate- controlling
membrane.
Example- Such as polyehylene, e.g. Poly(N-vinyl pyrrolidone),
polyvinylacetate Poly(ethylene-co-vinyl acetate).
2. Dissolution
• It is of types
Matrix type Encapsulation
Also called as Monolith dissolution Called as Coating dissolution
controlled system controlled system
Controlled dissolution by: Dissolution rate of coat depends upon
[Link] porosity of tablet. stability & thickness of Coating
[Link] its wettebility .
[Link] at slower rate.
First order drug release. Masks colour , odour , taste, minimising
GI irritation
Drug release determined by Examples: Ornade spansules.
dissolution rate of polymer.
Examples: Dimetane extencaps
3. Osmotic Pressure Controlled System
• Provides zero order release
• Drug may be osmotically active, or combined
with an osmotically active salt (e.g., NaCl).
• Semipermeable membrane usually made from
cellulose acetate.
• More suitable for hydrophilic drug.
• Examples: Glucotrol XL, Procardia XL.