MECHANISMS

1. Diffusion controlled
2. Dissolution controlled
3. Swelling controlled
4. Ion-exchange resins
5. Osmotic controlled
6. Degradation/Erosion controlled
 1. DIFFUSION-CONTROLLED
• Diffusion process based on the movement of drug molecules
from a region of a higher concentration to one of lower
concentration. The flux of the drug ‘J’, across a membrane in the
direction of decreasing concentration is given by Fick’s law.
J= - D dc/dx.
D=diffusion coefficient in area/time, dc/dx=change of
concentration 'c' with distance 'x‘

In common form, when a water insoluble membrane encloses a

core of drug, it must diffuse through the membrane, the drug
release rate dm/dt is given by,
dm/ dt= ADKΔC/L
Where A = area, K = Partition coefficient of drug between the
membrane and drug core, L= diffusion path length [i.e. thickness
of coat]
Classification
Reservoir system:
• In this system a water insoluble polymeric material encases a core
of drug. Drug will partition into the membrane and exchange with
the fluid surrounding the particles (or) tablet. The active agent is
released to the surrounding environment by diffusion process
through the rate limiting membrane.
• Based on initial drug concentration/drug solubility within the
device, reservoir systems are either non-constant (initial drug
concentration is below the saturated solubility of drug) or
constant (initial drug concentration is above the saturated
solubility of drug) activity source.
• Advantages: Zero order delivery is possible, release rates variable
with polymer type.
• Disadvantages: (i) System must be physically removed from
implant sites, (ii) Difficult to deliver high molecular weight
compound, (ii) generally increased cost per dosage unit, (iv)
potential toxicity if system fails, (iv) Burst effect on storage.
Diffusion system:
• In the matrix devices the drug or active is dispersed in polymer matrix to form
a homogeneous system known as a matrix system. Diffusion occurs when the
drug passes from the polymer matrix into the external environment.
• The rate of release of drug is dependent on the rate of drug diffusion and not
on the rate of solid dissolution.
• Higuchi has derived the appropriate equation for drug release for this system,
Q = Dε/ T [2 A –εCs] Cst ½

• Where; Q = weight in gms of drug released per unit area of surface at time t, D
= Diffusion coefficient of drug in the release medium, ε = porosity of the
matrix, Cs = solubility of drug in release medium, T= Tortuosity of the matrix, A
= concentration of drug in the tablet, as
gm/ ml.
• Advantages: (i) Easier to produce than reservoir or encapsulated devices, (ii)
can deliver high molecular weight compounds.
• Disadvantages: (i) Cannot provide zero order release since the rate varies with
the square root of time, (ii) removal of remaining matrix (ghost matrix) is
necessary for implanted system.
 2. DISSOLUTION-CONTROLLED
• In these systems, the rate of dissolution of the drug is controlled
by slowly soluble polymers or by micro-encapsulation. Once the
coating is dissolved, the drug becomes available for dissolution.
By varying the thicknesses of the coat and its composition, the
rate of drug release can be controlled. Some preparations
contain a fraction of the total dose as an immediate release
component to provide a pulse dose soon after administration.
• Dissolution-controlled products can be sub divided into two
types:-
a) Encapsulation Dissolution controls.
b) Matrix Dissolution control
Encapsulation Dissolution controls.
• These systems method involves coating of individual particles (or)
granules of drug with a slow dissolving material (granule coated or
microencapsulated product). The coated particles can be compressed
directly into tablets (or) placed in capsules. The rate of dissolution of
the drug (and thereby availability for absorption) is controlled by micro
encapsulation.
• They can be made to be sustaining in different ways: (i) By alternating
layers of drug with the rate controlling coats (a pulsed delivery can be
achieved). If the outer layer is quickly releasing bolus dose of the drug,
initial levels of the drug in the body can be quickly established with
pulsed intervals. Although this is not a true sustained release system,
the biological effects can be similar (Figure).
• (ii) An alternative method is to administer the drug as group of beads
that have coating of different thickness. Since the beads have different
coating thickness, their release occurs in a progressive manner.
Thinnest layer will provide initial dose and thicker layers will provide
maintainance dose. Ex. Spansule capsule (Smithkline Beecham)
• These products should not be chewed as the coating may be damaged.
• One of the advantages of encapsulated pelleted products is that the onset of
absorption is less sensitive to stomach emptying. The entrance of the pellets
into the small intestine (where the majority of drug absorption occurs) is usually
more uniform than with non-disintegrating sustained-release tablet
formulations.
Matrix Dissolution control
• In this system an alternative approach is to compress the drug
with a slow dissolving carrier. Here the rate of drug release is
controlled by the rate of penetration of the dissolution fluid into
the matrix, porosity, presence of hydrophobic additives and the
wetability of system and surface of particle.
•
 3. SWELLING-CONTROLLED
• Two most important consequences of polymer
swelling resulting drug-release kinetics are:
1. The length of diffusional pathways increases leading to decrease in drug
concentration gradient and drug release rate.
2. Significant increase in polymer molecular mobility thereby increasing drug
diffusivity inside polymer matrix.
• Depending on the type of polymer and type of drug, one of these
two effects (increase in diffusion pathway length and increase in
the drug mobility) might dominate, resulting in either decreasing
or increasing drug release rates compared to a non-swellable
drug delivery system.
• Example- HPMC matrix
 4. ION-EXCHANGE
• Ion exchange systems generally use resins composed of water-
insoluble cross –linked polymers having salt-forming functional
groups in repeating positions.
• The drug is bound to the resin and released by exchanging with
appropriately charged ions in contact with the ion exchange
groups.
 5. OSMOTICALLY CONTROLLED
• In these systems, osmotic pressure is the driving force that
generates controlled release of drug.
• This system is fabricated by applying a SPM around a core of an
osmotically active drug or a core of an osmotically inactive drug in
combination with an osmotically active salt.
• A delivery orifice is drilled in each system by laser or by a high
speed mechanical drill.
• The optimum size of the orifice can be calculated by following
equation
As = (LV/t) (8∏) (η/P)1/4
• As is cross-section area, V/t is volume released per unit time, L is
diameter of the orifice, η is the viscosity of solution moving out
from inside to outside, h is the hydrostatic pressure difference.
• When an osmotic system is exposed to water or any body fluid,
water will flow into the core due to an OP difference across the
coating membrane. Under this OP gradient, the volume flow of
water into the core reservoir, dV/dt, is expressed as:

• Where A, k and h are area, membrane permeability, and

thickness respectively.

• If the orifice is sufficiently large, the hydrostatic pressure

difference will be small compared to OP difference and equation
became;
• The drug will be pumped out of the system
through the orifice at a controlled rate, dM/dt,
which is equal to the volume flow rate of water
into the core multiplied by the drug concentration
(Cs). Thus,

• The delivery system dispenses drug continuously at

a zero-order rate until the concentration of the
osmotically active salt in the system is below
saturation solubility, whereupon a non-zero-order
release pattern results.
Advantages
• The delivery rate of zero-order is achievable with osmotic systems.
• Delivery may be delayed or pulsed, if desired.
• Higher release rates are possible with osmotic systems compared
with conventional diffusion-controlled drug delivery systems.
• The release rate of osmotic systems is highly predictable and can
be programmed by modulating the release control parameters.
• For oral osmotic systems, drug release is independent of gastric pH
and hydrodynamic conditions.
• The release from osmotic systems is minimally affected by the
presence of food in gastrointestinal tract.
• A high degree of in vivo- in vitro correlation (IVIVC) is obtained
in osmotic systems.
LIMITATIONS
• Special equipment is required for making an orifice in the system.
• Residence time of the system in the body varies with the gastric
motility and food intake.
• It may cause irritation or ulcer due to release of saturated solution
of drug.
Types of osmotic pumps
• These systems are generally appeared in two forms;
A. Osmotic delivery systems for solids
• Type I: Single compartment. In this design, the drug and the
osmotic agent are located in the same compartment and are
surrounded by the semipermeable membrane (SPM). Both the
core components are dissolved by water, which enters the core via
osmosis.
• Type II: Multiple compartments. In this design, drug is separated
from the osmotic compartment by an optional flexible film, which
is displaced by the increased pressure in the surrounding osmotic
compartment, which, in turn, displaces the drug solution or
suspension.
B. Osmotic delivery systems for liquids
• In this, liquid active agents typically are enclosed in a soft gelatin
capsule, which is surrounded by an osmotic layer that, in turn, is coated
with a semipermeable membrane. When the system takes up water
from its surroundings, the osmotic layer squeezes the innermost drug
reservoir. The increasing internal pressure displaces the liquid from the
system via a rupturing soft gelatin capsule.
 Bioerodible/Biodegradation
• Polymer Erosion is the process of material loss from the polymer bulk.
Such materials can include monomers, oligomers, parts of polymer
backbone or even parts of the polymer bulk.
• Depending on the relative velocities of water penetration in to the drug
delivery system and polymer chain cleavage, two erosion mechanisms
can be distinguished: (i) surface (heterogenous) and (ii) bulk
(homogenous erosion).
• In case of surface-eroding DDS, the rate at which the polymer chains
are cleaved is much higher than the rate at which water penetrates the
device. Thus, polymer degradation is mainly restricted to the surface
regions of the systems. Consequently, the device shrinks with time and
drug is released by the disappearance of the surrounding polymer
matrix. The inner structure (porosity, relative drug content and
distribution) remains unaltered.
• Polymers containing very reactive functional groups in their backbone
degrade rapidly and show surface erosion. Ex. Polyanhydrides
• In case of bulk-eroding DDS the water penetration rate is much
greater than the polymer chain-cleavage rate. Thus, the entire
device is rapidly wetted upon contact with aqueous media and
polymer chain cleavage occurs throughout the system. Due to the
presence of water, the drug becomes mobile and diffuse out of
the system
• Ex. PLA and PLGA
• Polymer degradation is the process of chain
scission by which macromolecules are cleaved
into shorter-chain molecules and finally
oligomers and monomers.