Controlled drug delivery system part 2 mechanism and different approaches of controlled drug delivery system diffusion-controlled drug delivery dissolution controlled drug delivery ion-exchange resin system

1. Approaches to design controlled release
formulations based on Diffusion,
Dissolution and Ion exchange principles
PART - II

2. Different approaches for CRDDS
• Chemical Approach
• Biological approach
• Pharmaceutical approach
Classification
CRDDS can be classified into
1. On the basis of technical sophistication
2. On the basis of route of administration
On the basis of technical sophistication
1. Rate programmed DDS
2. Stimuli-activated DDS
3. Site-targeted DDS
4. Feedback-regulated DDS
• The drug
• The rate
controlling element
• Energy source that
activates the DDS
3 major components

3. 1. Rate programmed DDS
The release of drug molecules from the delivery systems has been preprogrammed at specific rate
profiles
2. Stimuli-activated DDS / Activation modulated DDS
The release of drug molecules from the delivery system is activated by some physical, chemical or
biochemical processes and/or facilitated by the energy supplied externally. Then the rate of drug release
is then controlled by regulating the process applied or energy input
3. Site-targeted DDS
It is constructed from a biodegradable polymer backbone having 3 types of attached functional groups
• A site-specific targeting moiety that leads the DDS to the vicinity of a target tissue
• A solubilizer that enables the DDS to be transported to and preferentially taken up by a target tissue
• A drug moiety that is covalently bonded to the polymer backbone through a spacer and contains a
cleavable group that can be cleaved only by a specific enzymes at the target tissue
4. Feedback-regulated DDS
The release of drug molecules from the delivery system is activated by a triggering agent, such as a
biochemical substance in the body and regulated by concentration of triggering agent detected by a
sensor in via the feedback-regulated mechanism
a. Bioerosion-regulated DDS
b. Bioresponsive DDS
c. Self-regulating DDS

4. Major classes of controlled release drug delivery system

5. 1. Rate programmed DDS
(Classification of CDDS with reference to release control or mode of drug release )
• Diffusion controlled drug delivery system
• Dissolution controlled drug delivery system
• Erosion controlled drug delivery system
• Combination of dissolution, diffusion and/or erosion controlled drug delivery
system
2. Stimuli activated DDS / Smart DDS
A. Activation by
physical process
• Pressure activated
DDS
• Magnetically
activated DDS
• Mechanical force
activated DDS
• Electrically activated
DDS
• Thermally activated
DDS
• Photo activated DDS
B. Activation by
chemical process
• pH activated DDS
• Ion-activated DDS
• Hydrolysis activated
DDS
• Chelation activated
DDS
C. Activation by
biological systems
• Enzyme activated
DDS
• Antibody interaction-
activated DDS
• Antigen activated
DDS
• Inflammation
activated DDS

7. Rate-programmed DDS
These DDS are those from which the drug release has been programmed at specific rate
profiles
These systems can be designed into
• Reservoir systems (membrane-controlled system)
• Matrix systems (monolithic- soluble/ erodible/ Swellable/degradable systems)
• Hybrid systems (membrane-cum-matrix system)
Hybrid system
Matrix system Reservoir system
• Swellable
film
• Non-
Swellable
film
(porous)
• Hydrophilic
Swellable
Free swelling
Restricted
swelling
Swellable and
erodible
• Hydrophobic
Erodible
Non-Erodible
Porous
Non-porous
Dissolved drug
Dispersed drug

8. Matrix system
• In which the drug is uniformly dissolved or dispersed in a release retarding material
• Depending upon the physical properties of the matrix, two types of devices are
possible
Hydrophilic matrix –
• These are porous systems
• Release retarding material is water-swellable or swellable and erodible hydrocolloid
Ex: High molecular weight HPMCs, HPC, HEC, Xanthan gum, Sodium alginate, Guar
gum, Polyethylene oxide and cross-linked polymers of acrylic acid
Depending upon the swelling behaviour of hydrophilic polymer, 2 types of matrices are
possible
Free-swelling matrix: in which polymer swelling is unhindered
Restricted-swelling matrix: in which the surface of the device is partially coated with an
impermeable polymer film that restricts the hydration of swellable matrix material

9. Hydrophobic matrix
Release-retarding material is either
• Slowly soluble, erodible or digestible
Ex: waxes such as glyceryl monostearate, cetyl alcohol, hydrogenated vegetable oils,
beeswax, carnauba wax
• Insoluble or non-digestible
Ex: ethyl cellulose, polymethacrylates
Depending upon the manner of incorporation of drug in the matrix, they can be classified
into
• Porous matrix (heterogeneous) –Release pattern: Higuchis theory
In which the drug and release retarding matrix micro particles are simply mixed with
each other and compressed into a tablet or
The drug is dispersed in the polymer solution followed by evaporation of the solvent
• Non-porous matrix (homogenous)
In which the release retarding material is first melted and the drug is then incorporated in it
by thorough mixing followed by congealing the mass while stirring
Dissolved drug non-porous system- drug is dissolved in the molten release retarding matrix
material Release pattern: Fick's Second Law
Dispersed drug non-porous system-the quantity of the drug is greater than its solubility in
molten matrix polymer Release pattern: Fick's First Law

10. Hybrid system
In which the drug in matrix of release retarding material is further coated with a release controlling
polymer membrane. Hence this device combines the constant release kinetics of reservoir system
with the mechanical robustness of matrix system
Reservoir system
In which the drug is present as a core in a compartment of specific shape encased/encapsulated
within a rate controlling wall, film or membrane having a well-defined thickness
The drug in the core must dissociate from the crystal lattice and dissolve in the surrounding medium,
partition and diffuse through the membrane
Depending upon the physical properties of the membrane, 2 types of reservoir system exists
Non-swelling reservoir system
These reservoir type is more common
It includes coated drug particles, crystals, granules, pellets, mini-tablets and tablets
In which the polymer membrane does not swell or hydrate in an aqueous medium. These materials
control drug release owing to their thickness, insolubility or slow dissolution or porosity
Ex: ethyl cellulose and polymethacrylates
Swelling-controlled reservoir system
In which the polymer membrane swells or hydrates upon contact with aqueous medium, so drug
release is delayed for the time period required for hydration of barrier and after attaining this, drug
release proceeds at a constant rate

11. 1. Diffusion controlled drug delivery system
Rate controlling step: diffusion of dissolved drug molecule through the rate-controlling
element
Depending upon the mechanism by which the rate controlling element controls drug
diffusion
a. Porous matrix-controlled diffusion system
Design- Matrix system: In which rate of release is controlled by diffusion of dissolved drug
in the matrix, In which rate controlling element is either a
 Non-swellable water insoluble polymer
• Porous
• Hydrophobic matrix
• Hydrophobic polymers like ethyl cellulose, polymethacrylates
• Mechanism: controls drug release through the micropores present in their matrix structure
• Porous matrix: In which the drug and release retarding matrix micro particles are
simply mixed with each other and compressed into a tablet or the drug is dispersed in the
polymer solution followed by evaporation of the solvent

12.  Water swellable material
• Porous
• Hydrophilic matrix
• Hydrophilic polymers and gums like guar gum, tragacanth, HPMC, HPC, CMC,
alginates & Xanthan Gum
• Mechanism:
Free-swelling matrix: in which polymer swelling is unhindered
or
Restricted-swelling matrix: in which the surface of the device is partially coated with
an impermeable polymer film that restricts the hydration of swellable matrix material

13. CONCLUSION

15. b. Porous membrane-controlled diffusion system
Design- Reservoir System: In which polymer content in coating, thickness of coating &
hardness of micro‐capsules control the release of the drug
In which the rate controlling element is a
 Non-swellable water-insoluble polymer
• Porous
• Hydrophobic polymer membrane
• Ex: Ethylcellulose and Polymethacrylate which controls drug release through the
micropores present in their membrane
• Mechanism: In which the polymer membrane does not swell or hydrate in an aqueous
medium. The drug in the core must dissociate from the crystal lattice and dissolve in the
surrounding medium, partition and diffuse through the membrane

18. 2. Dissolution controlled drug delivery system
In which drug is homogeneously dispersed and rate limiting phenomenon responsible for
imparting the controlled release characteristics to the DDS is either of
a. Drug- Dissolution controlled
(Slow dissolution rate of the drug)
The drug present in this system may be
• Drug with inherently slow dissolution rate
Act as natural prolonged release products
Ex: Griseofulvin, Digoxin and Nifedipine
• Drug that transforms into a slow dissolving form- upon contact with GI fluids
Ex: Ferrous sulphate

19. b. Polymer-Dissolution controlled
(Slow dissolution rate of the reservoir membrane or matrix)
The drug present in this system may be the one having high aqueous solubility and
dissolution rate Ex: Pentoxifylline and metformin
• Embedment in slowly dissolving, degrading or erodible matrix
Matrix have low porosity or poor wettability
The drug is homogeneously dispersed throughout a rate controlling medium
They employ waxes such as beeswax, carnauba wax, hydrogenated castor oil etc which
control drug dissolution by controlling the rate of dissolution fluid penetration into the
matrix by altering the porosity of tablet, decreasing its wettability or by itself getting
dissolved at a slower rate
The drug release is often first order from such matrices
The wax embedded drug is generally prepared by dispersing the drug in molten wax and
solidifying and granulating the same

21. • Encapsulation or Coating with slow-dissolving, degrading or erodible substances
The rate of dissolution fluid penetration or wettability of the reservoir system are controlled.
The drug particles are coated or encapsulated by microencapsulation techniques with slowly
dissolving materials like cellulose, poly ethylene glycols, polymethacrylates, waxes etc. The
dissolution rate of coat depends upon the solubility and thickness of the coating. Those with
the thinnest layers will provide the initial dose. The maintenance of drug levels at late times
will be achieved from those with thicker coating.

24. Slowly soluble and erodible materials
• Hydrophobic substances
Ethyl cellulose (containing an added water-soluble release modifying agent such as
PVP)
Polymethacrylates with pH independent solubility (ex: Eudragit RS and RL 100)
Waxes such as Glyceryl monostearate
• Hydrophilic materials Ex: Sodium CMC
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 and coating drug particles or granules with
polymeric materials of varying thickness
The rate limiting step for dissolution of a drug is the diffusion
across the aqueous boundary layer. The solubility of the drug
provides the source of energy for drug release, which is countered by
the stagnant-fluid diffusional boundary layer. The rate of dissolution
can be approximated by Noyes Whitney's Equation

27. Microreservoir Dissolution-Controlled Drug Delivery System
• An approach to achieve a constant
drug release profile from a matrix-
type drug delivery system
• These are composed of a
homogenous dispersion of numerous
microscopic spheres (<30µm) of drug
suspension in a solid polymer matrix
• These drug-containing spheres exist
homogenously throughout the cross-
linked polymer matrix as a discrete,
immobilized, unleachable liquid
compartment
• The drug molecules can elute out of
the MDD only by; first dissolution in
the liquid compartment and
partitioning into and diffusion
through the polymer matrix, and then
partitioning into the surrounding
elution solution
A cross-section of MDDS. The microscopic liquid
compartments, which encapsulate drug particles, are
homogenously dispersed as discrete, immobilized,
unleachable spheres (with diameter ≤30µm) in a cross-
linked polymer matrix. D,P and h are the diffusivity,
permeability and thickness respectively. The subscripts p, m
and d denote the polymer matrix, polymer coating
membrane and diffusion layer respectively

28. 3. Dissolution and Diffusion Controlled Release Systems
The drug core is enclosed in a partially soluble membrane. Pores are thus created due to
dissolution of parts of the membrane which permit entry of aqueous medium into the core
and hence drug dissolution and diffusion of dissolved drug out of the system. An example of
obtaining such a coating is using a mixture of ethyl cellulose with poly vinyl pyrrolidiene
or methylcellulose

29. Category: Stimuli-activated Drug Delivery System
Sub-category: Activation by chemical process
Definition: Ion exchange resins are cross-linked insoluble polymers carrying
ionizable functional groups and have the ability to exchange counter-ions within
aqueous solutions surrounding them
The ion exchange resins are complexed with drug to form resinates by batch or
column process. Microencapsulated resinates provides better control over the drug
release because of the rate controlling membrane
The formulations are developed by embedding the drug molecules in the ion-
exchange resin matrix and this core is then coated with a semi-permeable coating
material such as ethyl cellulose
This system reduces the degradation of drug in the GIT
The most widely used and safe ion-exchange resin is Divinylbenzene sulphonate
4. Ion-Exchange Drug Delivery System

30. Advantages
• Ion-exchange resinates of drugs can help in reducing the dose
• Reduced fluctuations in blood and tissue concentrations and maintenance of
drug concentration below toxic level can be achieved
• Use of ion exchange resins into drug delivery systems have been encouraged
because of their physico-chemical stability, inert nature, uniform size, spherical
shape assisting coating and equilibrium driven reproducible drug release in
ionic environment
• Advantageous for the drugs that are highly susceptible to degradation by
enzymatic process
• Effectively useful in low concentration (5-20%w/w)
• Resins have high drug loading capacity
• Economic and readily available
• Free from local and systemic toxicities
Disadvantages
• Release rate is proportional to the concentration of the ions present in the area
of administration
• Release rate of drug can be affected by variability in diet, water intake and
individual intestinal content

31. Drugs to be formulated into resinates,
• Should have in their chemical structure acidic or basic groups
• Biological half life should be between the ranges of 2 to 6 hours, drugs with t1/2 < 1hr
or > 8hrs are difficult to formulate
• It should be well absorbed from all the areas of the gastrointestinal tract
• Drugs should be stable sufficiently in the gastric juice
Drugs Suitable for Resinate Preparation

32. • Cation exchange resins contain covalently bond negatively charged functional groups and
exchanges positively charged ions
• Anionic exchange resins have positively charged functional groups and it exchange negatively
charged ions
Acid base strength: The acid base strength of an exchange is dependent on various ionogenic
groups, incorporated into the resin
• Resin containing sulfonic, phosphonic or carboxylic acid (as an integral part of the resin)
exchange groups have approximate pKa values of 1, 2-3 and 4-6 respectively- Cationic-
exchangers
• Anionic-exchangers are quaternary, tertiary or secondary ammonium groups having
apparent pKa values of greater than 13, 7-9 or 5-9 respectively
The pKa value of the resin will have a significant influence on the rate at which the drug will be
released from resinates in the gastric fluid

34. Mechanism and Principle
• Anion exchange resins involve basic functional groups capable of removing anions from acidic
solutions while Cation exchange resins contain acidic functional group, capable of removing cations
from basic solutions
• The use of IER to prolong the effect of drug release is based on the principle that positively or
negatively charged pharmaceuticals, combined with appropriate resins to yield insoluble polysalt
resinates
In The Stomach:
1) Drug resinate + HCl ↔ acidic resin + drug hydrochloride
2) Resin salt + HCl ↔ resin chloride + acidic drug
In The Intestine:
1) Drug resinate + NaCl ↔ sodium resinate + drug hydrochloride
2) Resin salt + NaCl ↔ resin chloride + sodium salt of drug

35. Cross-sectional view of an ion-activated DDS

36. Pharmaceutical Applications of Ion-Exchange Resin

39. TERMINOLOGY/ DEFINITIONS

48. Comparison between Conventional and Controlled release system

49. Parameters to be considered while designing into CRDDS