This document discusses controlled drug delivery systems. It begins by defining controlled drug delivery systems and their goal of releasing therapeutic doses of a drug in the desired location and time period. It then discusses various types of modified release dosage forms like sustained release, extended release, and controlled release. The document covers advantages and disadvantages of these systems as well as factors influencing their design and performance. It provides examples of commercial modified release products and discusses approaches to designing controlled release formulations.

1. C.D.D.S
INDORE MAHAVIDHAYALA
JUHI BHADORIA
ASSITANT PROFESSOR

2. C.D.D.S
 A controlled drug delivery system is aimed at releasing the
correct dose of a therapeutic directly in the desired zone
and during the required period of time.

3.  Sustained release, sustained action, controlled release, extended
action, time release dosage forms are the terms used in identify
drug delivery system that are designed to achieve a prolonged
therapeutic effect by continuously releasing medication over and
extended period of time.

4.  ADVANTAGES:-
1.Improve patient convenience.
2.Reduction in fluctuation in steady state level.
3.Increase the safety margin of high potency drug.
4.Reduction in total health are cost.
5.Able to improve the bioavailability of the drug by
preventing its premature degradation.
6.Maintaining its concentration within therapeutic range.
7.Reducing concentration fluctuation and ultimately
reducing the potential side effects.
8.Maintenance of drug level within the desired range.
9.Reduces dosing frequency.

5. 10.Eliminates over or under dosing
11.Prevention or reduction of side effects
12.Improved efficacy in the treatment
13.Reduction in adverse side effects and improvement
in tolerability
14.Improved patient compliance
15.Employ less amount of total drug
16.Minimizes or eliminates local or systemic side
effects
17.Minimal drug accumulation on chronic usage.

6.  DISADVANTAGES:-
1.Decrease systemic availability.
2.Poor in vitro- in vivo correlation.
3.Increased risk of toxicity.
4.Difficult in case of toxicity.
5.System must be physically removed from implant sites.
6.Difficult to deliver high molecular weight compound,
generally increased cost per dosage unit, potential
toxicity if system fails.
7.Provides less scope for dosage adjustment.

7. 8.May increase the first pass clearance.
9.Effective drug release period is influenced and limited
by the gastric residence time.

10. Immediate release dosage forms:
 The conventional dosage forms belong to this class.
The dosage form releases the drug present in it after
administration to achieve rapid and complete systemic
absorption. After absorption of the drug from the
dosage form, plasma concentration of the drug starts
decreasing according to its pharmacokinetic profile.
 Finally, the concentration falls below the minimum
therapeutic concentration (MEC) and therapeutic
activity ceases.

11.  The period at which the drug concentration remains
within the therapeutic window is called the duration
of action and the time at which the maximum
concentration is attained is called the onset of action.
Modified release dosage form:
 The dosage forms, in which the rate of release of the
drug and the time at which the release of the drug
would take place are different from conventional type,
are called modified release dosage form.

12.  For example, erythromycin gets decomposed in the
stomach; hence it is formulated as an enteric coated
tablet.
Site-specific targeting:
 These systems refer to targeting the release of a drug
straight to a particular biological location. In this case,
the target is adjacent to or in the diseased organ or
tissue.

13. Receptor targeting:
 These systems refer to targeting a specific biological
receptor. In this case, the target is the specific receptor
for a drug within an organ or tissue. Site-specific
targeting and receptor targeting systems satisfy the
spatial aspect of drug delivery and are also considered
to be sustained drug delivery systems.
Delayed release dosage form:
 When a dosage form does not release the drug
immediately after administration like immediate
release or conventional dosage form but releases the
drug in portions at a predetermined time or at times, it
is called delayed release dosage form.

14. Extended-release dosage form:
 If a dosage form reduces the frequency of dose at
least by two-fold as compared to the frequency of
administration of immediate release or conventional
dosage form, the dosage form is said to be the
extended release dosage form.
Sustained release dosage form:
 The drug release from sustained release dosage form
exhibit a predetermined rate in order to maintain an
approximately constant drug concentration in the
body over a prolonged period.

15. Prolonged action dosage form:
 In this type of dosage form the drug is released at a
rate relatively slower rate, but for a long period; so
that, the therapeutic action of the drug remains for an
extended period.

16. SELECTION OF DRUG CANDIDATES:-
 Solubility
 Partition coefficients
 Oral bioavailability
 salt and crystal forms
 chemical stability
 Very short or very long half-life
 Significant first pass metabolism
 Poor absorption throughout the GI tract
 Low solubility
 Large no of dose
 Mechanism of absorption
 First pass effect

17. DRUG SELECTION CRITERIA :-
1.Drug with molecular weight <1000 Da.
2.Drug solubility should be greater than 0.1µg/ml.
3.Drugs with high permeability should be selected, as
matrix tablets are release rate limiting but not
permeation rate limited.
4.A drug that is passively absorbed through the GIT is
an ideal candidate for sustained release matrix tablets.
5.Drugs with low half-life.
6.Drugs with larger therapeutic window.
7.The drug should not be influenced by pH and
enzymes.

18. TYPES OF DRUG DELIVERY SYSTEMS:-
 Oral drug delivery systems.
 Parenteral drug delivery systems.
 Mucosal drug delivery systems.
 Nasal drug delivery systems.
 Pulmonary drug delivery systems.
 Ocular drug delivery systems.
 Transdermal drug delivery systems.
 Vaginal and intrauterine drug delivery systems.
 Rectal drug delivery systems.
 Targeted drug delivery systems.

19. CLINICAL 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

20. COMMERCIAL / INDUSTRIAL ADVANTAGES:-
 Illustration of innovative/technological leadership
 Product life-cycle extension
 Product differentiation
 Market expansion
 Patent extension
Major Limitations:-
 Delay in the onset of action
 The possibility of dose dumping in the case of a
poor formulation strategy
 Increased potential for first-pass metabolism
 Greater dependence on the gastric residence time
of the dosage form
 The possibility of less accurate dose adjustment in
some cases

21.  Cost per unit dose is higher when compared with
conventional doses
 All drugs are not suitable for formulating into ER
dosage form

22. Factor Influencing the Design and Performance of
Controlled Drug Delivery System:-
1. Biopharmaceutic characteristics of the drug
The molecular weight of the drug
The aqueous solubility of the drug
Apparent partition coefficient
Drug pKa and ionization physiological pH
Drug stability
Mechanism and site of absorption
Route of administration.

23. 2. Pharmacokinetic characteristics of the drug
Absorption rate
Elimination half-life
Rate of metabolism
Dosage form index
3. Pharmacodynamic characteristic of the drug
Therapeutic range
Therapeutic index
Plasma–concentration-response relationship

24. S.No. Drug Branded
Formulation
Technology
1 Bupropion WellbutrinWL Diffusion controlled-release
2 Zolpidem tartarate Ambien CR Matrix system (Tablet)
3 Chlorpheniramine
Polistirexand
Hydrocodone Polistirex
TussionexPennkinetic
ER suspension
Ion-exchange system
4
Chlorpheniramine
MaleateGlipizide
Efidac 24®
Glucotrol XL®
Osmosis-based system
Elementary osmotic
pump
Push-pull osmotic system
5 Propranolol HCl Inderal ® LA pH independent formulation
6 Levodopa and Benserazide Modapar Altered density formulation

25.  The modified-release dosage form can be categorized
into the following;
 Delayed release
 Extended-release
 Sustained release
 Controlled release
 Timed release
 Prolonged release

26. APPROACHES TO DESIGN CONTROLLED-
RELEASE FORMULATIONS:-
 Primarily there are two approaches or concepts to
design and prepare controlled/sustained release
dosage form:
(a) Modification of the drug molecule, and
(b) Modification of the dosage form.
There are hundreds of commercial products based
on controlled release technologies. Only a few
show distinct mechanisms of controlled drug
release. . Oral controlled-release formulations are
designed mainly based on physical mechanisms.
The chemical degradation, enzymatic degradation,
and prod rug approach are less.

27.  Based on the mechanism of drug-release and carrier
used, the modified-release dosage form can be
classified into the following six categories;
 Diffusion sustained system
(a) Reservoir type (b) Matrix type
 Dissolution sustained the system.
(a) Reservoir type (b) Matrix type
 Methods using Ion-exchange
 Methods using osmotic pressure
 pH-independent formulations
 Altered-density formulations

28. 1.Diffusion-controlled release:-
 These systems may be of two types:
1. Diffusion-controlled encapsulation, and
2. Osmotic pressure is rate limiting.
Diffusion controlled encapsulation
 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
formulations can be divided into categories:
1.Reservoir system, and
2.Monolithic systems.

29.  In nonporous reservoir systems, 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. The partition
coefficient of a drug . If the drug loading is higher than
the drug’s solubility, the monolithic system is called
monolithic dispersion.
 Fick’s law gives the flux of the drug J (in amount/area -
time), across a membrane in the direction of
decreasing concentration.
 J = – D dc/dx Where, D = diffusion coefficient in area/
time,
 dc/dx = change of concentration 'c' with distance ‘x’

30. 1. Reservoir Type: In the 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.
 The rate of drug released (dm/dt) can be calculated using
the following equation
 dm = ADK Δc dt l
 Where, A = Area,
 D = Diffusion coefficient,
 K = Partition coefficient of the drug between the drug core
and the membrane,
 ℓ = Diffusion path length and
 ΔC= Concentration difference across the membrane.

31.  Advantage
1. Zero-order delivery is possible with this method,
2. Release rates variable with polymer type.
 Disadvantages
1. The system must be physically removed from implant
sites.
2. Difficult to deliver high molecular weight compound,
3. Generally increased cost per dosage unit,
4. Potential toxicity may occur if the system fails.

32. 2. Matrix Type: A solid drug powder is homogeneously
dispersed within a rate controlling medium, an insoluble
matrix. The waxes such as beeswax, carnauba wax,
hydrogenated castor oil, etc. are used to prepare the
matrix. The drug release from such matrices follows the
first order kinetics. The wax-the embedded drug is
generally prepared by dispersing the drug in molten wax
and solidifying and granulating the same.
 Advantages
1. Production of this system is more accessible than
reservoir or encapsulated devices,
2. High molecular weight compounds can be delivered.

33.  Disadvantages
1. Cannot provide zero order release,
2. Removal of the remaining matrix is necessary for the
implanted system
 Osmosis-Based Formulations: Osmosis is the
movement of a 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.

34.  These systems are made-up by encapsulating an
osmotic drug core) comprising an osmotically active
drug (or a blend of an osmotically inactive drug with an
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 pressures 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
24hrs.
 This type of drug system provides drug solutes
continuously at a zero-order rate and release of the
drug is independent of the environment of the
gastrointestinal tract but depends on the osmotic
pressure of the release medium.

37. 2.Dissolution controlled release:-
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 from the
solid surface to the bulk solution through an unstirred
liquid film is the rate-limiting step.
dc = Kd A (C-C)
dt

38. Where,
dC
dt = Dissolution rate.
 KD = Dissolution rate constant.
 Cs = Saturation solubility of drug, and
 C = The concentration of drug in bulk of the solution.
 There are two ways to prepare dissolution-controlled
preparations:
 Dissolution-controlled encapsulated/coated system
 Dissolution-controlled matrix system

39.  Dissolution-controlled encapsulation: In this
method, the particles or granules of the drug are
coated individually with slowly dissolving coating
material. The coated particles are compressed into a
tablet directly; such as space tabs or Spansules.

40.  Erosion-controlled systems
Erosion-controlled drug delivery systems are
alternatively called stimuli-induced systems. These
systems are activated by an external stimulus, such as
pH, temperature, enzymes or osmotic pressure and
release the drug. Drug release occurs depending on
the mechanism of erosion surface or bulk.

41.  Dissolution-controlled matrix 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 penetration of the medium is controlled by
the porosity of the tablet 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 sustained release. In the case of
water-soluble drugs, a water-insoluble carrier is
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.

42.  Hybrid systems
These are a combination of the robustness of matrix
systems with the constant-release kinetics of reservoir
systems. The drug is incorporated (entrapped) into a
release- controlled matrix, and the matrix is then coated
with a polymer. High molecular weight compounds can
also be incorporated. The advantages of this system
are many folds –
 Cost-effectiveness,
 Easy to manufacture, and
 Can be prepared by conventional processes and
equipment.

43. 3. Based on Ion exchange Principles:- Ion exchange
resins are also used to control the release of drugs. The
water-insoluble polymeric materials containing ionic
groups are used as resins. 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 simple:
1. The ionized drug is absorbed onto the ion-exchange
resin granules; for example, codeine base (drug) is
absorbed onto amberlite (resin).

44. 2. The resins are filtered from the alcoholic medium,
3. The filtered drug-resin complex 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 ions 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.

45.  The rate of diffusion is controlled by:
a) The area of diffusion,
b) Diffusion path length
c) The rigidity of resin.
 Advantage
 It offers a protective mechanism by temporarily
changing the substrate.
 Suitable for the drugs which are highly susceptible to
degradation by enzymatic processes.

46.  Limitation
1.The release rate is proportional to the concentration of
the ions present in the proximity of the granules in the
site of administration.
2. The rate release varies with diet, water intake, and
intestinal contents.

47.  Physicochemical Properties of Drugs Suitable for
Controlled Release Formulations:-
1. The molecular weight of the drug: Drugs of lower
the molecular weight, more accurately, of lower
molecular size, are absorbed faster and more
completely. Through passive diffusion, about 95% of
the drugs are absorbed.
Diffusivity is well-defined as the ability of a substance
(drug) to diffuse through the membrane. It is inversely
related to the molecular size.

48. 2. The diffusion coefficient and molecular size:
After reaching the systemic circulation, the drug needs to
diffuse
(1) through rate-controlling polymeric membranes or
matrix (in case of extended-release or matrix system),
and through.
(2) different biological membranes. The capacity of a
drug to diffuse through these membranes is called
diffusibility or diffusion coefficient.

49. 3. The aqueous solubility of the drug: For oral
controlled release dosage form, the drug should have
excellent aqueous solubility and are independent of pH;
such drugs are good candidates. The solubility of the
drug is a factor for selection of the mechanism to be
employed for preparing CRDDS.
Solubility refers to the concentration of solute in a
saturated solution. In other words, solubility can be
expressed as the amount of solute remaining in a
solution containing a given volume of solvent with some
un-dissolved solute in equilibrium– saturated solution.

50.  The amount of drug absorbed into systemic circulation
is a function of the amount of the drug present in an
unionized form in a solution of G.I fluid. This is the
intrinsic solubility of the drug and permeation of drug
under such condition is called intrinsic permeability.
 Before absorption, the drug must go into a solution of
GI fluid and then partitions into the absorbing
membrane. Thus, absorption of a drug is related to its
partitioning between the lipid layer and an aqueous
phase, and the rate of dissolution is related to its
aqueous solubility.

51. 4. Apparent partition coefficient:- Larger the apparent
partition coefficient of a drug (Ko/w), greater its
lipophilicity and hence, greater would be its rate and
extent of absorption. These types of drugs even cross
the highly selective blood-brain barrier. This parameter
is also significant in deciding the release rate of a drug
from a lipophilic matrix or device.
i) Both permeation of a drug across the biological
membrane and diffusion through the rate controlling
membrane or matrix depend on the partition coefficient
of the drug.
ii) After administration and before elimination from the
body the drug is supposed to diffuse through various
biological membranes. These membranes perform
primarily as a lipid-like barrier.

52. K = Τhe concentration of drug in oil Co
The concentration of drug in water Cw
K- are readily soluble in oil and partition easily into
membranes.
Co represents the equilibrium concentration of all forms
of the drug in an organic phase.
Cw represents the equilibrium concentration of all forms
of the drug in the aqueous phase.

53. 5. Drug pKa and ionization at physiological pH: The
pKa value can indicate the strength of an acid or a
base. Thus, at a particular pH, the charge on a drug
molecule can be determined through its pKa value.
The amount of drug that remains in unionized form is a
function of its dissociation constant and pH of the fluid
at the site of absorption

54. 6. Drug stability: Drugs which are unstable in the GI
environment are not suitable candidates for controlled
release systems. Drugs which are unstable in gastric
pH can be designed for release in the intestine with
limited or no release in stomach and drugs which are
unstable in intestinal pH (alkaline pH) can be designed
for release in the stomach with limited or no release in
the intestine.
 Some amount of the drug administered orally may be
lost in the GI tract due to acid hydrolysis and
metabolism in the liver. Omeprazole, pantoprazole,
lansoprazole, rifampicin, erythromycin, riboflavin, etc.
are the most common examples of acid- susceptible
drugs; i.e., these are unstable in the stomach.

55.  The relative bioavailability of a drug which is unstable
in the stomach can be improved significantly by
making a slowly releasing or controlled releasing
formulation.
7. Mechanism and site of absorption: Drugs which
are absorbed by carrier- mediated transport
procedure or through a window are not entirely
suitable candidates for the development of controlled
release systems, such as Vitamin B.
8. Route of administration: Oral and parenteral routes
are the most preferred for controlled release, this is
followed by transdermal.

56. 1. Oral route: The drug should have the following
properties to be a successful candidate
It must get absorbed through the entire length of GIT.
The main limitation is transit time (mean of 14 hours),
which can be extended for 12-24 hours.
2. Intramuscular/subcutaneous route: This route is
preferred because
The action is to be prolonged for 24 hours to 12
months.
A small amount of drug is administered (2mL/2gm).
Factors important are solubility of the drug in
surrounding tissue, molecular weight, partition
coefficient and pKa of the drug.

57. 3. Transdermal route: This route is selected for drugs
which show extensive first-pass metabolism upon
oral administration or drugs with a low dose.
Important factors to be considered are:
The partition coefficient of drugs,
Contact area,
Skin condition,
Skin permeability of drug,
Skin perfusion rate, etc.