To clarify the advanced drug delivery systems.

1. Advanced Drug Delivery
Systems

2. The term “drug delivery systems” refers to the technology
utilized to present the drug to the desired body site for
drug release and absorption. The first drug delivery
system developed was the syringe, invented in 1855,
used to deliver medicine by injection. The modern
transdermal patch is an example of advanced drug
delivery system.
The goal of any drug delivery system is to provide a
therapeutic amount of drug to the proper site in the body
to promptly achieve and then maintain the desired drug
concentration.
This idealized objective points to the two aspects most
important to the drug delivery, namely:
*Spatial placement: relates to targeting of a drug to a
specific organ or tissue.
*Temporal delivery of a drug: refers to controlling the
rate of drug delivery to the target tissue.

3. Dosage Forms
There are numerous dosage form into which a drug substance
can be incorporated for the convenient and efficacious treatment
of a disease. Dosage forms can be designed for administration by
all possible delivery routes to maximize therapeutic response.
Dosage Forms Available For Different Administration Routs:
Oral- Solutions, syrups, elixirs, suspensions, emulsions,
gels, powders, granules, capsules, tablets.
Topical- Ointments, creams, pastes, lotions, gels, solutions,
topical aerosols.
Parenteral- Injections (solutions, suspensions, emulsions forms),
implants, irrigation and dialysis solutions.
Rectal- Suppositories, ointments, creams, solutions, powders.
Lungs- Aerosols (solutions, suspensions, emulsions, powder
forms), inhalation, sprays, gases.
Nasal- Solutions, inhalations.
Eye- Solutions, ointments.
Ear- Solutions, suspensions, ointments.

4. Conventional Dosage Form or Immediate – Release
Dosage Form
Conventional / Immediate – release dosage form is a dosage form
which is formulated / designed to give rapid and complete release
of the drug contained therein immediately after administration.
Kinetic scheme for the extra vascular administration the
conventional dosage form of a drug that follows one –
compartment open model for disposition:
Dosage
Form
Absorption Pool Body Compartment
Urine
Drug
Release
Kr
Absorption
( INPUT )
Elimination
( OUTPUT )
Ka
Ke
Kr, Ka and Ke : first order rate constants for drug release, absorption and overall elimination
respectively.

5. Immediate release from a convenient dosage form implies that
Kr >>> Ka. This means that absorption of a drug across a
biological membrane (e.g. GI epithelium) is the rate–timing
step in delivery of the drug to the body compartment.
For non–immediate–release dosage forms Kr <<< Ka.
i.e. release of drug from the dosage form is the rate limiting
step. Therefore the above scheme reduces to the following:
Dosage
Form
Body
Compartment
Urine
Drug
Release
Kr
Elimination
Ke
Essentially, the absorptive phase of the kinetic scheme
becomes insignificant compared to the drug release. Thus the
effort to develop a non–immediate–release dosage form must
be primarily directed at altering the release rate by affecting the
value of Kr.

6. Typical drug blood level vs. time curve / profile for
extra vascular administration of a single dose of the
conventional dosage form of a drug following one –
compartment open model for disposition:
MTC /
MSC
IV rout
Absorption
phase
Ineffective
range
MEC
Therapeutic
range
Rate of drug input
= Rate of drug output
Toxic range
Time

7. Typical drug blood level – time profile for multiple dosage
(non–immediate–release) regimen (equal doses of the
drug at fixed intervals) of a conventional dosage form:
A) For time intervals allowing complete elimination of the
previous dose: A series of isolated single dose profiles
are obtained
MSC
MEC
Dose
Time
Dose Dose

8. B) For the dosing time intervals shorter than the time required
for complete elimination of the previous dose:
MSC
MEC
Time
D DD D D D D D
At the start of the multiple dosage regimen, the blood levels of drug tends
to increase in successive doses. But the rate of drug elimination will
increase as the average blood level of drug rises (first order kinetics) and a
situation is eventually reached when the overall rate of elimination of drug
becomes equal to the overall rate of supply. This situation is called “Steady
State”.
For a drug administered at equal time intervals, the time required
for the average blood levels to reach the 95% of the steady state value is
4.3 times the biological half–life (t½) of the drug. The corresponding figure
for 99% is 6.6 times.

9. Advantages of Conventional Dosage Form:
1. Per unit cost of conventional dosage form is less
than non-immediate release dosage form.
2. More flexibility for the physician for adjusting
dosage form in conventional dosage form.
3. Conventional dosage form can accommodate the
patient variation.
4. No problems with drug having too small half life.
5. Potent drugs can’t be formulated as sustained
release dosage form.

10. Limitations of Conventional Drug Therapy:
1. Unable to maintain therapeutic blood level for a prolonged
period of time.
2. Fluctuation of blood level over successive dosing intervals
(giving peak and valley pattern).
3. Risk of over medication or under-medication because of
drug blood level fluctuation.
4. Require frequent dosing Patient inconvenience + Poor
patient compliance Therapeutic failure / Inefficiency.
5. No therapeutic action during overnight no dose period
Risk of symptom break through in chronic disease.
6. Total amount of drug required is higher over the entire
course of therapy. (compared to SRDF)
7. Local/systemic side effect + overall health care cost is high.

11. Non-Immediate Release Dosage Form
Non-immediate release dosage form is those which do not
release whole amount of drugs contained, immediately after
administration.
Why Non-Immediate Release Dosage Form?
a) Delayed release of an immediate release unit. Ex: Enteric
coated tablet or capsule.
b) Repetitive intermittent release of two or more immediate
release unit incorporated into a single dosage form. Ex:
Repeat action tablet or capsule.
***Although a repeat action dosage form exhibits the same
“peak and valley” pattern as associated with conventional
dosage forms, but it improves patient compliance by reducing
dosing frequency.

12. Types of Non-Immediate Release
Dosage Form :
1. Delayed release dosage form
2. Sustained release dosage form
a) Control release
b) Prolonged release
3. Site specific release dosage form
4. Receptor release dosage form

13. Site–Specific Release and Receptor–
Release Dosage Forms
Site–specific and receptor release dosage
forms offer targeted delivery of a drug directly
to a certain biological location.
In case of site–specific release dosage
forms, the target is the specific receptor for
the drug within an organ or tissue.

14. Sustained Release Dosage
Forms
Sustained release dosage
forms are those dosage forms
which are designed to release drug
continuously at sufficiently slow or
controlled rate over an extended
period of time to provide prolonged
therapeutic effect.
In case of oral dosage forms, this
period is usually measured in
hours. But in case of injectable
dosage forms, the period may
range from days to months or even
years.

15. Sustained release dosage forms can further be
categorized as:
a) Controlled release Dosage forms: The controlled
release system is to deliver a constant supply of the
active ingredient, usually at a zero-order rate, by
continuously releasing, for a certain period of time,
an amount of the drug equivalent to the eliminated by
the body. An ideal Controlled drug delivery system is
the one, which delivers the drugs at a predetermined
rate, locally or systematically, for a specific period of
time.
b) Prolonged release dosage forms: which cannot
maintain a constant blood level, but the blood level
declines at such a sufficiently slow rate that it
remains within the therapeutic range for a satisfactory
prolonged period of time.

16. c) Repeat action preparation: A dose of the drug
initially is released immediately after administration,
which is usually equivalent to a single dose of the
conventional drug formulation. After a certain period
of time, a second single dose is released. In some
preparation, a third single dose is released after a
certain time has elapsed, following the second dose.
Advantage:
It provides the convenience of supplying additional
Dose or doses without the need of readministration.
Disadvantage:
That the blood levels still exhibit the “Peak and
valley” characteristic of conventional intermittent
drug therapy.

17. Extended-Release formulation:
Extended-Release formulations are usually designed to reduce
dose frequency and maintain relatively constant or flat plasma
drug concentration. This helps avoid the side effects associated
with high concentration.
Delayed release preparations:
The drug is released at a later time after administration. The
delayed action is achieved by the incorporation of a special coat,
such as enteric coating, or other time barriers such as the
formaldehyde treatment of soft and hard gelatin capsules. The
purposes of such preparations are to prevent side effects related to
the drug presence in the stomach, protect the drug from
degradation in the highly acidic pH of the gastric fluid.

18. Site specific targeting:
These systems refer to targeting of a drug directly to a certain
biological location. In this case the target is adjacent to or in the
diseased organ or tissue.
Receptor targeting:
These systems refer to targeting of a drug directly to a certain
biological location. In this case the target is the particular receptor for
a drug with in organ or tissue. Site specific targeting and receptor
targeting systems satisfy the spatial aspect of drug delivery and are
also considered to be controlled drug delivery systems.

19. Time (hrs)
MSC
MEC
A
B
Fig: The blood level–time profile of (A) Controlled–
release (B) Prolonged–release dosage form

20. Advantages of Controlled Release Drug Delivery System.
1) Therapeutic advantage: Reduction in drug plasma level fluctuation,
maintenance of a steady plasma level of the drug over a prolonged time period,
ideally simulating an intravenous infusion of a drug.
2) Reduction in adverse side effects and improvement in tolerability: Drug
plasma levels are maintained within a narrow window with no sharp peaks and
with AUC of plasma concentration Vs time curve comparable with total AUC
from multiple dosing with immediate release dosage form.
3) Patient comfort and compliance: Oral drug delivery is the most common and
convenient for patient and a reduction in dosing frequency enhances compliance.
4) Reduction in Health care cost: The total cost of therapy of the controlled
release product could be comparable or lower than the immediate release product
with reduction in side effects. The overall expense in disease management also
would be reduced. This greatly reduces the possibility of side effects, as the scale
of side effects increases as we approach the maximum safe concentration.
5) Avoid night time dosing: It also good for patients to avoid the at night time.

21. DISADVANTAGES [9]
1) Dose dumping: Dose dumping is a phenomenon whereby relatively large quantity of
drug in a controlled release formulation is rapidly released, introducing potentially toxic
quantity of the drug into systemic circulation. Dose dumping can lead to fatalities in case
of potent drugs, which have a narrow therapeutic index.
2) Less flexibility in accurate dose adjustment: In conventional dosage forms, dose
adjustments are much simpler e.g. tablet can be divided into two fractions. In case of
controlled release dosage forms, this appears to be much more complicated. Controlled
release property may get lost, if dosage form is fractured.
3) Poor In-vitro In-vivo correlation: In controlled release dosage form, the rate of drug
release is deliberately reduced to achieve drug release possibly over a large region of
gastrointestinal tract. Here the so- called ‘absorption window’ becomes important and may
give rise to unsatisfactory drug absorption in-vivo despite excellent in-vitro release
characteristics.
4) Increased potential for first pass clearance: Hepatic clearance is a saturable process.
After oral dosing, the drug reaches the liver via portal vein. The concentration of drug
reaching the liver dictates the amount metabolized. Higher the drug concentration, greater
is the amount required for saturating an enzyme surface in the liver.

22. Conversely, smaller the concentration found with the controlled release and a
sustained release dosage form, lesser is the possibility of saturating the enzyme
surface. The possibility of reduced drug availability due to the first pass
metabolism is therefore greater with controlled release and sustained released
formulation than with conventional dosage form.
5) Patient variation: The time period required for absorption of drug released
from the dosage form may vary among individuals. Co-administration of other
drugs, presence or absence of food and residence time in gastrointestinal tract is
different among patients. This also gives rise to variation in clinical response
among the patients.
6) Administration of controlled release medication does not permit prompt
termination of therapy. Immediate changes in drug levels during therapy, such as
might be encountered if significant adverse effects are noted, can not be
accommodated.
7) There is danger of an ineffective action or even absence of it if the therapeutic
substance is poorly absorbed from GIT.

23. 8) Therapeutic agents for which single dose exceeds 1 gm, the technical
process requirements may make the product very difficult or sometimes
impossible to prepare.
9) Therapeutic agents which absorbed by active transport are not good
candidates for controlled release dosage form e. g. Riboflavin.
10) Economic factors must also be taken into account, since more costly
processes and equipments are involved in manufacturing of many controlled
release dosage forms.

24. While selecting a drug candidate for sustained release system we must
be careful. Drugs having fallowing characteristics are not suitable for
sustained release systems:
1. Those which are not effectively absorbed in the lower intestine
2. Those having short biological half-lives (<1hr) e.g. Furosemide
3. Those having long biological half-lives (>12hrs) e.g. diazepam
4. Those for whom large dose is required e.g. sulphonamides
5. Those with low therapeutic indices e.g. Phenobarbital
6. Those for which no clear advantage of sustained release system e.g.
griseofulvin.
7. Those with extensive first pass metabolism.
8. Those candidates with low solubility and/or active absorption

25. Criteria of a Drug Required for Designing as Sustained
Released Dosage Form:
• They exhibits neither very slow nor very fast
rates (t½<2hrs) of absorption and excretion.
[Drugs having biological half lives of between 4
& 6 hours make good candidates in sustained –
release formulations.]
• They are uniformly absorbed from the GIT.
• They are administered in relatively low dose.
• They are used in the treatment of chronic rather
than acute conditions.
• They possess a good margin of safety.
[Accidental dose dumping from potent drugs
may be strongly hazardous.]

26. Drug properties influencing the dosage form: The design of a
controlled release system depends on various factors such as the
route of delivery, the type of drug delivery system, the disease being
treated, the length of therapy, and the properties of the drug. Most
important factor is properties of the drug that are as follows.
A) Physicochemical properties:
1) Aqueous solubility and pKa: Absorption of poorly soluble drugs
is often dissolution rate-limited. Such drugs do not require any
further control over their dissolution rate and thus may not seem to
be good candidates for oral controlled release formulations.
Controlled release formulations of such drugs may be aimed at
making their dissolution more uniform rather than reducing it.

27. 2) Partition coefficient: Drugs that are very lipid soluble or very
water-soluble i.e., extremes in partition coefficient, will
demonstrate either low flux into the tissues or rapid flux followed
by accumulation in tissues. Both cases are undesirable for
sustained release system.
3) Stability of the drug: Since most oral controlled release
systems are designed to release their contents over much of the
length of GI tract, drugs that are unstable in the environment of the
intestine might be difficult to formulate into prolonged release
system.
4) Size of the dose: For drugs with an elimination half-life of less
than 2 hours as well as those administered in large dosages, a
controlled release dosage form may need to carry a prohibitively
large quantity of drug.

28. 5) Molecular size and diffusivity: In addition to diffusion through
a variety of biological membranes, drugs in many sustained release
systems must diffuse through a rate controlling membrane or
matrix. The ability of drug to pass through membranes, its so called
diffusivity, is a function of its molecular size (or molecular weight).
An important influence upon the value of diffusivity, D, in
polymers is the molecular size of the diffusing species. The value of
D thus is related to the size and shape of the cavities as well as size
and shape of the drugs. Generally, the values of diffusion
coefficient for intermediate molecular weight drugs i.e., 150-400,
through flexible polymers range from 10-6 to 10-9 cm2/sec, with
values on the order of 10-8 being most common. For drugs with
molecular weight greater than 500, the diffusion coefficients in
many polymers frequently are so small that they are difficult to
quantify, i.e., less than 10-12 cm2/sec. Thus high molecular weight
of drug should be expected to display very slow release kinetics in
sustained release devices where diffusion through polymeric
membrane

29. B) Biological properties:
1) Absorption: Slowly absorbed drugs or the drugs absorbed with
a variable absorption rate are poor candidates for a controlled
release system. Water-soluble but poorly absorbed potent drugs
and those absorbed by carrier mediated transport processes or
absorbed through window are poor candidates for controlled
release system.
2) Metabolism: Drug metabolism can result in either inactivation
of an active drug or conversion of an inactive drug to an active
metabolite. The process of metabolism can take place in variety of
tissues but the organ mainly responsible for metabolism is liver as
it contains variety of enzyme systems and thus greatest metabolic
alteration of a drug takes place after its absorption into the
systemic circulation. Thus the metabolic pattern of a drug may
influence the choice of the route of administration

30. There are two factors associated with metabolism that significantly
limit controlled release product design. First, if a drug is capable of
either inducing or inhibiting enzyme synthesis it will be difficult to
maintain uniform blood levels of drug upon chronic administration.
Second, if the drug undergoes intestinal (or other tissue) metabolism
or hepatic first pass metabolism, this also will result in fluctuating
drug blood levels. Examples of drugs that undergo intestinal
metabolism upon oral administration are hydralazine,
salicylamide, nitroglycerin, isoproterenol, chlorpromazine, and
levodopa. Examples of drugs that undergo hepatic first pass
metabolism are; propoxyphene, nortriptyline, phenacetin,
propranolol and lidocaine. Successful controlled release products
for drugs that are extensively metabolized can be generated as long
as the location, rate and extent and metabolism are known and the
rate constant(s) are not too large. It can be assumed that a controlled
release product can be developed as long as the metabolism remains
predictable.

31. 3) Elimination or Biological half-life: The rate of elimination of
drug is described quantitatively by its biological half- life. The
biological half-life and hence the duration of action of a drug plays
a major role in considering a drug for controlled release systems.
Drugs with short half-life and high dose impose a constraint
because of the dose size needed and those with long half-lives are
inherently controlled.
4) Safety considerations and Side effects: For certain drugs the
incidence of side effects is believed to be a function of plasma
concentration. A controlled release system can, at times, minimize
side effects for a particular drug by controlling its plasma
concentration and using less total drug over the time course of
therapy. The most widely used measure of the margin of safety of a
drug is its therapeutic index (TI), which is defined as
TI = TD50/ED50

32. Where, TD50 is median toxic dose & ED50 is median effective
dose.
In general, larger the value of TI, safer is the drug. Drugs with
very small values of TI usually are poor candidates for formulation
into CR products primarily because of technological limitations of
precise control over release rates. A drug is considered to be
relatively safe if its TI value exceeds 10.
5) Protein binding: The characteristics of protein binding by a
drug can play a significant role in its therapeutic effect, regardless
of the type of dosage form. Extensive binding to plasma proteins
will be evidenced by a long half-life of elimination for the drug,
and such drugs generally do not require a sustained release dosage
form.

33. 6) Disease state: Disease state is an important factor in considering
a drug for controlled release system. In some instances better
management of the disease can be achieved by formulating the drug
as controlled release system. For example, in case of rheumatoid
arthritis, sustained release form of aspirin would provide desired
drug blood levels, particularly throughout the night, thus relieving
morning stiffness. Other examples include nitroglycerin in the
management of angina pectoris and belladonna alkaloids and
synthetic anti-cholinergics in the treatment of peptic ulcers.
7) Circadian rhythm: Many biological parameters like liver
enzyme activity, blood pressure, intraocular pressure and some
disease states like asthma, acute myocardial insufficiency, and
epileptic seizures have been shown to be influenced by circadian
rhythm. Hence the response to certain drugs like digitalis
glycosides, diuretics, amphetamines, barbiturates,
carbamazepine, ethyl alcohol, and chlordiazepoxide display time
dependent nature.

34. Formulation Methods for Oral SRDF
Common methods used in the design of orally
administered SDRF include three general principles:
A. Barrier principle
1. Reservoir systems or devices
2. Osmotic Pumps or Systems
B. Embedded matrix principle
1. Matrix Systems or Devices
C. Physico-chemical Modification
1. Ion–Exchange Resin Complexes
2. Other Drug Complexes
3. Drug Adsorbates
4. Prodrugs

35. 1. Reservoir Systems or Devices (Barrier Principle)
These systems or devices consists of a core of drug
material is surrounded by a coat of retardant
barrier (polymeric membrane). The layer of
retardant material separates the drug and the
elution medium.
Drug
Reservoir
C
B
AD
A

36. Mechanism of drug release from a reservoir device:
The release of drug from the reservoir can occur by four
mechanisms:
• i. Diffusion of drug present in the reservoir as a solution or
suspension through the barrier. Here the barrier is
impermeable to the elution medium. For the case of
solution , the release is first order. For suspensions,
release is zero order if membrane diffusion is slower than
dissolution. This principle has been successfully applied in
the development of ophthalmic , intra–vaginal and
transdermal controlled release devices.
• ii. Penetration / permeation of elution medium through the
barrier occurs followed by dissolution of the drug in the
reservoir. Later diffusion of the dissolved drug through the
barrier results in availability of drug for absorption.
• iii. Timed erosion of the barrier after sufficient moisture /
elution medium has permeated the membrane.
• IV. Rupture of the barrier after sufficient moisture has
permeated the membrane.

37. Common methods employed to develop
reservoir systems/devices Include:
A. Coating
B. Microencapsulation
A. Coating: A number of reservoir devices
can be prepared by applying the
technology of coating which includes:
a. Mixed release coated granules/ pellets
b. Uniform release coated granules/ pellets
c. Microdialysis cells
d. Drug coat of retardant material over
placebo pellets

38. a. Mixed release coated granules
Drug pellets/ granules are divided into 3 to 4
groups. One group is left uncoated to provide
the initial loading dose and the other groups of
pellets/ granules are coated to different
thicknesses. The various groups are mixed
together and placed in capsules or compressed
into tablets.
Mechanism of drug release: Moisture
penetration through the barrier→ swelling of the
core → rupture of the barrier.

39. The retardant materials used for coating
includes:
-Combination of waxes, fatty acids, alcohols and
esters.
-Enteric materials such as cellulose acetate
phthalate and formalized gelatin.
-Mixture of solid hydroxylated lipids such as
hydrogenated castor oil or glyceryl trihydroxy-
stearate mixed with modified celluloses.
Examples of drugs designed as SRDF by this
method include Erythromycin, Pancreatin etc.

40. b. Uniform release coated granules / pellets
In this method, drug granules / pellets are
uniformly coated by a retardant material that
slowly release drug over sufficiently prolonged
period of time.
Retardant materials employed for this purpose
include hydrolyzed styrene maleic acid
copolymer, partially hydrogenated cotton seed oil
etc.
Examples of drugs designed as SRDF by this
technique include Crystals of ascorbic acid,
Methylprednisolone etc.

41. c. Microdialysis cells
Drug pellets are coated with a mixture of ethyl
cellulose (a water insoluble and pH insensitive
polymer) and sodium chloride particles or some other
water soluble materials (e.g. polyethylene glycol).
Release mechanism: Ethyl cellulose when in contact
with GI fluid, the water soluble material will dissolve
and salt will leach out forming pores which acts as a
dialytic membrane. The elution media then permeates
through dialytic membrane causing dissolution of the
drug and the drug solution then diffuses through the
essentially intact membrane.
Examples of drugs designed as SRDF by this technique
are Nitroglycerin, Propoxyphene, Aspirin etc.

42. d. Drug coat of retardant material over placebo
pellets
The drug is suspended in the coating of retardant
material applied onto placebo pellets. The
prepared pellets are placed in capsules. The drug
is released by erosion or rupture of the barrier.
Retardant materials employed include
polyethylene glycol, modified ethyl cellulose,
shellac or cellulose acetate phthalate.
Example of drugs designed as SRDF by this
technique is theophylline.

43. B. Microencapsulation:
Microencapsulation means encapsulation of drug
material in microscopic size particles of a ‘wall
forming’ material.
Microencapsulation is a process by which solids,
liquids or even gases may be encapsulated into
microparticles whose size ranges from several
tenths of 1µ to 5000µ in size through the formation
of thin coating of wall material around the substance
being encapsulated.
Retardant coating materials used are gelatin,
polyvinyl alcohol, ethyl-cellulose, polyvinyl chloride.
The most common method of microencapsulation is
coacervation. Other techniques like, spray drying.

44. Coacervation: In this technique, the prospective
wall–forming material e.g. gelatin, is dissolved in
water. The drug material to be microencapsulated is
added to the solution and the two–phase mixture is
thoroughly stirred until the drug material is broken up
to the desired particle size.
Then a solution of a second material (usually acacia)
is added which concentrates gelatin into tiny liquid
droplets called “coacervates” that encircle drug
particles.
The particles are coated to different thicknesses,
mixed together and compressed into tablets or
placed in capsules.
The drug is released by dissolution of coating
materials.

45. Applications of microencapsulation:
• For masking test, (acetaminophen tab)
• To reduce gastric irritation (KCl)
• To separate the incompatible ingredients
(Aspirin tab)
• To prevent volatilization (menthol)
• To protect drugs from moisture and oxidation
(vit A palmitate)
Disadvantages:
• Incomplete or discontinuous coating
• Inadequate stability
• Economic limitations
Examples : Micro – K ( KCl )

46. 2. Osmotic Systems / Pumps (Barrier Principle)
This is an example of membrane- controlled release
technology. These systems employ osmotic pressure as the
driving force to cause the release of drug. A constant release of
drug can be achieved if a constant osmotic pressure is
maintained and a few other features of the system are
controlled.
A number of osmotic pumps / systems have been designed by
pharmaceutical manufacturers including:
1. Oral Osmotic Systems
2. Push – Pull Osmotic System
3. Multi Directional Osmotic Drug Absorption System

47. Mechanism of Drug Release:Mechanism of Drug Release: GI fluid enter theGI fluid enter the
tablet core across the semi-permeable membrane →tablet core across the semi-permeable membrane →
dissolve drug→ creates an osmotic gradient acrossdissolve drug→ creates an osmotic gradient across
the membrane →pumps the drug out through thethe membrane →pumps the drug out through the
delivery orifices.delivery orifices.
The rate of drug solution release is approximatelyThe rate of drug solution release is approximately
one to two drops per hour.one to two drops per hour.

48. 1. Matrix Devices (Embedded Principle)
• In this case, the drug is dispersed (embedded) in
a matrix of retardant material, which may be
encapsulated in particulate form or compressed
into tablets. The drug may be insoluble (Network
model) or soluble (Dispersion model) in the
retardant material.
Among the innumerable method used in controlled
release drug from pharmaceutical dosage form,
the matrix system is the most frequently applied;
it’s release system for delay and control of the
release of the drug that is dissolved or dispersed
in a resistant supports to disintegration.

49. Fig. Network model (Drug is
insoluble in the retardant material)
Fig. Dispersion model (Drug is
soluble in the retardant material)

50. To define matrix, it is necessary to know the characters
that differentiate it from other controlled release
dosage forms. Hence the following must be
considered:
• The chemical nature of support (generally, the
support are formed by polymeric net)
• The physical state of drug (dispersed under
molecular or particulate form or both)
• The matrix shape and alteration in volume as a
function of time.
• The route of administration (oral administration
remains the most widely used but other route are
adaptable)
• The release kinetic model.

51. Types of matrix material/devices:
On the basis of the solubility of the materials matrix
devices can be classified into two:
1. Matrix may be soluble: Hydrophilic polymers
2. Matrix may be insoluble:
a. Insoluble polymer matrix (plastic matrix)
b. Lipid matrix
c. Insoluble but potentially erodable matrix

52. 1. Soluble Matrix: (Hydrophillic Matrix)
Drug can be dispersed in soluble matrix and drug
release depends on slow dissolution of the matrix by
elution media. This delivery system is also called
swellable soluble matrix.
In general they comprise a compressed mixture of
drugs and water swellable hydrophilic polymer. The
systems are capable of swelling, followed by gel
formation, erosion and dissolution in aqueous media.
Hydrated matrix layer on contact of water further
controls the diffusion of water. When outer layer is
fully hydrated, it erodes and drug contained is
released. Thus, drug diffusion and tablet erosion
controls the rate of drug release.

53. Hydrophilic materials: e.g. Hydroxy propyl
methyl cellulose, sodium CMC,
methylcellulose, Hydroxy ethyl cellulose.
Natural gums: Galactomannose (guargum),
chitosan, gum acacia, locust bean gum,
sodium alginate, karaya gum, pectins, xanthan
gum.
Examples of Drugs:
Sodium diclofenac
Oramorph SR tablets (Morphin sulfate)

54. 2. Insoluble matrix
a. Plastic or “Skeleton” matrix: These are insoluble
inert polymers such as polyethylene, polyvinyl
chloride, methyl acrylate-methacylate copolymer
and ethyl cellulose. The mixture of drug and ground
polymer may be directly compressed into tablets.
• Release mechanism: Drug is slowly released from
the inert matrix by diffusion following liquid
penetration. If channeling agent is used, diffusion
occurs through channels. Release rate can be
modified by changes in the porosity (pore-forming
salts) and compression force of the matrix.
This occurs when the matrix is insoluble in water, and
the drug is insoluble in the matrix but soluble in water.

55. • b. Lipid matrix: These are also water
insoluble matrix. Here drug delivered by
diffusion or by surface erosion.
Release mechanism: In this model, it is
assumed that drug is released by primarily
diffusion of drug through the matrix and
secondarily partition between matrix and water.
This occurs when the matrix is insoluble in
water, but the drug is soluble in the matrix and
has a high solubility in water/elution media.

56. c. Insoluble erodable matrix: This matrix is water
insoluble but potentially erodable. The matrix
includes waxes, lipids and related materials.
Examples include carnauba wax, castor wax
(hydrogenated castor oil) and triglycerides.
• The drug and additives are generally depressed in
molted wax, which is then congealed, granulated
and placed into capsules and compressed into
tablets. The loading dose is provided as untreated
granules or as an outer core.
Release mechanism: In this model, it is assumed
that solid drug dissolves from the surface layer of
the device first; when this layer completes
delivering drug, the next layer begins to be
depleted by dissolution and diffusion through the
matrix to the external solution.

57. Factors influencing the drug release from
matrix
• Choice of matrix material.
• Amount of drug incorporated in the matrix.
• Viscosity of the hydrophilic material in aqueous
system at a fixed concentration.
• Drug: matrix ratio.
• Tablet hardness, porosity, and density variation.
• Tablet shape and size.
• Solubility of drug in aqueous phase.
• Surfactants and other additives.

58. Advantages of matrix devices
1. With proper control of the manufacturing process, reproducible
release profiles are possible. The variability associated with
them is slightly less than coated release form.
2. Structure allows an immediate release of small amount of
active principle, there is no risk of dose dumping.
3. Their capacity to incorporate active principle is large, which
suits them to delivery of large doses.
4. The manufacturing processes are notably simple. Tablet
formulation can be done via direct compression or by wet
granulation techniques.
5. Large variety of non-expensives gelling agents is approved for
oral use by the competent official organization.
6. The safety margin of high-potency drugs can be increased.
7. The drug release from hydrophilic matrices show a typical time
dependent profile i.e. decreased drug release with time
because of increased diffusion path length.

59. 4. Ion – Exchange Resin Complexes
Ion – exchange resins are water insoluble polymers
containing salt forming groups on the polymer chain.
Resins used are special grades of styrene / divinyl
benzene copolymers that contain substituted acidic
groups (carboxylic and sulfonic for cation
exchanges) or basic groups (quaternary ammonium
for anion exchanges).
Drug is bound to the resin by repeated exposure of
the resin to the drug in a chromatographic column or
by prolonged contact of the resin with the drug
solution.

60. For example, drug-resin salts may be prepared by percolation of
the sodium salt of the resin with a concentrated solution of a drug
hydrochloride salt. The following equation represents the drug
release in-vivo:
Resin – SO3Na + Drug HCl → NaCl + Resin-SO3. Drug H
Similarly drug-resinates are prepared by reaction of sodium salts
of acidic drugs with resin chloride.
Resin – NH4Cl + Drug Na → NaCl + Resin-NH4. Drug
The resin.drug complex is then washed with ion-free water and
dried. The resulting product can be encapsulated, tabletted or
suspended in ion-free vehicles.
Release in-vivo :
Resin – NH4.Drug + NaCl (body fluid) → Drug Na + Resin-NH4Cl

61. 5. Other Drug Complexes
Certain drug substances that are only slowly soluble in the body
fluids are inherently long acting (Griseofulvin).
Thus drugs that are, high water soluble may be bound to
suitable complexing agents to form complexes which are poorly
water soluble and consequently give sustained action.
The steps or mechanism involved in controlling the
release of drug from drug complexes in GI fluid can be
illustrated as follows:
Examples include:
Tannic acid complexes of basic drugs like amphetamine and
antihistamines.
Other complexing agents to prepare complexes of basic drugs
include polygalacturonic acid, algenic acid and arabogalactose
sulfate.
Dissolution Dissociation
DC . solid DC . solution D

62. 6. Drug Adsorbate
Drug adsorbates represent a special case of complex
formation in which the product is essentially insoluble.
Drug availability is determined only by the rate of dissociation
(desorption) and access of the adsorbent surface to water as
well as the effective surface area of the adsorbate.
The mechanism involved in controlling the release of drug from
adsorbates can be illustrated as follows:
The adsorbate, can be formulated as liquid suspensions,
tablets or capsules.
Desorption
AD. Solid D

63. 7. Prodrugs
Prodrugs are therapeutically inactive drug derivatives
that regenerate the parent drug in-vivo by enzymatic or non-
enzymatic hydrolysis.
The steps or mechanisms involved in controlling release of
drug from a prodrug can be depicted by the following scheme:
Desorption Absorption
PD. Solid PD. Solution PD. Plasma
Metabolism
D
Elimination

64. Conventional Drug Therapy
1. Rapid and complete release of
drug immediately after
administration.
2. Absorption is the rate-limiting
step (kr >>> ka).
3. Blood level fluctuates (Peak and
Valley).
4. There is risk of overmedication
or under medication at periods
of time.
5. Frequent dosing.
6. Patient non compliance.
Therapeutic inefficiency / failure.
7. Inconvenience of patient.
Sustained-Release Drug Therapy
1. Slow/controlled release of drug over
an extended period of time.
2. Drug release from the dosage form is
the rate-limiting step (ka >>> kr ).
3. Constant blood level is maintained
over a prolonged period (Reduced
fluctuation).
4. Reliable therapy as the risk is
minimized.
5. Reduced frequency of dosing.
6. Improved patient compliance.
7. Enhanced patient convenience with
day-time and night-time medication.
Comparison between conventional and sustained-release drugs

65. 8. No therapeutic action during
overnight no dose period.
9. Risk of symptom breakthrough.
10. Incidence and severity of
untoward effects related to high
-peak plasma concentration ↑.
11. More total dose over the entire
course of therapy.
12. More side effects.
13. Health care cost ↑.
14. Permits prompt testing of
therapy.
15. Incidence of severity of GI side
effects due to dose dumping of
irritant drugs ↑.
16. More flexibility for physician in
adjusting dosage required.
8. Maintains therapeutic action during
overnight no dose period.
9. Improved treatment of many chronic
diseases (minimizing symptom
breakthrough).
10. Incidence and severity of untoward
effects related to high – peak plasma
concentration ↓.
11. Less total dose over the entire
course of therapy.
12. Minimize/eliminate incidence of
local/systemic side effects.
13. Health care cost ↓.
14. Does not prompt.
15. Incidence of severity of GI side
effects due to dose dumping of irritant
drugs ↓.
16. Less flexibility.

66. 17. Can accommodate abnormal
cases of disease safety offering
drug disposition etc.
18. ↓ Chance of at any site of GIT
(local irritation ).
19. No problems for drugs with too
short half lives.
20. Per unit cost is less. ↓
21.
17. Can not accommodate.
18. ↑ Chance of at any site of GIT (local
irritation).
19. Not suitable for drugs with too short
half lives, drugs needing specific
requirements for absorption from GIT.
20. Per unit cost is more. ↑
21.
Time Time