“CONTROLLED AND SUSTAINED

RELEASE DOSAGE FORMS”

KHALSA COLLEGE OF PHARMACY

AMRITSAR

SUBMITTED TO:- PRESENTED

BY:-
Dr. Gurjeet Singh Mehak
M.Pharm 1stSem
(Pharmaceutics)
 DRUG DELIVERY SYSTEM
 A drug delivery system (DDS) is defined as a device that enables the
introduction of therapeutic substance in the body and improves its
efficacy and safety by controlling the rate, time and place of release of
drug in the body.
 A drug delivery system acts as the interface between the drug and the
patient.
 The design of any DDS should be primarily aimed to achieve the more
predictability or reproducibility to control the drug release, drug
concentration in the target tissue & optimization of therapeutic effect
of drug by controlling its release in the body with lower & less
frequent dose.
 CONTROLLED DRUG DELIVERY SYSTEM
 Controlled release dosage forms covers a wide range of
pharmaceutical formulations which provide continuous release of their
active ingredients at a predetermined rate & for a predetermined time.
 The Controlled release system is designed to deliver a constant supply
of drug in a quantity equivalent to the amount eliminated from the
body,usually at a zero-order rate, by continuously releasing it for a
certain period of time.
 Most of the controlled release systems are passive pre- programmed
(Rate of release is predetermined & is not influenced by external
biological environment).
 SUSTAINED DRUG DELIVERY SYSTEM
 Sustained release dosage form is defined as the type of dosage form in
which a portion i.e. (loading dose) of the drug is released
immediately,in order to achieve desired therapeutic response more
promptly, & the remaining (Maintenance dose) is then released slowly,
thereby, achieving a therapeutic effect which is prolonged, but not
constant.
 The rate of release of maintenance dose in SRDF’s is designed so that
the amount of drug loss from the body by elimination is constantly
replaced.
 The primary objective of SRDF’s is to achieve steady state blood level
for an extended period of time.
 Drug release in SRDF’s may or may not be controlled.
PLASMA CONCENTRATION-TIME PROFILE

Fig:- A hypothetical plasma concentration-time profile from conventional multiple

dosing and single doses of sustained & controlled delivery formulations.
 To overcome the short-comings of conventional dosage forms:-
RATIONALE OF DEVELOPING SR & CR DOSAGE FORMS

• Drugs with short half-life require frequent administration,which increases chances of missing
dose of drug leading to poor patience compliance.

• A typical peak-valley plasma conc. time profile is obtained which makes attainment of steady
state condition difficult.

• The unavoidable fluctuations in the drug concentration may lead to under-medication or over-
medication.
 To provide uniform drug delivery with minimum fluctuations in plasma level.

 To extend the duration of action of the drug,thereby, increasing the patient compliance as well.

 To reduce adverse effects.

 To reduce the frequency of dose administration.

 TERMINOLOGY

Delayed release dosage forms-

These are the dosage forms that utilize repetitive, intermittent dosing
of a drug from one or more immediate release units incorporated into a
single dosage form.
for e.g:- enteric coated tablets.

Prolonged action dosage forms:-

These are the dosage forms which are designed to release the drug
slowly so as to provide a continuous supply of drug over an extended
period.They prevent very rapid absorption of the drug,which could
result in extremely high peak plasma drug concentration.
CONT..
Repeat action dosage forms:-
These are the dosage forms that are designed to release a dose of
drug initially followed by second dose of drug at a later time.

Targeted drug delivery system:-

A targeted drug delivery system is the one which delivers the drug
only to its site of action & not to the non-target organs or tissues.

Extended release:-
Pharmaceutical dosage forms that release the drug slower- than- normal
manner at a predetermined rate and necessarily reduces the dosage
frequency by two folds.
CONT..

Temporal drug delivery:-

It refers to the process of controlling the rate of drug delivery to
the target site.

 Spatial drug delivery:-

It refers to the process of targeting the drugs to specific organs, cells,
tissues, or even sub cellular compartments.
ADVANTAGES OF SR & CR DOSAGE FORMS:-
 Frequency of drug administration is reduced.
 Patient compliance can be improved.
 More consistent & prolonged therapeutic effect.
 Reduction in dose.
 Decreased incidence of adverse effects & toxicity.
 Reduction in health care cost.
 Better drug utilization
 Increased bioavailability of some drugs.
 Reduced fluctuations in circulating drug levels.
 Safety margin of potent drug is increased by technically excellent
designing of formulation.
CONT..
 Improved efficacy in treatment which is achieved by:-
• Cure or control of condition.
• Patient care time is reduced.
• Night time dosing can be avoided for patient convenience.
• Product life time is increased in sustained release formulations.As the
particles of drug are coated with matrix or entire product is matrix
coated which avoid exposure of drug to the environment & render it
stable.
• Make use of specific effects like SR Aspirin for morning relief of
arthritis.

11 06/19/2021
 DISADVANTAGES OF CR & SR DOSAGE FORMS
 Toxicity due to dose dumping.
 Increased variability among dosage units.
 Increased cost.
 Need for additional patient education & counselling.
 Stability problems.
 Termination of therapy is difficult in case of toxicity, poisoning or
hypersensitivity reactions.
 Dose adjustment is difficult.
 Longer time to achieve therapeutic blood concentrations due to
incomplete release, increased first – pass metabolism, increased
instability, pH-dependent solubility etc.
 Poor in-vivo in-vitro correlation (IVIVC).
 DIFFERENCE BETWEEN CONTROLLED
RELEASE & SUSTAINED RELEASE DOSAGE
FORMS
Sustained Release Controlled Release
 Constitutes dosage form that provides Constitutes dosage form that maintains
medication over extended period of constant drug levels in blood or tissues.

time.
 These dosage forms do not attain zero Maintains constant drug levels in the
order release kinetics. blood or target tissue by releasing the
drug in zero order pattern.

 SRDF do not contain methods to promote These dosage forms contain methods
localization of the drug at the active site. to promote localization of the drug at
active site.

 Drug release may or may not be controlled. Drug release is always controlled.
FACTORS INFLUENCING THE DESIGN
OF SR & CR DOSAGE FORMS
 Physicochemical properties of drug:-

Drug properties like Stability, solubility, partition coefficient

and protein binding are to be considered.
 Route of Administration:-

On chronic administration,some routes exert a negative influence

on drug efficacy, therefore, route of delivery of drug should be
taken into account.
 Target Sites:-

Unwanted side effects can be minimized by delivering the

maximum fraction of applied dose to the target site.
CONT..
 Acute or Chronic therapy:-
Consideration of whether one expects to achieve cure or control of a
condition and the expected length of drug therapy are important factors in
designing CR & SR dosage forms.

 Condition of the patient:-

Whether the patient is ambulatory or bedridden, obese or gaunt, old or
young etc. can influence the design of controlled & sustained release dosage
forms.

 The Diseased State:-

Pathophysiological state of subject plays an essential role in the design of
suitable drug delivery system.
15 06/19/2021
 BIOPHARMACEUTICAL FACTORS
INFLUENCING FABRICATION OF CR & SR
DOSAGE FORMS
1) Physicochemical factors 2) Biological properties
AQUEOUS SOLUBILITY & pKa ABSORPTION

DISTRIBUTION
PARTITION COEFFICIENT
METABOLISM
DRUG STABILITY
ELIMINATION HALF LIFE
PROTEIN BINDING
THERAPEUTIC INDEX
MOLECULAR SIZE &
PLASMA CONCENTRATION
DIFFUSIVITY
RESPONSE RELATIONSHIP
DOSE SIZE SIDE EFFECTS & MARGIN OF

SAFETY

ROLE OF DISEASED STATE

AQUEOUS SOLUBILITY:-
 Aqueous solubility is an important consideration while designing the controlled or
sustained release dosage forms. The aqueous solubility exerts its control on the
absorption process in two ways:-
• By influencing dissolution rate of a compound, which establishes the drug
concentration in solution.
• By having an effect on the drug’s ability to penetrate tissues.

 Dissolution rate is related to aqueous solubility by the Noyes Whitney equation

under the sink condition(( CGIT»C).

dc/ dt= KD ACS

Where, dc/dt –Dissolution rate

KD - Dissolution rate constant
A- Total surface area of drug particles.
CS- Aqueous saturation solubility.
CONT..
 Drugs with low aqueous solubility (0.1mg/ml) have low dissolution rate and usually
suffer oral bioavailability problems, because of limited GI transit time of
undissolved drug particles & limited solubility at the absorption site.
For e.g:-Tetracycline dissolves to a greater extent in the stomach than in intestine,
although it is best absorbed in the intestine.
 Drugs with high aqueous solubility tend to release the dosage form in a burst & thus,
is absorbed quickly leading to a sharp increase in the blood drug concentration.
 It is often very difficult to incorporate a highly water- souble drug in the dosage
form & retard the drug release, especially when the dose is high.
 Slightly soluble drugs are also poor candidates for diffusion controlled systems,since
the driving force for drug release i.e drug’s concentration in solution will be low.
CONT..
 Drugs which are aqueous soluble & depicts pH-independent solubility serves as a

good candidate for CDDS & SRDDS. e.g:- Pentoxyphylline.

 Drugs with pH-dependent aqueous solubility,e.g:-Phenytoin and drugs which are

soluble in non-aqueous solvents,e.g:- steroids are also good candidate for controlled
drug delivery system.
pka:-
The
 degree of ionization (pKa) of a drug is a unique physicochemical property that control its ionization state when it is in solution.

The
 absorption of the unionized drug occurs rapidly as compared to ionized drugs from the biological membranes.Generally,the highly

ionized drug are poor candidates for CDDS & SRDDS. For e.g:-Hexamethonium

Most
 of the drugs are weakly acidic & weakly basic in nature. The Henderson-Hasselbach equation provides an estimate of ionized &

unionized drug concentration, by function of pH.

FOR WEAKLY ACIDIC DRUG:-

pH=pKa+log ([ionized]/[unionized])

FOR WEAKLY BASIC DRUGS:-

pH= pka+log([unionized]/[ionized])
CONT..
 The pKa range for acidic & basic drugs, whose ionization is pH sensitive is 3.0-7.5
and 7.0- 11.0, respectively.
 In drug delivery design, it is important to calculate the degree of ionization to otain
an indication of whether absorption from a particular site or transport can be
assumed to be unrestricted in case of passive diffusion.
 For the optimum absorption by passive diffusion, the percentage of unionized drug
at that site should be between 0.1-5%.
PARTITION COEFFICIENT:-
 The partition coefficient is defined as the fraction of drug in an oil phase to that of

an adjacent aqueous phase.

 It influences not only the penetration of drug across the biological membranes,

but also influences its diffusion across the rate limiting membrane or matrix.
 Between the time of administration of drug & its elimination, it diffuses through

several biological membranes that act primarily as lipid-like barrier’s.

 Oil/Water partition coefficient plays a major role in evaluating the relative

lipophilicity of drug. It is expressed

K=Co/Csas follows:-

Where,
Co= Equilibrium concentration in organic phase.
Cs= Equilibrium concentration in aqueous phase.
CONT..

 High partition coefficient compounds are predominantly lipid soluble and have very

low aqueous solubility. These compounds can penetrate biological membranes very
easily, but cannot proceed further.
 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 & controlled release dosage forms.
 DRUG STABILITY :-
 The stability of drug in the environment to which it is exposed is another

physicochemical factor to be considered in the design of controlled/sustained release

systems.
 Drugs that are unstable in gastric pH (rifampicin,rabeprazole etc) can be developed

as slow release dosage forms & drug release can be delayed until the dosage form
reaches the intestine.
 Drugs that undergo gut wall metabolism & show instability in small intestine

( captopril, ranitidine etc) are not suitable for CR & SR system due to decreased
bioavailability problem.To overcome the problem associated with these drugs, a
different route of administration should be chosen. e.g:- Controlled release of
nitroglycerin.
PROTEIN BINDING:-
 It refers to the formation of complex of the blood proteins ( like albumin) with the

absorbed drug. It is well-known that many drugs bind to plasma proteins with a
concomitant influence on their duration of action.
 The binding of a drug to plasma proteins will decrease its plasma to tissue

concentration gradient, thereby slowing the rate of transfer of the drug across the
capillaries.
 Extensive binding to plasma proteins will result in enhanced biological half life of

the drug for elimination & prolonged duration of action. Thus, such drugs need not
to be fabricated as sustained/controlled release dosage form. E.g :- Amitriptyline etc.
 Drug-protein binding also influences the distribution of the drug i.e Drugs which are

highly bound to the plasma proteins may distribute less widely because they remain
trapped in the peripheral vasculature.
MOLECULAR SIZE & DIFFUSIVITY
In
 addition to diffusion through a variety of biological membranes, drugs in CRDDS have to diffuse
through a rate controlling membrane or matrix.
The
 ability of a drug to pass through such membranes is called diffusivity.It is related to molecular size
of drug by the following equation:-

Log D = -Svlog V + Kv = -Smlog M+ Km

where, D= Diffusion coefficient i.e diffusivity.
M= Molecular mass.
V= Molecular volume.
Km, Sm, Sv , Kv = Constants in particular medium.
The
 value of Diffusion constant ( D) depends on molecular size of the drug as well as on the size &
shape of cavities of membrane.Generally,lower the molecular weight,faster & more complete is the
diffusion.
 CONT..
 Drugs with high molecular weight are not considered as a good candidate for

sustained release dosage form because they are expected to show very slow release
of medicament.e.g:- Phenothiazines.
 For drugs of intermediate molecular weight i.e 150-400 Daltons, diffusivities

through flexible polymers are typically of the order of 10-8 cm 2 / sec, but for drugs
with molecular weight >500 Daltons, diffusion coefficients in many polymers are
frequently so small that they are difficult to quantify.
 BIOLOGICAL FACTORS
 ABSORPTION:-

 The rate, extent and uniformity in the absorption of drug are some important factors which are

to be considered while formulating any sustained/controlled release dosage forms.

 To maintain constant blood or tissue level of the drug, it must be uniformly released from the

controlled release systems & then uniformly absorbed. So, it is desirable in CDDS to have the
released drug completely absorbed.
 Usually, the rate – limiting step in drug delivery from a controlled release product is the

release from the dosage form rather than absorption. Thus, rapid drug absorption, relative to
drug release from a dosage form (kr<<ka) ,is expected for the suitability of CDDS & SRDDS.
 If the GI transit time of the dosage form is about 8-12 hours,then the maximum biological

half-life should be approximately 3-4 hrs. Otherwise, the dosage form will pass out of
absorptive region before the drug release is complete.
CONT..
 Therefore, the compounds with lower absorption rate constants are poor candidates

for CDDS. For e.g:-Iron is not uniformly absorbed along the length of the GIT as the
greatest uptake of this drug occurs at upper part of duodenum, with significantly
reduced absorptive capacity in the lower segment of intestine.
 Drugs which are either absorbed from a specific area of GIT due to pH-related

solubility(Gentamycin) or show absoption by carrier-mediated transport (Riboflavin)

also influence the design of CDDS & SRDDS.
 METABOLISM:-
 Metabolism of a drug is a process resulting in either inactivate an active drug or convert an

inactive drug to an active metabolite.

 For optimal bioavailability, the route of drug administration may be dictated by the drug’s

metabolic pattern.
 Drugs selected for controlled release system should be completely metabolized but the rate

of metabolism should not be too rapid. Two factors, associated with metabolism process,
significantly affect the design of controlled release drug product:-
 Nature of drug:-If a drug is liver enzyme inhibitor/ inducer, it will create problem in

maintaining uniform plasma concentration on chronic administration.

• Examples of enzyme inducers:- antiepileptics, barbiturates (phenobarbitone), Rifampin,

Griseofulvin, phenybutazone etc.

• Examples of enzyme inhibitors:-azithromycin, cimetidine, cyclosporine, metronidazole,

valproic acid etc.

 CONT..
 Secondly, variations in blood drug level either through intestinal ( or other tissue)

metabolism or through first-pass effect will also make preparation of sustained

release dug product difficult.

Example:- Hydralazine, bromocriptine etc are drugs which suffers from reduced
bioavalability problem due the first-pass effect & are undesirable to be formulated as
SRDDS.
BIOLOGICAL HALF-LIFE:-
 The biological half-life of a drug plays an indispensable role in the process of

considering a drug for controlled or sustained release.

 Drugs with short half-life i.e 2-5 hours (paracetamol, atropine, indomethacin etc)

require frequent dosing to minimize fluctuations in the blood level . Thus, they can
be formulated as SRDF as dose frequency can be reduced.
 Drugs with shorter half-life i.e below 2 hours (Aspirin, ampicillin, furosemide,

lignocaine etc) cannot be fabricated as sustained release drug product as they require
faster rate of release at a larger dose.
 Drugs with longer half-life i.e >8 hours (Theophylline, thyroxin, imipramine etc) are

also not used in sustaining system,as their effect is already sustained.

 THERAPEUTIC INDEX:-
 Therapeutic index is most widely used to measure the margin of safety of a drug.It

can be expressed as:-

Therapeutic index= Median toxic dose/ Median effective dose.

 A drug is considered to be relatively safe with therapeutic index more than 10 i.e

higher the therapeutic index, more safer will be the drug.

 Drugs with very small values of therapeutic index are considered as the poor
candidates for formulation into controlled release products due to limitation of
precised control over the release rates.
 MECHANISM OF DRUG DELIVERY
FROM SR/CR FORMULATIONS
 Dissolution controlled release:-

 In this system, controlled release products are prepared by decreasing the dissolution

rate of drugs which are highly water soluble.This can be done by:-
• Preparing an appropriate salt or derivatives.

• By coating the drug with a slowly dissolving material.

 The basic principle of dissolution control is Fick’s law i.e If the dissolution proces is

diffusion layer controlled, where the rate of diffusion from the solid surface through
an unstirred liquid film to the bulk solution is rate limiting, the flux J is given by:-

J= -D (dc/dx)

where D= diffusion coefficient

CONT..
dc/dx= concentration gradient from solid solution to bulk solution.
 Two common dissolution controlled systems are as follows:-

 Matrix dissolution system.

 Encapsulated dissolution system .

 Matrix dissolution system:-

• Matrix dissolution devices are prepared by compressing the drug with a slowly

dissolving polymer carrier into a tablet. Two general methods of preparing them
are:-

1. Congealing

2. Aqueous dispersion methods.

• Examples of matrix dissolution system:-Nicobid, pentritol etc.

Fig:- Matrix dissolution system

 Encapsulated dissolution system:-

• This dissolution system can be prepared by microencapsulation technique.The most

common method of microencapsulation is coacervation, which involves addition of

a hydrophilic substance to a colloidal dispersion.
CONT..
• Once the coating material get dissolved, all the drug inside the microcapsule is

immediately available for dissolution & absorption.

• Thus, drug release can be controlled by adjusting the thickness (1µm-200µm) &

dissolution of the coat.

• Examples:- Combid, Hispril etc.

Fig:- Encapsulated dissolution system

DIFFUSION CONTROLLED SYSTEM:-
 In diffusional systems, the release rate of drug is determined by its diffusion through a

water insoluble polymer. There are two types of diffusional devices:-

 Reservoir devices:-

• In this system, a drug is enclosed by a water-insoluble polymeric material. Drug will

partition into the membrane and exchange with the fluid surrounding the particle.Then,
the additional drug will enter the membrane, diffuse to the periphery & exchange with
surrounding media.
• Common methods used to develop reservoir type devices include microencapsulation

of drug particles and press coating of whole tablets or particles.

• The release of a drug from reservoir device is governed by Fick’s first law of diffusion.

• Examples:- Nico-400, Nitro-Bid etc.

 Matrix diffusion devices:-

• In these devices, a dispersed or dissolved drug is distributed uniformly throughout

an inert polymeric matrix. The rate of drug release is dependent on the rate of drug
diffusion, but not on the rate of solid dissolution.
• Examples:- Forhistal, priscoline etc.
COMBINATION OF DIFFUSION & DISSOLUTION CONTROLLED
SYSTEMS:-
 In this system the drug core is enclosed with a partially soluble membrane.

 Pores are created due to dissolution of part of the membrane which permits entry of aqueous

medium into the core.

 Hence, drug dissolution occurs which lead to diffusion of dissolved drug out of the system.

 The release profile of drug from such type of product can be described by following equation:-

Release rate- AD(C1-C2) / L

where, A- surface area

D- Diffusion coefficient of drug through pore.

L- Diffusion path length.

C1 & C2- Concentration of drug in core & dissolution medium.

DRUG DELIVERY FROM COMBINATION OF
DIFFUSION AND DISSOLUTION SYSTEM

Insoluble membrane

Entry of dissolution fluid

Diffusion of dissolved drug

Pore created by dissolution

of soluble fraction membrane
ION- EXCHANGE RESINS:-
 It is considered as an attractive method for controlled drug delivery because, in this

system, the drug release characteristics rely on the ionic environment of the resin
containing drug & therefore, is less susceptible to environmental conditions such as
enzyme content and pH at the site of absorption.
 Drug molecules attached to the resin are released by exchanging with appropriately

charged ions in the GIT, followed by diffusion of the drug molecule out of the resin.
 The rate of diffusion is controlled by the area of diffusion, diffusional pathlength &

extent of crosslinking in the resin.

 Examples:- Biphetamine capsules etc.
OSMOTICALLY CONTROLLED RELEASE:-

 In this type of drug delivery system, osmotic pressure is the driving force that

generates constant drug release.

 This system is fabricated by applying a semipermeable membrane around a core of

an osmotically active drug or core of an osmotically inactive drug in combination

with an osmotically active salt.
 This drug delivery system is based on the principle of dispensing the drug

continuously at a zero- order rate until the concentration of the osmotically active
salt in the system is below saturation solubility, whereupn a non-zero order release
pattern results.
44 06/19/2021