Factors Influencing the Design and Performance of Oral Sustained/Controlled Release Dosage Forms

Abstract

Of all drug delivery systems, oral drug delivery remains the most preferred option for administration for various drugs. Availability of wide variety of polymers and frequent dosing intervals helps the formulation scientist to develop sustained/controlled release products. Oral Sustained release (S.R) / Controlled release (C.R) products provide an advantage over conventional dosage forms by optimizing bio-pharmaceutic, pharmacokinetic and pharmacodynamic properties of drugs in such a way that it reduces dosing frequency to an extent that once daily dose is sufficient for therapeutic management through uniform plasma concentration providing maximum utility of drug with reduction in local and systemic side effects and cure or control condition in shortest possible time by smallest quantity of drug to assure greater patient compliance. This review describes the various factors influencing the design and performance of sustained/controlled release products along with suitable illustrations.

Full text

Review Article
Factors Influencing the Design and Performance of
Oral Sustained/Controlled Release Dosage Forms
Ranjith Kumar Mamidala, Vamshi Ramana, Sandeep G, Meka Lingam,
Ramesh Gannu and Madhusudan Rao Yamsani*
University College of Pharmaceutical Sciences, Kakatiya University, Warangal, (AP), India.
ABSTRACT: Of all drug delivery systems, oral drug delivery remains the most preferred option for administration for
various drugs. Availability of wide variety of polymers and frequent dosing intervals helps the formulation scientist to
develop sustained/controlled release products. Oral Sustained release (S.R) / Controlled release (C.R) products provide an
advantage over conventional dosage forms by optimizing bio-pharmaceutic, pharmacokinetic and pharmacodynamic
properties of drugs in such a way that it reduces dosing frequency to an extent that once daily dose is sufficient for
therapeutic management through uniform plasma concentration providing maximum utility of drug with reduction in local
and systemic side effects and cure or control condition in shortest possible time by smallest quantity of drug to assure
greater patient compliance. This review describes the various factors influencing the design and performance of
sustained/controlled release products along with suitable illustrations.
KEYWORDS: Sustained release; Absorption window; Stability; Receptor-occupation; Lipophilicity; Clearance;
Apparent volume of distribution; Half-life
Introduction
Oral drug delivery method is the most widely utilized
routes for administration among all alternatives that have
been explored for systemic delivery of drug via various
pharmaceutical products of different dosage forms.
Popularity of the route may be ease of administration as
well as traditional belief that by oral administration the
drug is due to the well absorbed into the food stuff ingested
daily (Howard and Loyd, 2005). Sustained release (S.R)/
(Since their introduction). Controlled release (C.R)
pharmaceutical products have gradually gained medical
acceptance and popularity. Regulatory approval for
marketing and their pharmaceutics superiority and clinical
benefits over immediate release pharmaceutical products
have been increasingly recognized (Lachman et al., 1998).
Modified release oral dosage forms have brought new
lease of life into drugs that have lost market potential due
to requirement of frequent dosing, dose related toxic
effects and gastro intestinal disturbances.
Terminology
Modified Release Drug Product: The term modified
release drug product is used to describe products that alter
the timing and/or the rate of release of the drug substance.
Types of Modified Release Drug Products
Extended Release Dosage Forms: A dosage form that
allows at least a two fold reduction in dosage frequency as
compared to that drug presented as an immediate release
form. Ex: Controlled release, Sustained release.
Sustained release: It includes any drug delivery system
that achieves slow release of drugs over an extended period
of time not particularly at a pre-determined rate.
Controlled release: It includes any drug delivery system
from which the drug is delivered at a predetermined rate
over a long period.
Delayed Release Dosage Forms: A dosage form releases a
discrete portion of drug at a time or times other than
promptly after administration, although one portion may be
released promptly after administration. Ex: Enteric coated
dosage forms.
International Journal of Pharmaceutical Sciences and Nanotechnology
Volume 2 Issue 3 October – December 2009
583
* For correspondence: Madhusudan Rao Yamsani,
Tel.: +91 870 2438844, Fax : +91 870 2453508
E-mail: yamsani123@gmail.com

584 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2  Issue 3 October - December 2009
Targeted Release Dosage Forms: A dosage forms that
releases drug at /near the intended physiological site of
action. Targeted release dosage forms may have extended
release characteristics.
Repeat Action Dosage Forms: It is a type of modified
release drug product that is designed to release one dose or
drug initially followed by a second dose of drug at a latter
time.
Prolonged Action Dosage Forms: It is designed to release
the drug slowly and to provide a continuous supply of drug
over an extended period.
Advantages of Sustained/Controlled
Release Dosage Forms:
 Reduction in dosing frequency.
 Reduced fluctuations in circulating drug levels.
 Avoidance of night time dosing.
 Increased patient compliance.
 More uniform effect.
Disadvantages of Sustained/Controlled
Release Dosage Forms:
 unpredictable or poor in vitro-in vivo correlation.
 Dose dumping.
 Reduced potential for dosage adjustment.
 Poor systemic availability in general.
Factors Governing the Design of
S.R /C.R Forms:
Physico-Chemical Properties
Molecular Size and Diffusivity:
A drug must diffuse through a variety of biological
membranes during its time course in the body. In addition
to diffusion through these biological membranes, drugs in
many extended-release systems must diffuse through a
rate-controlling polymeric membrane or matrix. The
ability of a drug to diffuse in polymers, its so-called
diffusivity (diffusion coefficient D), is a function of its
molecular size (or molecular weight). For most polymers,
it is possible to relate log D empirically to some function
of molecular size as
log D = -sv log u + kv = -sM log M + km
Where, v is molecular volume, M is molecular weight,
sv, sM, kv and km are constants. The value of D, thus is
related to the size and shape of the cavities as well as size
and shape of drugs. Generally, values of the diffusion
coefficient for drugs of intermediate molecular-weight (i.e,
150 to 400 Da) through flexible polymers range from 10-6
to 10-9 cm2/sec, with values in the order of 10-8 being most
common (Alfonso R., 2002). A value of approximately 10-6
is typical for these drugs through water as the medium.
For drugs with a molecular weight greater than 500 Da,
their diffusion coefficients in many polymers are
frequently so small that they are difficult to quantify (ie,
less than 10-12 cm2/sec). Thus, high-molecular-weight
drugs should be expected to display very slow release
kinetics in extended release devices using diffusion
through polymeric membranes or matrices as the releasing
mechanism (Joseph and Vincent, 2002).
Aqueous Solubility
Solubility is defined as the amount of material that remains
in solution in a given volume of solvent containing un-
dissolved material. It is the thermodynamic property of a
compound. The fraction of drug absorbed into the portal
blood is a function of the amount of drug in the solution in
the G.I tract, i.e., the intrinsic permeability of the drug
For a drug to be absorbed, it must dissolve in the aqueous
phase surrounding the site of administration and then
partition into the absorbing membrane. The aqueous
solubility of a drug influences its dissolution rate, which in
turn establishes its concentration in solution and, hence,
the driving force for diffusion across membranes.
Dissolution rate is related to aqueous solubility, as shown
by the Noyes-Whitney equation that, under sink
conditions, is
dC/dt = kD A.Cs …..(1)
where dc/dt is the dissolution rate, kD is the dissolution rate
constant, A is the total surface area of the drug particles,
and Cs is the aqueous saturation solubility of the drug. The
dissolution rate is constant only if a remains constant, but
the important point to note is that the initial rate is directly
proportional to Cs. Therefore, the aqueous solubility of a
drug can be used as a first approximation of its dissolution
rate. Drugs with low aqueous solubility have low
dissolution rates and usually suffer from oral
bioavailability problems.
The aqueous solubility of weak acids or bases is
governed by the pKa of the compound and the pH of the
medium. For a weak acid
S
t = S0(1+Ka/[H+]) = S0(1+10pH-pKa) …..(2)
Where St is the total solubility (both the ionized and
unionized forms) of the weak acid, S0 is the solubility of
the unionized form. Ka is the acid dissociation constant,
and [H+] is the hydrogen ion concentration in the medium.
Similarly, for a weak base
S
t = S0(1+[H+]/Ka) = S0(1+10pKa-pH) …..(3)
Where St is the total solubility (both the conjugate acid
and freebase forms) of the weak base, S0 is the solubility of
the free-base form, and Ka is the acid dissociation constant
of the conjugate acid, Equations 2 and 3 predict that the
total solubility of a weak acid or base with a given pKa can
be affected by the pH of the medium.

Ranjith Kumar Mamidala et al. : Factors Influencing the Design and Performance of… 585
Considering the pH partition hypothesis, the
importance of Equations 2 and 3 relative to drug
absorption is evident. The pH – partition hypothesis
simply states that the unionized form in the stomach (pH =
1 to 2), their absorption will be excellent in such an acidic
environment. On the other hand, weakly basic drugs exist
primarily in the ionized form (conjugate acid) at the same
site, and their absorption will be poor. In the upper portion
of the small intestine, the pH is more basic (pH = 5 to 7),
and the reverse will be expected for weak acids and bases.
The ratio of Equation 2 or 3 written for either the pH of the
gastric or intestinal fluid and the pH of blood is indicative
of the driving force for absorption based on pH gradient.
For example, consider the ratio of the total solubility of
aspirin in the blood and gastric fluid.
R = (1 + 10pHb-pKa)/(1+10pHg-pKa) …..(4)
Where pHb is the pH of blood (pH 7.4), pHg is the pH
of the gastric fluid (pH 2), and the pKa of aspirin is about
3.4. Substitution these values into Equation 4 gives a value
for R of 103.8, indicating that aspirin is readily absorbed
within the stomach. The same calculation for intestinal pH
(about 7) yields a ratio close to 1, indicating less driving
force for aspirin absorption within the small intestine.
Ideally, the release of an ionizable drug from an extended-
release system should be programmed in accordance with
the variation in pH of the different segments of the
gastrointestinal tract so that the amount of preferentially
absorbed forms, and thus the plasma level of the drug, will
be approximately constant throughout the time course of
drug action (Alfonso R., 2002).
The Bio-pharmaceutical Classification System (BCS)
allows estimation of likely contribution of three major
factors solubility, dissolution and intestinal permeability
which affect the oral drug absorption.
Classification of drugs according to BCS
Class I: High solubility-High permeability
Class II: Low solubility-High permeability
Class III: High solubility-Low permeability
Class IV: Low solubility-Low permeability
High solubility: Largest dose dissolves in 250 ml of water
over a pH range 1-8
High permeability: Extent of absorption is > 90%
Class III and Class IV drugs are poor candidates for
S.R/C.R dosage forms. Compound with solubility below
0.1mg/ml face significant solubilization obstacles, and
often compounds with solubility below 10mg/ml present
difficulties related to solubilization during formulation
(Bechgaard et al., 1978).
In general, extremes in aqueous solubility of a drug are
undesirable for formulation into an extended-release
product. A drug with very low solubility and a slow
dissolution rate will exhibit dissolution-limited absorption
and yield an inherently sustained blood level. In most
instances, formulation of such a drug into an extended-
release system may not provide considerable benefits over
conventional dosage forms. Even if a poorly soluble drug
were considered a candidate for formulation into an
extended-release system, a constraint would be placed on
the type of delivery system that could be used. For
example, any system relying on diffusion of the drug
through a polymer as the rate-limiting step in release
would be unsuitable for a poorly soluble drug, since the
driving force for diffusion is drug concentration in the
polymer or solution, and this concentration would be low.
For a drug with very high solubility and a rapid dissolution
rate, it is often quite difficult to decrease its dissolution rate
and slow its absorption (Madhukat et al., 2005). A drug of
high water solubility can dissolve in water or
gastrointestinal milieu readily and tends to release from its
dosage form in a burst and thus is absorbed quickly,
leading to a sharp increase in the drug blood concentration.
Compared to less soluble drugs, it is often difficult to
sequester a highly water soluble drug in the dosage form
(such as tablet) and retard the drug release, especially
when the drug dose is high. Preparing a slightly soluble
form of a drug with normally high solubility is one
possible method for producing extended –release dosage
forms (Guidance for Industry, 1997).
The pH dependent solubility, particularly in the
physiological pH range would be another problem for
S.R/C.R formulation because of the variation in the pH
throughout the gastro intestinal tract and hence variation in
dissolution rate. Ex: Phenytoin.
Examples of drugs which are poor candidates for
S.R/C.R release systems:
Drugs, limited in the absorption by their dissolution
rates are: Digoxin, Warfarin, Griseofulvin, and
Salicylamide.
 Drugs poorly soluble in the intestine (acid soluble
basic drugs) are: Diazepam, Diltiazem, Cinnarizine,
Chlordiazepoxide, and Chlorpheniramine.
Drugs having lower solubility in stomach:
Furosemide.
pKa - Ionization Constant
The pKa is a measure of the strength of an acid or a base.
The pKa allows us to determine the charge on a drug
molecule at any given pH. Drug molecules are active in
only the undissociated state and also unionized molecules
cross these lipoidal membranes much more rapidly than
the ionized species.

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The amount of drug that exists in unionized form is a
function of dissociation constant of a drug and pH of fluid
at absorption site. For a drug to be absorbed, it must be in
unionized form at the absorption site. Drugs which exist in
ionized form at the absorption site are poor candidates for
sustained/controlled dosage forms (James et al., 2007).
Partition Coefficient
Partition coefficient influences not only the permeation of
drug across the biological membranes but also diffusion
across the rate controlling membrane or matrix.
Between the time when a drug is administered and
when it is eliminated form the body, it must diffuse
through a variety of biological membranes that act
primarily as lipid-like barriers. A major criterion in
evaluation of the ability of a drug to penetrate these lipid
membranes (i.e, its membrane permeability) in its apparent
oil/water partition coefficient, defined as
K = CO/CW …..(5)
Where CO is the equilibrium concentration of all forms
of the drug in an organic phase at equilibrium, and CW is
the equilibrium concentration of all forms in an aqueous
phase In general, drugs with extremely large values of K
are very oil-soluble and will partition into membranes
quite readily. The relationship between tissue permeation
and partition coefficient for the drug generally is defined
by the Hansch correlation, which describes a parabolic
relationship between the logarithm of the activity of a drug
or its ability to be absorbed and the logarithm of its
partition coefficient (Jain N.K., 1997). The explanation for
this relationship is that the activity of a drug is a function
of its ability to cross membranes and interact with the
receptor. As a first approximation, the more effectively a
drug crosses membranes, the greater its activity. There is
also an optimum partition coefficient below this optimum
result in decreased lipid solubility, and the drug will
remain localized in the first aqueous phase it contacts.
Values larger than the optimum result in poorer aqueous
solubility but enhanced lipid solubility, and the drug will
not partition out of the lipid membrane once it gets in. The
value of K at which optimum activity is observed is
approximately 1000/1 in n-octanol/water. Drugs with a
partition coefficient that is higher or lower than the
optimum are, in general, poorer candidates for formulation
into extended – release dosage forms.
Example: The third generation dihydro-pyridines have an
added additional property to this class of drugs: high
lipophilicity. Currently one of these drugs commercially
available is Lercanidipine. As a result of the lipophilic
character, this compound is relatively quickly cleared from
the plasma building up within phospholipid bilayer of cell
membranes. The dihydropyridine [DHP] thus accumulated
can interact with its target, the DHP site of target, the L –
type calcium channel which lies within the double layer of
the cell membrane as well. This phenomenon explains the
slow onset and long duration of action. The sustained
release of drugs which exhibit this type of property will
offer no special advantages over conventional dosage
forms. (Gasser R et al., 1999).
Stability
One important factor for the loss of drug is through acid
hydrolysis and/or metabolism in the GIT when
administered orally. It is possible to significantly improve
the relative bioavailability of a drug that is unstable in G.I.
by placing it in a slowly available controlled release form.
For those drugs that are unstable in the stomach the most
appropriate controlling unit would be one that release its
contents only in the intestine. The release in the case for
those drugs that are unstable in the environment of the
intestine, the most appropriate controlling such a in this
case would be one that releases its contents, only in the
stomach. So, drugs with significant stability problems in
any particular area of the G.I. tract are less suitable for
formulation into controlled release systems that deliver the
contents uniformly over the length of GIT (Venkataraman
et al., 2000; Wagner., 1971).
Acid unstable drugs (stomach):
Examples: Rabeprazole, pantoprazole, omeprazole,
lansoprazole, esomeprazole, rifamipicin, mesalazine,
erythromycin, riboflavin
Alkaline unstable drugs (drugs that are unstable in
intestine and colon):
Ex: Captopril, Ranitidine.
Pharmacokinetic and Pharmacodynamic
Considerations
Release Rate and Dose
Conventional dosage forms include solutions, suspensions,
capsules, tablets, emulsions, aerosols, foams, ointments,
and suppositories. For purposes of this discussion, these
dosage forms can be considered to release these active
ingredients into an absorption pool immediately. This is
illustrated by the following simple kinetic scheme.

Ranjith Kumar Mamidala et al. : Factors Influencing the Design and Performance of… 587
kr ka ke
Dosage form Absorption Pool Target Area
Drug release Absorption Elimination
The absorption pool represents a solution of the drug at
the site of absorption, and the terms kr , ka and ke are first
order rate constants for drug release, absorption, and
overall elimination, respectively. Immediate release from
a conventional dosage form implies that kr>>>ka or,
alternatively, that absorption of drug across a biological
membrane, such as the intestinal epithelium, is the rate-
limiting step in delivery of the drug to its target area. For
non immediate-release dosage forms, kr<<<kw that is,
release of drug from the dosage form is the rate-limiting
step. This causes the above kinetic scheme to reduce to
kr ke
Dosage form Target Area
Drug release Elimination
Essentially, the absorptive phase of the kinetic scheme
becomes insignificant compared with the drug release
phase. Thus, the effort to develop a non-immediate-release
delivery system must be directed primarily to altering the
release rate by affecting the value of kr.
Although it is not necessary or desirable to maintain a
constant level of drug in the blood or target tissue for all
therapeutic cases, this is the ideal starting goal of an
extended-release delivery system. In fact, in some cases
optimum therapy is achieved by providing oscillating,
rather than constant drug levels. An example of this is
antibiotic therapy, where the activity of the drug is
required only during the growth phase of the
microorganism (Higuchi. T., 1963).
The ideal goal in designing an extended-release system
is to deliver drug to the desired site at a rate according to
the needs of the body (i.e., a self-regulated system based
on feedback control). However, this is a difficult
assignment. Although some attempts have been made to
achieve this goal, such as with the self-regulating insulin
pump, there is no commercial product representing this
type of system as yet. In the absence of feed back control,
we are left with a simple extending effect. The pivotal
question is at what rate should a drug be delivered to
maintain a constant blood drug level. This constant rate
should be the same as that achieved by continuous
intravenous infusion where a drug is provided to the
patient at a constant rate just equal to its rate of
elimination. This implies that the rate of delivery must be
independent of the amount of drug remaining in the dosage
form and constant over time. That is, release from the
dosage form should follow zero-order kinetics, as shown
by
K
0
r=Rate In = Rate Out = ke.Cd.Vd
Where k
0
r is the zero-order rate constant for drug
release (amount/time), ke is the first-order rate constant for
overall drug elimination (time-1), Cd is the desired drug
level in the body (amount/volume), and Vd is the volume of
the space in which the drug is distributed. The values of
ke, Cd, and Vd needed to calculate kr
0 are obtained from
appropriately designed single-dose pharmacokinetic
studies. The above equation provides the method to
calculate the zero-order release rate constant necessary to
maintain a constant drug blood or tissue level for the
simplest case, where drug is eliminated by first order
kinetics. For many drugs, however, more complex
elimination kinetics and other factors affecting their
disposition are involved. This in turn affects the nature of
the release kinetics necessary to maintain a constant drug
blood level (Chien Y W., 1992). It is important to
recognize that while zero-order release may be desirable
theoretically, non-zero-order release may be equivalent
clinically to constant release in many cases. Aside from
the extent of intra and inter subject variation is the
observation that for many drugs, modest changes in drug
tissue levels do not result in an improvement in clinical
performance. Thus, a non-constant drug level may be
indistinguishable clinically from a constant drug level.
To achieve a therapeutic level promptly and sustain the
level for a given period of time, the dosage form generally
consists of two parts: an initial priming dose, Di, that
releases drug immediately, and a maintenance or
sustaining dose, Dm. The total dose, W, thus required for
the system is
W = Di + Dm
For a system in which the maintenance dose releases
drug by a zero-order process for a specified period of time,
the total dose is
W = Di + kr
0Td – kr
0Tp
Where Td is the total time required for extended release
from one dose. If the maintenance dose begins release of
drug at the time of dosing (t = 0), it will add to that which
is provided by the initial dose, thus increasing the initial
drug level. In this case a correction factor is needed to
account for the added drug from the maintenance dose
W = Di + kr
0Td – Kr
0Tp
The correction factor kr
0Tp is the amount of drug
provided during the period from t = 0 to the time of the
peak drug level, Tp. No correction factor is needed if the
dosage form is constructed in such a fashion that the
maintenance dose does not begin to release drug until time
Tp.

588 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2  Issue 3 October - December 2009
It already has been mentioned that a perfectly invariant
drug blood or tissue level versus time profile is the ideal
starting goal of an extended release system. The way to
achieve this, in the simplest case, is use of a maintenance
dose that releases its drug by zero-order kinetics.
However, satisfactory approximations of a constant drug
level can be obtained by suitable combinations of the
initial dose and a maintenance dose that releases its drug
by a first – order process. The total dose for such a system
is
W = Di + (keCd / krVd)
Where kr is the first-order rate constant for drug release
(time-1), and ke, Cd, and Vd are as defined previously. If
the maintenance dose begins releasing drug at t = 0, a
correction factor is required just as in the zero-order case.
The correct expression in this case is
W = Di + (keCd/kr)Vd - DmkeTp
To maintain drug blood levels within the therapeutic
range over the entire time course of therapy, most
extended-release drug delivery systems are, like
conventional dosage forms, administered as multiple rather
than single doses. For an ideal extended-release system
that releases drug by zero-order kinetics, the multiple
dosing regimen is analogous to that used for a constant
intravenous infusion (Alfonso R., 2002).
Since an extended-release system is designed to
alleviate repetitive dosing, it naturally will contain a
greater amount of drug than a corresponding conventional
form. The typical administered dose of a drug in a
conventional dosage form will give some indication of the
total amount of drug needed in an extended release
preparation. For the drugs requiring large conventional
doses, the volume of the sustained dose may be too large to
be practical or acceptable, depending on the route of
administration. The same may be true of drugs that require
a large release rate from the extended-release system
(e.g.,drugs with short half-lives).
If the dose of a drug is high (e.g., those that requiring a
daily dose exceeding 500 mg), it becomes more
challenging to develop sustained release oral dosage forms.
For short half-life drugs, to provide a once a day tablet, it
requires not only that a large amount of drug to be
incorporated in a dosage unit to provide the daily dose, but
also the dosage units be small in size to allow for ease of
swallowing by the human. The requirement for small sizes
would leave little space in the dosage unit for other
ingredients needed to control the drug release. The size of
the dosage unit becomes even more critical with highly
water-soluble drugs since even a larger amount of inactive
ingradients (e.g., more than 50% of the total weight) is
usually needed to provide the sustained release property,
according to the conventional SR methods (Brahma &
Kim, 2007)
Biological Factors
Absorption
The rate, extent, and uniformity of absorption of a drug are
important factors when considering its formulation into an
extended release system. The most critical incase of oral
administration is Kr<<<Ka.. Assuming that the transit time
of drug through the absorptive area of gastrointestinal tract
is between 9-12 hours, the maximum absorption half-life
should be 3-4 hours. This corresponds to a minimum
absorption rate constant Ka value of 0.17-0.23/hr necessary
for about 80-95% absorption over a 9-12hr transit time
(Gilberts et al.,2001).
For a drug with a very slow rate of absorption
(Ka<<0.17/hr), the first order release rate constant Kr less
than 0.17/hr results in unacceptably poor bioavailability in
many patients. Therefore slowly absorbed drug will be
difficult to be formulated into extended release systems
where the criterion Kr<<<Ka must be met (Rudnic &
Schawartz., 2000). If the drug were erratically absorbed
because of variable absorptive surface of gastrointestinal
tract, design of the sustained/controlled release product
would be more difficult or prohibitive. Ex: The oral
anticoagulant – Dicoumarol, Iron
Drugs absorbed by active transport system are
unsuitable for sustained/controlled drug delivery
system: Methotrexate, Enalapril, Riboflavin,
Pyridoxine, 5-Fluorouracil,5-Bromo uracil,
Nicotinamide, Fexofenadine, Methyl-dopa.
 Drugs absorbed through amino acid transporters
in the intestine: Cephalosporines, Gabapentine,
Baclofen, Methyl-dopa, Levo-dopa.
Drugs transported through Oligo – peptide
transporters: Captopril, Lisinopril, Cephalexine,
Cefadroxil, Cefixime.
 Drugs required to exert a local therapeutic action
in the stomach are unsuitable for sustained
/controlled drug delivery.
Ex: Misoprostol, 5-fluorouracil, Antacids, anti-
helicobacter pylori agents.
Absorption Window
Some drugs display region specific absorption which is
related to differential drug solubility and stability in
different regions of G.I.T, as a result of changes in
environmental pH, degradation by enzymes, etc. These
drugs show absorption window, which signifies the region
of G.I tract where absorption primarily occurs. Drugs
released from sustained/controlled release systems, after

Ranjith Kumar Mamidala et al. : Factors Influencing the Design and Performance of… 589
absorption window has been crossed goes waste with
little/no negligible absorption. Hence absorption window
can limit the bioavailability of orally administered
compounds and can be a major obstacle to the
development of sustained/controlled release drugs (Stanley
S., 2005 and Sanjay., 2003).
Examples of Drugs exhibiting the site specific absorption
in stomach or upper parts of small intestine (absorption
window) are: Acyclovir, Captopril, Metformin,
Gabapentin, Atenolol, Furosemide, Ranitidine, Levo-dopa,
Sotalol, Salbutamol, Riboflavin, Sulfonamides, Loratadine,
Cephalosporines, Tetracyclines Verapamil, Thiamine,
Sulpiride, Baclofen, Nimesulide, Cyclosporine,
Quinolines.
Distribution
The distribution of a drug into vascular and extra vascular
spaces in the body is an important factor in the overall
elimination kinetics. Apparent volume of distribution and
ratio of drug in tissue to plasma (T/P) concentration are
used to describe the distribution characteristics of a drug.
For drugs which have apparent volume of distribution
higher than real volume of distribution i.e., drugs which
are extensively bound to extra vascular tissues eg:
chloroquine, the elimination half life is decreased i.e.,
the drug leaves the body gradually provided drug
elimination rate is limited by the release of drug from
tissue binding sites and that drug is released from the
tissues to give concentrations exceeding the threshold level
or within the therapeutic range, one can assume that such
drugs are inherently sustained. The larger the volume of
distribution, the more the drug is concentrated in the
tissues compared with the blood. It is the drug in the blood
that is exposed to hepatic or renal clearance, so that when
the distribution volume is large these mechanisms have
fewer drugs to work on. By contrast, if the volume of
distribution is small, most of the drug in the body is in the
blood and is accessible to the elimination process. Table 1
shows drugs with apparent volume of distribution
higher than total volume of distribution. To avoid the
ambiguity inherent in apparent volume of distribution as
estimation of amount of drug in body, the T/P ratio is used.
If the amount of drug in central compartment ‘P’ is known,
the amount of drug in peripheral compartment ‘T’ and
hence the total amount of drug in the body can be
calculated by
T/P = k12 (k 21 – β)
Where, β = slow disposition rate constant.
Table 1 Drugs with apparent volume of distribution
higher than total volume of distribution.
Drug App. Vol. Distribution (lts )
Chloroquine 12950
Digoxin 500
Doxepin 1400
Flurazepam 1540
Haloperidol 1400
Azythromycin 2170
Amiodarone 4620
T/P ratio estimates the relative distribution of drug
between compartments while Vdss estimated extent of drug
distribution in the body. Refer Table 2 for Relation ship
between Vdss and T/P ratio.
Table 2 Relationship between Vdss and T/P ratio.
Drug T/P ratio Vdss
Diazepam 2.85 130
Digoxin 4.3 500
Furosemide 0.96 5
Procainamide 14.35 62
Meperidine 2 3000
Theophylline 0.9 40
Yet no conclusion can be made on the importance of
volume of distribution at steady state and T/P ratio is
estimating distribution characteristics of drugs.
Undoubtedly, these parameters contribute to this aspect of
drug disposition. Table 3 mentions the use of T/P ratio in
conjuction with total body clearance at steady state to
gain further view into drug disposition (Joseph and
Vincent., 2002).
Table 3 Use of T/P ratio in conjuction with total body
clearance at steady state to gain further view into
drug disposition.
T/P
ratio
Total body
clearance Disposition characteristics
High High Weak tissue binding
High Low Strong tissue/protein binding
Low Low Strong protein binding
Low High
Weak plasma protein
binding

590 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2  Issue 3 October - December 2009
Metabolism
The metabolism of a drug can either inactivate an active
drug or convert an inactive drug to active metabolite.
Complex metabolic patterns would make the S.R/C.R
design much more difficult particularly when biological
activity is wholly or partly due to a metabolite as in case
isosorbide 2, 5-dinitrate.
There are two areas of concern related to metabolism
that significantly restrict SR product design. First, if a drug
upon chronic administration is capable of either inducing
or inhibiting enzyme synthesis, it will be a poor candidate
for a S/R/C.R product because of the difficulty of
maintaining uniform blood levels of a drug.
Second, if there is a variable blood level of a drug
through either intestinal (or tissue) metabolism or through
first pass effect, this also will make formulation of SR
dosage form difficult, since most of the process are
saturable, the fraction of the drug loss would be dose
dependent and that would result in significant reduction in
bioavailability if the drug is slowly released over a
extended period of time (Joseph and Vincent, 2002).
Fluctuating drug blood levels due to intestinal
metabolism upon oral dosing: Examples: Salicylamide,
Isoproterenol, Chlorpromazine, Clonazepam Hydralazine
and Levodopa.
Fluctuating drug blood levels due to first pass hepatic
metabolism upon oral dosing:
Ex: Nortriptyline, phenacetin, morphine, propranolol.
Fluctuating blood levels due to enzyme induction are
poor candidates for Sustained/controlled Release dosage
forms:
Ex: Griseofulvin, Phenytoin, Primidone, Barbiturates,
Rifampicin, Meprobamate, Cyclophosphamide.
Fluctuating blood levels due to enzyme inhibition are
poor candidates for Sustained/Controlled Release dosage
forms:
Ex: Isoniazid, Cimetidine, Amiodarone,Erythromycin,
Fluconazole, Ketoconazole, MAO –inhibitors, Para -
aminosalicyclic acid, Allopurinol, Coumarins.
Dose Dependent Bio-Availability
In case of Propoxyphene bio-availability is dose
dependent. Only 18% of 65mg dose, 28% of 130 mg dose,
33% of 195 mg dose reaches the systemic circulation due
to first pass effect. It makes the S.R/C.R dosage form less
desirable.
Elimination Half Life
Half life is the time taken for the amount of drug in the
body (or the plasma concentration) to fall by half and is
determined by both clearance (Cl) and volume of
distribution (VD)
t
1/2 = 0.693.Vd/Cl
Half life is increased by increasing in volume of
distribution or a decrease in clearance, and vice-versa. The
larger the volume of distribution the more the drug is
concentrated in the tissues compared with the blood. If the
volume of distribution is small, most of the drug in the
body is in the blood and is accelerated to the elimination
process. Refer table no. 4 for effect of clearance and
volume of distribution in determining half life (Joseph
and Vincent, 2002).
For drugs that follow linear kinetics, the elimination half-
life is constant and does not change with dose or drug
concentration. For drugs that follow non-linear kinetics,
the elimination half-life and drug clearance both change
with dose or drug concentration Drugs with short half-
lives (<2hrs) and high dose impose a constraint on
formulation into sustained/controlled release systems
because of the necessary dose size and drugs with long
half-lives (>8hr) are inherently sustained (Birkett,1998).
Sustained release products for drugs with intrinsically long
biologic half-lives are available. As expected, little or no
therapeutic advantages have been demonstrated in these
products over conventional dosage forms. Examples:
Meprobamate (11.3 hr), Amytriptyline (21 hr).
Table 4 Effect of clearance and volume of distribution in determining half-life.
DRUG CLEARANCE(L/HR) VOLUME OF
DISTRIBUTION(L) HALF - LIFE(HR)
Ethosuximide 0.7 49 48.0
Flucytosine 8.0 4.9 4.2
Digoxin 7.0 420 40.0
Morphine 63.0 280 3.0
Haloperidol 46.0 1400 20.0
Chloroquine 45.0 12950 200.0

Ranjith Kumar Mamidala et al. : Factors Influencing the Design and Performance of… 591
Sustained release corticosteroids are unnecessary from
the stand point of therapy, undesirable from the point of
view side effects, and un-physiological from that of the
diurnal variations in cortisol secretions. Infact, SR
formulations of prednisolone sodium phosphate and
methyl prednisolone have been shown to be equally
effective as conventional oral tablets offering no
advantages over the latter. Refer tables 5, 6 for examples
of drugs with extremely short half-lives and long half-
lives (Joseph and Vincent, 2002).
Table 5 Examples of drugs with extremely short
half-lives.
Drug Half-life (min.)
Pencillin G 45
Levodopa 45
Spiranolactone 10
Furosemide 29.5
Propylthiouracil 63
Cephalexin 54
Cloxacillin 90
Ampicillin 100
Table 6 Examples of drugs with very long half-lives.
Drug Halflife
(hr)
Drug Half-life
(hr)
Telmisartan 24 Chloroquine 200 hrs
Amlodipine 30-50 Clomiphene 5-7
Ethamsylate 72 Nabumetone 22
Etoricoxib 22 Amitryptilline 21
Carbamazepine 25-65 Digitoxin
Piroxicam 30-86 diazepam 30
Leflunomide 2weeks pimozide
Meloxicam 16.2 Sertralin 26
Drug -Protein Binding
The drug can bind to components like blood cells and
plasma proteins and also to tissue proteins and
macromolecules. Drug protein binding is a reversible
process. As the free drug concentration in the blood
decreases, the drug-protein complex dissociates to liberate
the free drug and maintain equilibrium. Due to this
reversible binding of a drug, the free drug levels of the
drug are maintained for long time in the blood leading to a
long biological half-life. A protein bound drug due to its
high molecular size is unable to enter into hepatocytes,
resulting in reduced metabolism. The bound drug is not
available as a substrate for liver enzymes there by further
reducing the rate of metabolism.
The glomerular capillaries do not permit the passage of
plasma-protein and drug protein complexes. Hence only
unbound drug is eliminated. The elimination half-life of
drugs generally increases when the percent of bound drug
to plasma increases. Such drugs need not be formulated
into sustained/controlled release formulations. Since blood
proteins are mostly re-circulated, not eliminated, high drug
protein binding can serve as a depot for drug producing a
prolonged drug action.
The role of protein binding as a factor in formulation of
S.R/C.R dosage forms can be explained by considering
angiotensin-II antagonist class of drugs. The drugs of this
class are highly protein bound (99%). Tasosartan is a
long acting AT-II receptor blocker with a protein binding
of 99.8%, while it’s long acting active metabolite
Enoltasosartan has a protein binding 99.9%.
In a study AT-II receptor blockade effect of single
doses of Tasosartan (100mg oral and 25mg iv) and
Enoltasosrtan (25mg IV) were compared. It was found that
tasosartan induced rapid and sustained blockade of AT-II
receptors. Tasosartan blocked 80% of AT-II receptors 1-2
hrs of drug administration and still had 40% effect at 32
hrs. In contrast the blockade induced by the Enoltasosartan
was markedly delayed and hardly reached 60-70% despite
i.v administration and high plasma levels. This delayed in
vivo blockade effect for Enoltasosartan appears to be due
to high and tight protein binding, leading to decrease in
affinity for receptors and slower receptor association rate
(Marc Maillard et al., 2005). Table no. 7 shows
pharmacokinetic parameters of some highly protein
bound drugs.

592 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2  Issue 3 October - December 2009
Table 7 Pharmacokinetic parameters of some highly protein bound drugs.
Drug Oral bio-
availability (%)
Plasma protein
binding (%)
Clearance
ml/min/kg
Volume of
distribution (lts/kg)
Biological
half life (hrs)
Amiodarone 46 99.98 1.9 66 25
Dilflunisal 90 99.9 0.1 0.1 11
Itraconazole 55 99.8 23 14 21
Nabumetone 35 >99 0.37 0.78 23
Duration of Action
Duration of action is the time period for which the blood
levels remain above the MEC and below the MSC levels
(or) more specifically within the therapeutic window.
Drugs acting for long duration are unsuitable candidates
for formulation into S.R/C.R forms.
Receptor occupation, Tissue binding, Half life,
Metabolism, Partition coefficient Irreversible binding to
cells are some parameters which are responsible for long
duration of action of drugs. Refer table no. 8 for receptor
occupation of some antihistamines which are related to
their long duration of action (Del cavillo et al., 2006).
Table 8 Receptor occupation of some antihistamines.
Parameter Desloratadine Fexofenadine Levocetirizine
Dose (mg) 5 120 5
Binding to plasma proteins (%) 85 65 91
Free drug C4h (nM) 1 174 28
Free drug C24h (nM) o.3 1.4 4
T1/2 (h) 27 14 8
Ki (nM) 0.4 10 3
Receptor occupation after 4 h (%) 71 95 90
Receptor occupation after 24 h (%) 43 12 57
Maximum wheal inhibition after 4 h (%) 34 100 100
Wheal inhibition after 24 h (%) 32 15 60
The long duration of action of ACE inhibitors is
determined by Plasma half-life and the Affinity of binding
to tissue ACE (Taylor S.H., 1990). Drugs with short
plasma half- life but high tissue binding such as quinapril
are active for 24 hrs. Other drugs such as lisinopril have
weaker tissue ACE binding but much long plasma half life
is also long acting. In contrast captopril which has
relatively short duration of action has weaker tissue ACE
binding and short plasma half life. Table no.9 shows
comparative properties of ACE-inhibitors (Taylor S.H.,
1990).
Proton pump inhibitors forms covalent bond with
parietal cells and is irreversible and inhibits acid secretion
for life period of bonded parietal cell (18-24 hrs).
Since inhibition lasts for 24 hrs or more these proton pump
inhibitors are dosed once daily and offer no significant
advantage if formulated in sustained release dosage form.
Therapeutic Index
It is most widely used to measure the margin of safety of a
drug.
TI = TD50 /ED50
The longer the value of TI, the safer the drug. Drugs
with very small value of Therapeutic index are poor
candidates for formulation into sustained release products.
A drug is considered to be safe if its T.I value is greater
than 10. Refer Table no 10 for T.I values of some drugs.

Ranjith Kumar Mamidala et al. : Factors Influencing the Design and Performance of… 593
Table 9 Comparative properties of ACE – Inhibitors.
Captopril Enalapril Lisinopril Perindopril Fosinopril Ramipril Quinapril Trandolapril
Prodrug No Yes No Yes Yes Yes Yes Yes
Effect of food on
Absorption Up to 35% Nil Nil Up to 35% Little Nil Up to 35% Delay
Initial plasma
half –life (approx) 2 hours 11 hours 13hours 9 hours 4 hours 17 hours 3 hours 22 hours
Tissue ACE
Binding (relative) + ++ ++ +++ ++ ++++ ++++ ++++
Dosage regimen
For hyper tension bid-tds od-bd od od od od od od
Table 10 Therapeutic Index values of some drugs.
Drug Therapeutic Index
Aprobarbital 5.3
Phenobarbital 2.6
Digoxin 1.5-2
Conclusion
Extremes of aqueous solubility, oil/water partition
coefficient, tissue binding, extensive metabolism/
degradation of drug during transit, narrow therapeutic
index and absorption window are some of the limiting
factors in formulating effective sustained release products.
Theoretically each of these limitations can be overcome
and successful controlled drug delivery can be
accomplished by using physical, chemical and biomedical
engineering approaches alone or in combination.
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