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Overview on Controlled Release

Dosage Form
Ahmad Dzulfikri Nurhan

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BIPHASIC DRUG DELIVERY IN CONT ROLLED RELEASE FORMULAT IONS – A REVIEW

Srinivasa Rao Avanapu
International Journal of Pharma Sciences
Vol. 3, No. 4 (2013): 258-269
Review Article
Open Access
ISSN: 2320-6810

Overview on Controlled Release Dosage Form

Sathish Ummadi, B. Shravani, N. G. Raghavendra Rao*, M. Srikanth Reddy, B. Sanjeev
Nayak
Department of Pharmaceutics, Jyothishmathi Institute of Pharmaceutical Science, Thimmapur, Karimnagar - 505481, AP. India

* Corresponding author: N. G. Raghavendra Rao; e-mail: ngraghu@rediffmail.com

Received: 15 May 2013 Accepted: 26 June 2013 Online: 05 July 2013

ABSTRACT
An appropriately designed controlled release drug delivery system can be a major advance towards solving
problems concerning the targeting of a drug to a specific organ or tissue and controlling the rate of drug delivery
to the target site. The development of oral controlled release system has been a challenge to formulation scientist
due to their inability to restrain and localize the system at targeted areas of the gastrointestinal tract. Matrix type
drug delivery system is an interesting and promising option when developing an oral controlled release system.
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-pharmaceutics, pharmacokinetic and
pharmacodynamics 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: Controlled release system, Drug release mechanisms, In vitro drug release characterization
models, Absorption window

INTRODUCTION 2) A typical peak-valley plasma conc. time profile

Oral drug delivery is the most widely utilized route of is obtained which makes attainment of steady
administration among all the routes that have been state condition difficult.
explored for systemic delivery of drugs via 3) The unavoidable fluctuations in the drug
pharmaceutical products of different dosage form. Oral concentration may lead to under medication or
route is considered most natural, convenient and safe over medication as the Css values fall or rise
due to its ease of administration, patient acceptance, beyond the therapeutic range.
and cost effective manufacturing process.
Pharmaceutical products designed for oral delivery are The fluctuating drug levels may lead to precipitation of
mainly immediate release type or conventional drug adverse effects especially of a drug with small
delivery systems, which are designed for immediate therapeutic index, whenever over medication occurs.
release of drug for rapid absorption [1, 2].
Terminology
These immediate release dosage forms have some Controlled drug delivery or modified release delivery
limitations such as: systems may be defined as follows:-
1) Drugs with short half-life require frequent
administration, which increases chances of Controlled release formulation:
missing dose of drug leading to poor patient The controlled release system is to deliver a constant
compliance. 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

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eliminated by the body. An ideal Controlled drug Drug plasma levels are maintained within a narrow
delivery system is the one, which delivers the drugs at a window with no sharp peaks and with AUC of plasma
predetermined rate, locally or systematically, for a concentration Vs time curve comparable with total AUC
specific period of time. from multiple dosing with immediate release dosage
form.
Repeat action preparations:
A dose of the drug initially is released immediately 3] Patient comfort and compliance:
after administration, which is usually equivalent to a Oral drug delivery is the most common and convenient
single dose of the conventional drug formulation. After for patient and a reduction in dosing frequency
a certain period of time, a second single dose is enhances compliance.
released. In some preparation, a third single dose is
released after a certain time has elapsed, following the 4] Reduction in Health care cost:
second dose [3, 4]. The total cost of therapy of the controlled release
product could be comparable or lower than the
Advantage: it provides the convenience of supplying immediate release product with reduction in side
additional Dose or doses without the need of re- effects. The overall expense in disease management
administration. also would be reduced. This greatly reduces the
possibility of side effects, as the scale of side effects
Disadvantage: that the blood levels still exhibit the increases as we approach the maximum safe
“Peak and valley” characteristic of conventional concentration.
intermittent drug therapy.
Avoid night time dosing: It also good for patients to
Extended-Release formulation: Extended-Release avoid the at night time.
formulations are usually designed to reduce dose
frequency and maintain relatively constant or flat DISADVANTAGES [9]
plasma drug concentration. This helps avoid the side 1] Dose dumping:
effects associated with high concentration. Dose dumping is a phenomenon whereby relatively
large quantity of drug in a controlled release
Delayed release preparations: The drug is released at a formulation is rapidly released, introducing potentially
later time after administration. The delayed action is toxic quantity of the drug into systemic circulation.
achieved by the incorporation of a special coat, such as Dose dumping can lead to fatalities in case of potent
enteric coating, or other time barriers such as the drugs, which have a narrow therapeutic index.
formaldehyde treatment of soft and hard gelatin
capsules. The purposes of such preparations are to 2] Less flexibility in accurate dose adjustment:
prevent side effects related to the drug presence in the In conventional dosage forms, dose adjustments are
stomach, protect the drug from degradation in the much simpler e.g. tablet can be divided into two
highly acidic pH of the gastric fluid [5]. fractions. In case of controlled release dosage forms,
this appears to be much more complicated. Controlled
Site specific targeting: These systems refer to targeting release property may get lost, if dosage form is
of a drug directly to a certain biological location. In fractured.
this case the target is adjacent to or in the diseased
organ or tissue. 3] Poor In-vitro In-vivo correlation:
In controlled release dosage form, the rate of drug
Receptor targeting: These systems refer to targeting of release is deliberately reduced to achieve drug release
a drug directly to a certain biological location. In this possibly over a large region of gastrointestinal tract.
case the target is the particular receptor for a drug with Here the so- called ‘absorption window’ becomes
in organ or tissue. Site specific targeting and receptor important and may give rise to unsatisfactory drug
targeting systems satisfy the spatial aspect of drug absorption in-vivo despite excellent in-vitro release
delivery and are also considered to be controlled drug characteristics.
delivery systems [6].
4] Increased potential for first pass clearance:
Advantages of Controlled Release Drug Delivery Hepatic clearance is a saturable process. After oral
System [7,8] dosing, the drug reaches the liver via portal vein. The
1] Therapeutic advantage: concentration of drug reaching the liver dictates the
Reduction in drug plasma level fluctuation, amount metabolized. Higher the drug concentration,
maintenance of a steady plasma level of the drug over a greater is the amount required for saturating an
prolonged time period, ideally simulating an enzyme surface in the liver. Conversely, smaller the
intravenous infusion of a drug. concentration found with the controlled release and a
sustained release dosage form, lesser is the
2] Reduction in adverse side effects and improvement in possibility of saturating the enzyme surface. The
tolerability: possibility of reduced drug availability due to the first
pass metabolism is therefore greater with

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controlled release and sustained released important factor is properties of the drug that are as
formulation than with conventional dosage form. follows.

5] Patient variation: A] Physicochemical properties:

The time period required for absorption of drug 1] Aqueous solubility and pKa:
released from the dosage form may vary among Absorption of poorly soluble drugs is often dissolution
individuals. Co-administration of other drugs, presence rate-limited. Such drugs do not require any further
or absence of food and residence time in control over their dissolution rate and thus may not
gastrointestinal tract is different among patients. This seem to be good candidates for oral controlled release
also gives rise to variation in clinical response among formulations. Controlled release formulations of such
the patients. drugs may be aimed at making their dissolution
more uniform rather than reducing it.
6] Administration of controlled release medication
does not permit prompt termination of therapy. 2] Partition coefficient:
Immediate changes in drug levels during therapy, Drugs that are very lipid soluble or very water-soluble
such as might be encountered if significant adverse i.e., extremes in partition coefficient, will demonstrate
effects are noted, can not be accommodated. either low flux into the tissues or rapid flux followed by
accumulation in tissues. Both cases are undesirable for
7] There is danger of an ineffective action or even sustained release system.
absence of it if the therapeutic substance is poorly
absorbed from GIT. 3] Stability of the drug:
Since most oral controlled release systems are designed
8] Therapeutic agents for which single dose exceeds to release their contents over much of the length of GI
1 gm, the technical process requirements may make tract, drugs that are unstable in the environment of the
te product very difficult or sometimes impossible to intestine might be difficult to formulate into prolonged
prepare. release system.

9] Therapeutical agents which absorbed by active 4] Size of the dose:

transport are not good candidates for controlled For drugs with an elimination half-life of less than 2
release dosage form e. g. Riboflavin. hours as well as those administered in large dosages, a
controlled release dosage form may need to carry a
10] Economic factors must also be taken into account, prohibitively large quantity of drug.
since more costly processes and equipments are
involved in manufacturing of many controlled release 5] Molecular size and diffusivity:
dosage forms. In addition to diffusion through a variety of biological
membranes, drugs in many sustained release systems
While selecting a drug candidate for sustained release must diffuse through a rate controlling membrane or
system we must be careful. Drugs having fallowing matrix. The ability of drug to pass through membranes,
characteristics are not suitable for sustained release its so called diffusivity, is a function of its molecular
systems: size (or molecular weight). An important influence
1. Those which are not effectively absorbed in the upon the value of diffusivity, D, in polymers is the
lower intestine molecular size of the diffusing species. The value of D
2. Those having short biological half-lives (<1hr) e.g. thus is related to the size and shape of the cavities as
Furosemide well as size and shape of the drugs.
3. Those having long biological half-lives (>12hrs) e.g.
diazepam Generally, the values of diffusion coefficient for
4. Those for whom large dose is required e.g. intermediate molecular weight drugs i.e., 150-400,
sulphonamides through flexible polymers range from 10-6 to 10-9
5. Those with low therapeutic indices e.g. cm2/sec, with values on the order of 10-8 being most
Phenobarbital common. For drugs with molecular weight greater than
6. Those for which no clear advantage of sustained 500, the diffusion coefficients in many polymers
release system e.g. griseofulvin. frequently are so small that they are difficult to
7. Those with extensive first pass metabolism. quantify, i.e., less than 10-12 cm2/sec. Thus high
8. Those candidates with low solubility and/or active molecular weight of drug should be expected to
absorption display very slow release kinetics in sustained
release devices where diffusion through polymeric
Drug properties influencing the dosage form [10 – membrane or matrix is the release mechanism.
12]:
The design of a controlled release system depends on B] Biological properties:
various factors such as the route of delivery, the type of 1] Absorption:
drug delivery system, the disease being treated, the Slowly absorbed drugs or the drugs absorbed with a
length of therapy, and the properties of the drug. Most variable absorption rate are poor candidates for a

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controlled release system. Water-soluble but poorly Where TD50 is median toxic dose
absorbed potent drugs and those absorbed by carrier ED50 is median effective dose
mediated transport processes or absorbed through
window are poor candidates for controlled release In general, larger the value of TI, safer is the drug.
system. Drugs with very small values of TI usually are poor
candidates for formulation into CR products
2] Metabolism: primarily because of technological limitations of
Drug metabolism can result in either inactivation of an precise control over release rates. A drug is considered
active drug or conversion of an inactive drug to an to be relatively safe if its TI value exceeds 10.
active metabolite. The process of metabolism can take
place in variety of tissues but the organ mainly 5] Protein binding:
responsible for metabolism is liver as it contains The characteristics of protein binding by a drug can
variety of enzyme systems and thus greatest metabolic play a significant role in its therapeutic effect,
alteration of a drug takes place after its absorption into regardless of the type of dosage form. Extensive
the systemic circulation. Thus the metabolic pattern of binding to plasma proteins will be evidenced by a long
a drug may influence the choice of the route of half-life of elimination for the drug, and such drugs
administration. generally do not require a sustained release dosage
form.
There are two factors associated with metabolism
that significantly limit controlled release product 6] Disease state:
design. First, if a drug is capable of either inducing or Disease state is an important factor in considering a
inhibiting enzyme synthesis it will be difficult to drug for controlled release system. In some instances
maintain uniform blood levels of drug upon chronic better management of the disease can be achieved by
administration. Second, if the drug undergoes intestinal formulating the drug as controlled release system. For
(or other tissue) metabolism or hepatic first pass example, in case of rheumatoid arthritis, sustained
metabolism, this also will result in fluctuating drug release form of aspirin would provide desired drug
blood levels. Examples of drugs that undergo intestinal blood levels, particularly throughout the night, thus
metabolism upon oral administration are hydralazine, relieving morning stiffness. Other examples include
salicylamide, nitroglycerin, isoproterenol, nitroglycerin in the management of angina pectoris and
chlorpromazine, and levodopa. Examples of drugs belladonna alkaloids and synthetic anti-cholinergics in
that undergo hepatic first pass metabolism are; the treatment of peptic ulcers.
propoxyphene, nortriptyline, phenacetin, propranolol
and lidocaine. Successful controlled release products 7] Circadian rhythm:
for drugs that are extensively metabolized can be Many biological parameters like liver enzyme activity,
generated as long as the location, rate and extent and blood pressure, intraocular pressure and some
metabolism are known and the rate constant(s) are not disease states like asthma, acute myocardial
too large. It can be assumed that a controlled release insufficiency, and epileptic seizures have been shown
product can be developed as long as the metabolism to be influenced by circadian rhythm. Hence the
remains predictable. response to certain drugs like digitalis glycosides,
diuretics, amphetamines, barbiturates, carbamazepine,
3] Elimination or Biological half-life: ethyl alcohol, and chlordiazepoxide display time-
The rate of elimination of drug is described dependent nature.
quantitatively by its biological half- life. The biological
half-life and hence the duration of action of a drug plays ORAL CONTROLLED – RELEASE PRODUCTS [13]:
a major role in considering a drug for controlled Based on the release mechanism these are
release systems. Drugs with short half-life and high classified as follows:-
dose impose a constraint because of the dose size 1. Diffusion-controlled products.
needed and those with long half-lives are inherently 2. Dissolution-controlled products.
controlled. 3. Erosion products.
4. Osmotic pump systems.
4] Safety considerations and Side effects: 5. Ion exchange resins.
For certain drugs the incidence of side effects is
believed to be a function of plasma concentration. A 1. Diffusion – Controlled products [14]
controlled release system can, at times, minimize side In these systems, there is water – insoluble polymer
effects for a particular drug by controlling its plasma which controls the flow of water and the subsequent
concentration and using less total drug over the time release of dissolved drug from the dosage form.
course of therapy. The most widely used measure of the Diffusion occurs when a drug passes through the
margin of safety of a drug is its therapeutic index (TI), polymer that forms the controlled release device. The
which is defined as diffusion can occur through pores in the polymer
matrix or by passing between polymer chains. These
TI = TD50/ED50 are broadly divided into two categories:-

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A. Reservoir Devices. b) Matrix Dissolution control:

B. Matrix Devices. In this system an alternative approach is to compress
The basic mechanisms of drug release from these two the drug with a slow dissolving carrier. Here the rate of
systems are fundamentally different. drug release is controlled by the rate of penetration of
the dissolution fluid into the matrix, porosity, presence
A. Reservoir Devices: of hydrophobic additives and the wet ability of system
In this system a water insoluble polymeric material and surface of particle.
encases a core of drug. Drug will partition into the
membrane and exchange with the fluid surrounding the 3. Erosion products
particles (or) tablet. The active agent is released to the In this system drug or active agents are mixed with
surrounding environment by diffusion process through biodegradable polymers. These materials degrade
the rate limiting membrane. In the reservoir systems within the body as a result of natural biological
the drug delivery rate remains fairly constant. processes and drug release occurs at constant rate.
Most biodegradable polymers are designed to degrade
B. Matrix Devices: as a result of hydrolysis of the polymer chains into
In the matrix devices the drug or active is dispersed in biologically acceptable and progressively smaller
polymer matrix to form a homogeneous system known compounds. The release if drug from these products is
as a matrix system. Diffusion occurs when the drug controlled by the erosion rate of a carrier matrix. The
passes from the polymer matrix into the external rate of release is determined by the rate of erosion.
environment. As the release continues, its rate
normally decreases with this type of system, since the 4. Osmotic pump systems
active agent has a progressively longer distance to The osmotic pump is similar to a reservoir device but
travel and therefore requires a longer diffusion time to contains an osmotic agent (e.g., the active agent in salt
release. form) which acts to imbibe water from the surrounding
medium via a semi-permeable membrane. Pressure is
2. Dissolution-controlled products generated within the device which forces the active
In these products, the rate of dissolution of the drug is agent out of the device via an orifice (of a size designed
controlled by slowly soluble polymers or by micro to minimize solute diffusion, whilst preventing the
encapsulation. Once the coating is dissolved, the drug build-up of a hydrostatic pressure head which has the
becomes available for dissolution. By varying the effect of decreasing the osmotic pressure and changing
thicknesses of the coat and its composition, the rate of the dimensions{volume} of the device). The advantage
drug release can be controlled. Some preparations of this type of product is that the constant release is
contain a fraction of the total dose as an immediate- unaltered by the environment of the gastrointestinal
release component to provide a pulse dose soon after tract and relies simply on the passage of water into the
administration. The pellet dosage forms of diffusion- or dosage form. The rate of release can be modified by
dissolution- controlled products can be encapsulated or altering the osmotic agent and the size of the hole.
prepared as a tablet. Dissolution-controlled products
can be sub-divided into two types:- 5. Ion exchange resins
Drug-resin complexes (“resonates”) for extended
a) Encapsulation Dissolution controls. release are known and have been successfully used
b) Matrix Dissolution control. commercially. The drug is bound to the resin and
released by exchanging with appropriately charged
a) Encapsulation Dissolution control: ions in contact with the ion exchange groups. This
These systems method involves coating of individual technique is applicable to certain drugs which have
particles (or) granules of drug with a slow dissolving particular characteristics in terms of their relatively
material. The coated particles can be compressed affinity for the polymers being used.
directly into tablets (or) placed in capsules. The rate of
dissolution of the drug (and thereby availability for Rationale of controlled drug delivery system
absorption) is controlled by micro encapsulation. Once The basic rationale for controlled drug delivery is to
the coating is dissolved, the drug becomes available for alter the pharmacokinetics and pharmacodynamics of
dissolution. By varying the thicknesses of the coat and pharmacologically active moieties by using novel drug
its composition, the rate of drug release can be delivery systems or by modifying the molecular
controlled. These products should not be chewed as the structure and/or physiological parameters inherent in
coating may be damaged. One of the advantages of a selected route of administration. Thus, optimal design
encapsulated pelleted products is that the onset of of controlled release systems necessitates a thorough
absorption is less sensitive to stomach emptying. The understanding of the pharmacokinetics and
entrance of the pellets into the small intestine (where pharmacodynamics of drug [15].
the majority of drug absorption occurs) is usually more
uniform than with non-disintegrating sustained-release However, when doses are not administered on
tablet formulations. schedule, the resulting peaks and valleys reflect less
than optimum drug therapy. For example, if doses are
administered too frequently, minimum toxic

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concentration (MTC) of drug may be reached with toxic dissolution of polymer chains. At intermediate times,
side effects resulting. If doses are missed, periods of the gel layer may be of approximately constant
sub-therapeutic drug blood levels or those below the thickness, and release occurs at a relatively constant
minimum effective concentration (MEC) may result, rate.
with no patient benefit.
As an alternative to dissolution/partition/diffusion
Extended release tablets and capsules are commonly based devices, osmotic pumps have been developed to
taken only once or twice daily compared with provide zero order release. An elementary osmotic
counterpart conventional forms that may need to be pump, illustrated in Fig 3, is a tablet or capsule
taken three to four times daily to achieve the same consisting of a core of drug surrounded by a membrane
therapeutic effect. Typically, extended release products that is permeable to water but not to the drug. A small
provide an immediate release of drug which then is hole is drilled into the membrane. Upon ingestion,
followed by the gradual and continual release of water is osmotically imbibed into the core through the
additional amounts of drug to maintain this effect over semi permeable membrane, dissolving the drug. A
a predetermined period of time (Fig 1) [16]. constant osmotic pressure gradient is established
between core and the external medium, setting the
stage for water influx, which displaces drug through the
hole at a constant rate. Eventually, drug concentration
falls below its solubility, and the rate of osmotic
pumping decays.

The efficiency of osmotic devices can be improved by

enriching the core with excipients such as water
soluble polymers. For example, in push-pull osmotic
systems, depicted in Fig 3c, the drug formulation is
layered between the water soluble polymer and the exit
orifice. As water crosses the semi permeable
Figure 2. Characteristic representation of plasma membrane, drug is dissolved. Meanwhile, swelling of
concentrations of a conventional immediate release dosage the polymer excipients, which is also caused by
form (IR), a sustained release dosage form (SR) and an osmosis, pushes drug through the orifice
idealized zero-order controlled release (ZOCR) dosage form
(in combination with a start-up dose).

Drug-candidates suitable for sustained release

products [17]
For a successful sustained-release product, the drug
must be released from the dosage form at a
predetermined rate, dissolve in the gastrointestinal
fluids, maintain sufficient gastrointestinal residence
time, and be absorbed at a rate that will replace the
amount of drug being metabolized and excreted.

Zero order oral drug release can be achieved, in

principle, by surrounding a core tablet with a
membrane that is permeable to both drug and water, as
illustrated in Fig 3a. After swallowing, the core
becomes hydrated, and drug dissolves until it reaches
its saturation concentration or solubility. The core
serves as a saturated reservoir of drug. Drug release
proceeds by partitioning from the reservoir into the
membrane, followed by diffusion across the membrane
into the gastrointestinal fluid. So long as saturation is
maintained in the core, there will be a stationary
concentration gradient across the membrane, and
release will proceed at constant rate. Eventually, the
dissolved drug’s concentration in the core falls below
saturation, reducing the concentration gradient and
hence the release rate, which decays to zero. If the Figure 3. Schematics of devices designed for zero-order drug
membrane consists of a water-soluble polymer of high release. (a) Membrane diffusion controlled release. Drug in
molecular weight, then it will initially swell into a gel, core (granulated pattern) dissolves to form saturated solution
through which drug diffuses. The thickness of the gel (dilute dots). Drug then diffuses across membrane (thin
tipped arrows). (b) Elementary osmotic pump. Core is
layer initially increases with time due to swelling, but
ultimately it decreases due to disentanglement and

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surrounded by a semipermeable membrane, with a small,  Mixing with lubricant and disintegrant
drilled orifice. (c) Push–pull osmotic pump.  Compression of tablet.

PREFORMULATION STUDIES [18] 3) Sintering Technique

Preformulation testing is an investigation of physical  Sintering is defined as the bonding of adjacent
and chemical properties of drug substances alone and particle surfaces in a mass of powder, or in a
when combined with pharmaceutical excipients. It is compact, by the application of heat.
the first step in the rational development of dosage  Conventional sintering involves the heating of a
form. compact at a temperature below the melting
point of the solid constituents in a controlled
a) Determination of Melting Point: Melting point of environment under atmospheric pressure.
drug was determined by capillary method. Fine powder  The changes in the hardness and disintegration
of drug was filled in a glass capillary tube (previously time of tablets stored at elevated temperatures
sealed at one end). The capillary tube is tied to were described as a result of sintering.
thermometer and the thermometer was placed in the  The sintering process has been used for the
Thais tube and this tube is placed on fire. The powder fabrication of sustained release matrix tablets
at what temperature it will melt was noticed. for the stabilization of drug release.

b) Solubility: Solubility of drug was determined in pH FACTORS AFFECTING DRUG RELEASE [20]
1.2 and pH 6.8 buffers. Solubility Studies were Various factors could be accounted for the drug
performed by taking excess amount of drug in beakers release mechanism from hydrophilic matrices. These
containing the Solvents. The mixtures were shaken for factors include ; geometry of matrix , particle size of
24 hrs at regular intervals. The solutions were filtered polymers , matrix swelling ratio (which depend on
by using whattmann’s filter paper grade no. 41. The polymer type and controls water and drug diffusion
filtered solutions are analyzed spectrophotometrically coefficients),polymer and drug concentration , chain
at 260.5nm as pH 1.2 as blank and 262.4nm as pH 6.8 length and degree of substitution on HPMC as well as
as blank. drug characteristics.

c) Compatibility Studies: Compatibility study with The study of the drug release from the hydrophilic
excipients was carried out by FTIR. The pure drug and matrices requires knowledge of properties and
its formulations along with excipients were subjected interaction of the polymers used as the binder.
to FTIR studies. In the present study, the potassium
bromide disc (pellet) method was employed. 1. Polymer hydration: Dissolution of a polymer
includes absorption/adsorption of water in more
d) Identification of Drug: Weigh accurately about 0.25 accessible place, rapture of polymer-polymer linking
gm, dissolve in 50 ml of carbon dioxide-free water and with the simultaneous forming of water- polymer
titrate with 0.1 M sodium hydroxide using phenol red linkage, separation of polymeric chain, swelling and
solution as indicator. Repeat the operation without the finally dispersion of polymeric chain in the dissolution
substance under examination. The difference between medium. The Methocel K polymer, because of low
the titrations represents the amount of sodium content of methoxy groups, hydrate quickly, which
hydroxide required. justifies its application in the controlled release
matrices. Larger sized fraction of HPMC can hydrates
Methods for Preparation of Controlled Release more rapidly than smaller fraction. The first minutes of
tablets [19] hydration are the most important because they
1) Wet Granulation Technique correspond to the time when the protective gel coat is
 Milling and gravitational mixing of drug, polymer formed around matrices containing HPMC.
and excipients.
 Preparation of binder solution 2. Polymer composition: The complex composition of
 Wet massing by addition of binder solution or polymer cellulose ether precedes several reactions, as
granulating solvent hydroxyl groups, that can be reacting covalently with
 Screening of wet mass. many species. Both mono and poly functional, in order
 Drying of the wet granules. to stabilize and insolubilize their structure. The
 Screening of dry granules intermolecular interaction include the formation of
 Blending with lubricant and disintegrant to acetal with non-functional aldehydes, formation of
produce “running powder” hemeacetal or acetal with dialdehyde, formation of
 Compression of tablet. ether or methylene link with reagent containing methyl
groups and formation of ether links with epoxies,
2) Dry Granulation Technique ethylene imines derivatives, ethylene imine derivatives,
 Milling and gravitational mixing of drug , sulfones, and labile chlorine compounds.
polymer and excipients
 Compression into slugs or roll compaction 3. Polymer viscosity: With cellulose ether, polymer
 Milling and screening of slugs and compacted viscosity is used as an indication of the matrix weight.
powder

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Increasing the molecular weight or viscosity of the decrease the tortuosity of the diffusion path of the drug.
polymers in the matrix formulation increasing the gel But tricalcium phosphate does not diffuse outward,
layer viscosity and thus slows the drug dissolution. Also but rather get entrapped within the matrix and
the greater dilution and erosion thus control the drug bring about an increase in the release of the drug by
dissolution. Viscosity of the gelling agent retards or the fact that its presence necessarily decreases the gum
hastens the initial process of hydration (without concentration.
altering the release rate). Works applying DSC allows
conclusion that temperature affect HPMC hydration. Scope of polymers in controlled drug delivery
With increase of gel temperature, the HPMC looses systems [21, 22]
hydration water fallowed by decrease in relative Various synthetic and natural polymers have been
viscosity. examined in drug delivery applications. The three
key advantages that polymeric drug delivery products
4. Drug solubility: Absorption of poorly soluble drugs can offer are:
is often dissolution rate limited. Such drug does not
require any further control over their dissolution rate; 1] Localized delivery of drug: The delivery system
during the Pre-formulation phase it is necessary to can be implanted directly at the site where drug action
determine drug solubility not only in water but also at is needed and hence systemic exposure of the drug can
various pH values. The aqueous and pH dependent be reduced. This becomes especially important for toxic
solubility is of important for drug release. The hydro drugs, which produce various systemic side effects
solubility of drug play an important role in drug release (such as the chemotherapeutic drugs).
mechanism, soluble drugs are generally released by
diffusion mechanism while insoluble drugs are 2] Sustained delivery of drug: The drug encapsulated
release by erosion mechanism. is released over extended periods and hence eliminates
the need for multiple doses. This feature can improve
5. Polymer drug proportion: Studies completed by patient compliance especially for drugs meant for
Salomen, E. Docker demonstrated that the release rate chronic indications which requires frequent
increase for lower amount of HPMC with slightly administrations.
soluble drug, the proportion is dependent on gel
consistency, since it is affected by gel proportion. 3] Stabilization of the drug: The incorporated
polymer can protect the drug from the physiological
6. Polymer: drug interaction: The evaluation of environment of GIT and hence improve its stability in-
water concentration profile was calculated from vivo. This particular feature makes this technology
HPMC matrices with different molecular Weights. attractive for the delivery of labile drugs such as
The Thermal analysis of cellulose ether polymer proteins.
demonstrated that the drug polymer interaction occurs
at hydrated gel layer around the matrix tablet and is Evaluation Parameters [23, 24]
partially responsible for the drug release modulation. 1) Pre Compression Parameters:
A. Bulk density (Db): It is the ratio of powder to
Ford et al developed studies using water soluble drugs bulk volume. The bulk density depends on particle size
(Promethazine hydrochloride) to valuate the distribution, shape and cohesiveness of particles.
temperature effect on the drug release from matrices Accurately weighed quantity of powder was carefully
with several degrees of viscosity and HPMC K15M, drug poured into graduated measuring cylinder through
release decreases with increase of HPMC content, and large funnel and volume was measured which is called
the increase in temperature leads to increase in drug initial bulk volume. Bulk density is expressed in gm/cc
release rate. and is given by,
Db = M / Vo
7. Tablet hardness and density: Tablet hardness did Where, Db = Bulk density (gm/cc)
not show marked difference in as evaluated by an in- M is the mass of powder (g)
vitro method. Ladipus et al utilized to compression Vo is the bulk volume of powder (cc)
forces and observed no significant difference in drug B. Tapped density (Dt): Ten grams of powder was
release patterns from tablets of different densities. introduced into a clean, dry 100ml measuring cylinder.
Valasco MV et al evaluated effect of compression force The cylinder was then tapped 100 times from a
on drug release from HPMC matrices and reported constant height and tapped volume was read. It is
independence of drug release with compression force. expressed in gm/cc and is given by,
Dt = M / Vt
8. Effect of diluents: The inclusion of water soluble Where, Dt = Tapped density (gm/cc)
diluents (lactose) and water insoluble diluents (tribasic M is the mass of powder (g)
calcium phosphate) in matrix tablets showed Vt is the tapped volume of powder (cc)
divergence in the release profile of drug, because of the C. Compressibility index: The compressibility of the
difference in the solubility of the diluents and their powder was determined by the Carr’s compressibility
subsequent effect on the tortuosity factor. As the water index.
soluble diluents dissolves, they diffuse outward and Carr’s index (%) = = b=(v/b) X100

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 U. Satish et. al. / Int J Pharma Sci. 2013, 3(4): 258-269

Table 1. Grading of powders for their flow properties value of the load at that point gives a measure of
according to carr’s index hardness of the tablet. Hardness was expressed in
S.No Carr’s Index Flow Properties Kg/cm2.
1 5-15 Excellent
2 12-15 Good C. Friability (F):
3 18-21 Fair to Passable Tablet strength was tested by Friabilator USP EF-2. Pre
4 23-30 Poor weighed tablets were allowed for 100 revolutions
5 33-38 Very Poor (4min), taken out and were dedusted. The percentage
6 >40 Very Very Poor
weight loss was calculated by rewriting the tablets. The
% friability was then calculated by,
D. Hausner ratio: Hausner ratio = tapped density/
bulk density
Values of Hausner ratio; < 1.25: good flow
>1.25: poor flow
If Hausner ratio is between 1.25-1.5, flow can be
improved by addition of glidants.
D. Weight variation test [26]:
E. Angle of repose (θ): It is defined as the maximum
The weight of the tablet being made in routinely
angle possible between the surface of pile of the
measured to ensure that a tablet contains the proper
powder and the horizontal plane. Fixed funnel method
amount of drug. The USP weight variation test was
was used. A funnel was fixed with its tip at a given
done by weighing 20 tablets individually, calculating
height (h), above a flat horizontal surface on which a
the average weight and comparing the individual
graph paper was placed. Powder was carefully poured
weights to the average. The tablet meet the USP test if
through a funnel till the apex of the conical pile just
not more than 2 tablets are outside the percentage
touches the tip of funnel. The angle of repose was then
limits and if no tablets differs by more than 2 times the
calculated using the formula,
percentage limit. USP official limits of percentage
Tanθ =h/r
deviation of tablet are presented in the following table,
θ = tan-1(h/r)
where, θ = angle of repose,
Table 3. Weight variation limits [27]
h = height of pile, S. No. Average weight of Maximum %
r = radius of the base of the pile. tablet (mg) difference allowed
1
130 or less 10
Table 2. Comparison between angles of reposes and flow
property 2
130-324 7.5
S.No. Angle of repose Flow properties
3
1 <25 Excellent 324 or more 5
2 25-30 Good
3 30-40 Passable
4 >40 Very Poor

F. Total Porosity: Total porosity was determined by

measuring the volume occupied by a selected weight of Where, PD = Percentage deviation,
a powder (Vbulk) and the true volume of the powder W avg = Average weight of tablet,
blend (The space occupied by the powder exclusive of W initial =individual weight of tablet.
spaces greater than the intermolecular spaces, V).
Porosity (%) =Vbulk-V/Vbulkx 100 E. Uniformity of drug content:
G. Flow rate: Flow rate of granules influences the Five tablets of various formulations were weighed
filling of die cavity and directly affects the weight of the individually and powdered. The powder equivalent to
tablets produced. average weight of tablets was weighed and drug was
extracted in Phosphate buffer pH 6.8, the drug content
2. Post Compression Parameters [25] was determined measuring the absorbance at 262.4 nm
A. Thickness and diameter: after suitable dilution using a UV/Visible
Control of physical dimension of the tablet such as Spectrophotometer (UV-1800).
thickness and diameter is essential for consumer
acceptance and tablet uniformity. The thickness and In vitro drug release characterization models:
diameter of the tablet was measured using Vernier Mathematical Models [28, 29]:
calipers. It is measured in mm. Zero order release kinetics: Ideal delivery of drugs
would follow “zero order kinetics”, wherein blood
B. Hardness: levels of drugs would remain constant throughout the
The Mansanto hardness tester was used to determine delivery period. This ideal delivery is particularly
the tablet hardness. The tablet was held between a important in certain classes of medicines intended, for
fixed and moving jaw. Scale was adjusted to zero; load example, for antibiotic delivery, heart and blood
was gradually increased until the tablet fractured. The pressure maintenance, pain control and

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antidepressants. Consequently, there has been Q0 is the initial amount of the drug in tablet and
substantial activity by scientists searching for KHC is the rate constant for Hixson-Crowell rate
improved methods of achieving both controlled and equation.
sustained delivery of drugs.
Higuchi Model [32]: Ideally, controlled drug-delivery
Zero order release kinetics refers to the process of systems should deliver the drug at a controlled rate
constant drug release from a drug delivery device such over a desired duration. The primary objectives of the
as oral osmotic tablets, transdermal systems, matrix controlled drug-delivery systems are to ensure safety
tablets with low-soluble drugs and other delivery and to improve efficacy of drugs, as well as to improve
systems. In its simplest form, zero order release can be patient compliance. Of the approaches known for
represented as obtaining controlled drug release, hydrophilic matrix is
Q = Q0 + K0t recognized as the simplest and is the most widely used.
Where, Hydrophilic matrix tablets swell upon ingestion, and a
Q=the amount of drug released or dissolved (assuming gel layer forms on the tablet surface. This gel layer
that release occurs rapidly after the drug dissolves), retards further ingress of fluid and subsequent drug
Q0=the initial amount of drug in solution (it is usually release. It has been shown that in the case of
zero), and hydrophilic matrices, swelling and erosion of the
K0=the zero order release constant. The plot made: polymer occurs simultaneously, and both of them
cumulative % drug release vs. time (zero order kinetic contribute to the overall drug-release rate. It is well
model). documented that drug release from hydrophilic
matrices shows a typical time-dependent profile (ie,
First order release kinetics [30, 31]: The rate laws decreased drug release with time because of increased
predicted by the different mechanisms of dissolution diffusion path length). This inherent limitation leads to
both alone and in combination, have been discussed by first-order release kinetics.
Higuchi. However, the earliest equation expressing
dissolution rate in a quantitative manner was proposed Many controlled-release products are designed on the
by Noyes and Whitney as:- principle of embedding the drug in a porous matrix.
dc / dt = k (Cs – Ct ) Liquid penetrates the matrix and dissolves the drug,
where, dc/ dt is the rate of change in concentration which then diffuses into the exterior liquid. Higuchi
with respect to time, and tried to relate the drug release rate to the physical
k is the rate constant. constants based on simple laws of diffusion. Release
rate from both a planar surface and a sphere was
The integrated form of the equation is: considered. The analysis suggested that in the case of
In [Cs / (Cs – Ct ) ] = kt spherical pellets, the time required to release 50% of
Log C = Log C0 – kt / 2.303 the drug was normally expected to be 10% of the time
Where, C0 is the initial concentration of drug and K is required to dissolve the last trace of solid drug in the
first order constant. center of the pellet. Higuchi was the first to derive an
equation to describe the release of a drug from an
The equation in resemblance to the other rate law insoluble matrix as the square root of a time-dependent
equations, predicts a first order dependence on the process based on Fickian diffusion.
concentration gradient (i.e. Cs – Ct) between the static
liquid layer next to the solid surface and the bulk liquid. Qt = [2DS' (A - 0.5S')] 0.5*t0.5
Noyes and Whitney explained their dissolution data
using a concept similar to that used for the diffusion Simplifying,
model. These considerations relate to conditions in
which there is no change in the shape of the solid Qt = kH (t) 0.5
during the dissolution process (i. e. the surface area
remains constant). However, for pharmaceutical Where, Qt is the amount of drug released in time t, D is
tablets, disintegration occurs during the dissolution the diffusion coefficient,
process and the surface area generated therefore varies S is the solubility of drug in the dissolution medium, A
with time. is the drug content per cubic centimeter of matrix
tablet, and KH is the release rate constant for the
The Hixson-Crowell cube root law describes the release Higuchi model.
from systems where there is a change in surface area
and diameter of particles or tablets. For a drug powder The release of a solid drug from a granular matrix
consisting of uniformly sized particles, it is possible to involves the simultaneous penetration of the
derive an equation that expresses the rate of surrounding liquid, dissolution of the drug, and
dissolution based on the cube root of the particles. leaching out of the drug through interstitial channels or
pores. The volume and length of the opening in the
Q01/3-Qt1/3 =KHCt matrix must be accounted for in the diffusional
Where, equation, leading to a second form of the Higuchi
Qt is the amount of drug released in time t, equation:

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 U. Satish et. al. / Int J Pharma Sci. 2013, 3(4): 258-269

Q = [DK/L (2A- KCs) Cst] 0.5 which swell in water or biological fluids. This term
also includes polymer disentanglement and
Porosity, O, is the fraction of matrix that exists as pores erosion.
or channels into which the surrounding liquid can
penetrate.Tortuosity, P, is introduced in equation to Table 2 describes the limits of this analysis for
account for an increase in the path length of diffusion cylindrical shape, e.g. a tablet. The value of the release
due to branching and bending of the pores, as exponent in ibuprofen sustained release obtained as
compared to the shortest “straight- through” pores. 0.2465 which as per table 1 is beyond the limits of
Tortuosity tends to reduce the amount of drug release Korsmeyer model so-called power law. The power law
in a given interval of time. A straight channel has a can only give limited insight into the exact release
tortuosity of unity, and a channel through spherical mechanism of the drug. Even if values of the exponent n
beads of uniform size has a tortuosity of 2 or 3. are found that would indicate a diffusion controlled
drug release mechanism.
Korsmeyer-Peppas Model [33, 34]: Korsmeyer et al
(1983) derived a simple relationship which described Table 5. The following are the general categories which are
drug release from a polymeric system. To find out the used in controlled Release Dosage Form [37, 38]
mechanism of drug release, first 60% drug release data
was fitted in Korsmeyer–Peppas model:

Mt/MN = K tn

Where, Mt/ MN is fraction of drug released at time t,

and k is the rate constant and n is the release exponent.
The n value is used to characterize different release
mechanisms as given in table 1 for cylindrical shaped
matrices.

Table 4: [35, 36]

There are several simultaneous processes considered

in this model:
 Diffusion of water into the tablet
CONCLUSION
 Swelling of the tablet as water enters Oral Sustained release (S.R) / Controlled release (C.R)
 Formation of gel products provide an advantage over conventional
 Diffusion of drug and filler out of the tablet dosage forms by optimizing bio-pharmaceutics,
 Dissolution of the polymer matrix pharmacokinetic and pharmacodynamics properties of
drugs in such a way that it reduces dosing frequency to
Key attributes of the model include: an extent that once daily dose is sufficient for
 Tablet geometry is cylindrical therapeutic management through uniform plasma
 Water and drug diffusion coefficients vary as concentration providing maximum utility of drug with
functions of water concentration reduction in local and systemic side effects and cure or
 Polymer dissolution is incorporated control condition in shortest possible time by smallest
 Change in tablet volume is considered by quantity of drug to assure greater patient compliance.
incorporating the first 60% of release data, This review describes the various factors influencing
mechanism of release can be indicated according to the design and performance of sustained/controlled
Korsmeyer where n is the release exponent, release products along with suitable illustrations. The
indicative of mechanism of drug release. Fickian release models with major application and best
diffusional release and a case-II relaxational describing drug release phenomena are, in general, the
release are the limits of this phenomenon. Fickian Higuchi model, zero order model, first order model and
diffusional release occurs by the usual molecular Korsemeyer-Peppas model. Further, it can be added
diffusion of the drug due to a chemical potential that the physicochemical properties of the drug as well
gradient. Case-II relaxational release is the drug as polymer and the drug to polymer ratio govern the
transport mechanism associated with stresses and release of drug from the formulation and thus, modify
state-transition in hydrophilic glassy polymers the release kinetics accordingly.

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 U. Satish et. al. / Int J Pharma Sci. 2013, 3(4): 258-269

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