Controlled drug delivery systems: Introduction, terminology/definitions and rationale, advantages,

disadvantages, selection of drug candidates. Approaches to design controlled release formulations

based on diffusion, dissolution and ion exchange principles. Physicochemical and biological properties of
drugs relevant to controlled release formulations Polymers: Introduction, classification, properties,
advantages and application of polymers in formulation of controlled release drug delivery systems.
NOTES BACKGROUND The science of controlled release was first originated from the development of
oral sustained release products in the 1940s and early 1950s. First of all, the controlled release of
marine antifoulants (the 1950s) and controlled release of fertilizer (1970s) were formulated which had
only a single application in the soul science. The development of the pharmacology and
pharmacokinetics demonstrated the importance of drug release rate in determining therapeutic
effectiveness of therapy. This becomes the reason behind the development of controlled release. The
modified release dosage forms are entirely new. The first time Rhozes formulates mucilage coated pills
about A.D 900. This technique widely adopted in the10th century by European countries, in the form of
gold, silver and pearl coated tablets; this coating modifies the drug release rates. Advancement in the
coating technology including sugar & enteric coating on the pills & tablets in the late 1800s. The further
coating developed to the enteric coating of tablets followed by incorporation of the second drug to
sugar coating layer, this happened near about 1938. However, the first patent for oral sustained release
preparation went in the favour of Lipowski; his preparation contained small coated beads that were
releasing the drug slowly & constantly. This idea later developed by Blythe and launched the first
marketed sustained release product in 1952. Over the past 30 years as the complication involves in the
marketing of new drug increased and various advantages recognized of Controlled release drug delivery
system (CRDDS), the greater attention is being paid in this field. Today the oral controlled drug delivery
system becomes major drug delivery systems mainly drugs having high water solubility and short
biological half-life. Other than oral, the various routes like transdermal, ocular, vaginal & parenteral
route use for controlled release of various drugs. The history of controlled release technology is divided
into three time periods. From 1950 to 1970 was the period of sustain drug release. From 1970 to 1990
was involved in the determination of the needs of the control drug delivery. Post 1990 modern era of
controlled release technology. INTRODUCTION Controlled drug delivery systems can include the
maintenance of drug levels within a desired range, the need for fewer administrations, optimal use of
the drug in question, and increased patient compliance. While these advantages can be significant, the
potential disadvantages cannot be ignored like the possible toxicity or non-biocompatibility of the
materials used, undesirable by-products of degradation, any surgery required to implant or remove the
system, the chance of patient discomfort from the delivery device, and the higher cost of
controlledrelease systems compared with traditional pharmaceutical formulations. The ideal drug
delivery system should be inert, biocompatible, mechanically strong, comfortable for the patient,
capable of achieving high drug loading, safe from accidental release, simple to administer and remove,
and easy to fabricate and sterilize. The goal of many of the original controlled-release systems was to
achieve a delivery profile that would yield a high blood level of the drug over a long period of time. With
traditional drug delivery systems, the drug level in the blood follows the in which the level rises after
each administration of the drug and then decreases until the next administration. The key point with
traditional drug administration is that the blood level of the agent should remain between a maximum
value, which may represent a toxic level, and a minimum value, below which the drug is no longer
effective. TERMINOLOGY OR DEFINITION OFCONTROL RELEASE DOSAGE FORM S The United States
Pharmacopoeia (USP) defines1 the modified-release (MR) dosage form as “the one for which the drug
release characteristics of time course and/or location are chosen to accomplish therapeutic or
convenience objectives not offered by conventional dosage forms such as solutions, ointments, or
promptly dissolving dosage forms”. One class of MR dosage form is an extended-release (ER) dosage
form and is defined as the one that allows at least a 2fold reduction in dosing frequency or significant
increase in patient compliance or therapeutic performance when compared with that presented as a
conventional dosage form (a solution or a prompt drug-releasing dosage form). The terms “controlled
release (CR)”, “prolonged release”, “sustained or slow release (SR)” and “long-acting (LA)” have been
used synonymously with “extended release”. Controlled drug delivery is one which delivers the drug at
a predetermined rate, for locally or systemically, for a specified period of time. Sustained Drug Release.
Sustained release allows delivery of a specific drug at a programmed rate that leads to drug delivery for
a prolonged period of time. Prolonged-release products release the active ingredients slowly and work
for a longer time. A prolonged-release drug delivers a dose of a medication over an extended period of
time. The prolonged release or sustained release systems, which only prolong therapeutic blood or
tissue levels of the drug for an extended period of time, cannot be considered as controlled release
systems by this definition. They are distinguished from rate controlled drug delivery systems, which are
able to specify the release rate and duration in vivo precisely, on the basis of simple in vitro tests. The
difference between controlled release and sustained release, Controlled drug delivery- which delivers
the drug at a pre determined rate for a specified period of time. Controlled release is perfectly zero
order release that is the drug release over time irrespective of concentration. Sustain release dosage
form- is defined as the type of dosage form in which a portion i.e. (initial dose) of the drug is released
immediately, in order to achieve desired therapeutic response more promptly, and the
remaining(maintenance dose) is then released slowly there by achieving a therapeutic level which is
prolonged, but not maintained constant. Sustained release implies slow release of the drug over a time
period. It may or may not be controlled release. Drug targeting, on the other hand, can be considered as
a form of controlled release in that it exercises spatial control of drug release within the body.
RATIONALE The basic rationale of a controlled release drug delivery system is to optimize the
biopharmaceutics, pharmacokinetics, and pharmacodynamics properties of a drug in such a way that its
utility is maximized through reduction in side effects and cure or control of disease condition in the
shortest possible time by using smallest quantity of drug, administered by most suitable route. The
immediate release drug delivery system lacks some features like dose maintenance, controlled release
rate and site targeting. An ideal drug delivery system should deliver the drug at a rate dictated by the
need of body over a specified period of treatment. Fig. 1- Plasma drug concentration-time profile
Advantages of Control Release Dosage Forms Clinical Advantages  Reduction in frequency of drug
administration  Improved patient compliance  Reduction in drug level fluctuation in blood 
Reduction in total drug usage when compared with conventional therapy  Reduction in drug
accumulation with chronic therapy  Reduction in drug toxicity (local/systemic)  Stabilization of
medical condition (because of more uniform drug levels)  Improvement in bioavailability of some
drugs because of spatial control  Economical to the health care providers and the patient
Commercial / Industrial Advantages  Illustration of innovative/technological leadership  Product life-
cycle extension  Product differentiation  Market expansion  Patent extension Disadvantages of
CRDDS  Delay in onset of drug action  Possibility of dose dumping in the case of a poor formulation
strategy  Increased potential for first pass metabolism  Greater dependence on GI residence time of
dosage form  Possibility of less accurate dose adjustment in some cases  Cost per unit dose is higher
when compared with conventional doses  Not all drugs are suitable for formulating into ER dosage
form Selection of drug for formulation into extended release dosage form is the key step. Following
candidates are generally not suitable for ER dosage forms Selection of drug candidates or
characteristics that may make a drug unsuitable for Control release dosage form  Short elimination
half-life  Long elimination half-life  Narrow therapeutic index  Poor absorption  Active absorption
 Low or slow absorption  Extensive first pass effect Parameters for drug selection Parameter :
Molecular weight/ size: Solubility: Pka Non ionized moiety: Preferredvalue < 1000 > 0.1 µg/ml for pH 1
to pH 7.8 > 0.1% at pH 1 to pH 7.8 Apparent partition coefficient: High Absorption mechanism:
Diffusion General absorbability: From all GI segments Release: Should not be influenced by pH and
enzymes BIOPHARMACEUTIC AND PHARMACOKINETIC ASPECTS IN THE DESIGN OF CONTROLLED
RELEASE PER ORAL DRUG DELIVERY SYSTEMS Controlled release drug delivery systems are dosage forms
from which the drug is released by a predetermined rate which is based on a desired therapeutic
concentration and the drug’s pharmacokinetic characteristics Biological half-life (t ½) The shorter the t
½ of a drug the larger will be the fluctuations between the maximum steady state concentration and
maximum steady state concentration upon repetitive dosing. Thus drug product needs to be
administered more frequently. Minimum effective concentration (MEC) If a minimum effective
concentration, MEC is required either frequent dosing of a conventional drug product is necessary or a
controlled release preparation may be chosen. Dose size and Extent of duration The longer the extent
of duration the larger the total dose per unit delivery system needs to be. Hence there is a limitation to
the amount of drug that can be practically incorporated into such a system. Relatively long t1/2 or
fluctuation desired at steady state It is the belief of some that neither a SR nor a CRDDS is needed or
useful for drugs having a t ½ of 12 hours or more. This is not so because there are two cases for which a
12 or 24 CRDDS seems to be indicated: 1. A drug having a t ½ between 12 and 72 hours may be
designed for a CRDDS permitting application for every two to three days. The decline of the blood level
time curve after release of the drug from the system will depend on the drug’s t ½. Naturally, fluctuation
between Css max and Css min may accordingly be relatively large in other words on adds slow release to
the slow elimination process. For some drugs having a t1/2 between 20 and 100 hrs ,and which are
intended for long term use ,one may desire small fluctuations between peaks and troughs at steady 2.
states either to achieve a certain therapeutic effect or because the therapeutic range is narrow.
DESIRED BIOPHARMACEUTIC CHARACTERISTICS OF DRUG TO QUALIFY FOR CDDS Molecular weight or
size Small molecules may pass through pores of a membrane by convective transport. This applies to
both, the drug release from the dosage form and the transport across a biologic membrane. For biologic
membranes the limit may be a molecular weight of 150 and 400 respectively for spherical molecules and
chain like compounds respectively. Solubility For all mechanisms of absorption the drug must be
present at the site of absorption in the form of solution. During the Preformulation study it is necessary
to determine the solubility of the drug at various pH values. If the solubility is less than 0.1 μg/ml (in
acidic medium) one may expect variable and reduced bioavailability. If the solubility is less than 0.01
μg/ml absorption and availability most likely become dissolution limited dissolution limited. Hence
driving force for diffusion may be inadequate. It seems that drugs are well absorbed by passive diffusion
from the small intestine upon per oral administration if at least 0.1 to 1% is non ionised form. Apparent
partition coefficient (APC) Drugs being absorbed by passive diffusion must have a certain minimal APC.
The higher the APC in an n-octanol/buffer system the higher is the flux across a membrane for many
drugs. The APC should be determined for the entire pH range in the GI tract. The APC must also be
applied for partition of the drug between CRDDS and the biological fluid. General absorption
mechanism For a drug to be a variable candidate for per oral CRDDS, its absorption mechanism must be
by diffusion throughout the entire GI tract. The term diffusion here refers to the dual pathway of
absorption either by partitioning into the lipid membrane (across the cells) or by passing through water
filled channels (between the cells). It is also important that absorption occurs from all segments of the
GI tract which may depend on the drug’s pKa, the pH in the segment, binding of drug to mucus, blood
flow rate, etc. The absorption process seems to be highly dependent on the hydrodynamics in the GI
lumen. Even though that first order and square root of time release can result in highly effective drug
delivery systems it is widely believed that the ultimate goal is zero order release profile. Zero order
release invitro release will produce zero order in vivo release and zero order in vivo absorption only if;
(1) the entire GI tract behaves as a one compartment model, i.e. the various segments throughout the
GI tract are homogeneous with respect to absorption, and (2) drug release rate is the rate limiting step
in the absorption process. With first order release on the other hand, smaller and smaller amounts are
released per unit of time with increasing time. Assuming that rate of absorption gets slower past the
small intestine due to increased viscosity, decreased mixing, and decreased intestinal surface area, less
drug is absorbed. In any case, the drug release from the CRDDS should not be influenced by pH changes
within the GI tract, by enzymes present in the lumen, peristalsis, etc For all practicality, the one
compartment open model is quite suitable to design CRDDS for most drugs. Pharmacokinetic
parameters Elimination half life (t ½) Drugs having a t ½ and 8 hours are ideally suited for CRDDS. If the t
½ is less than 1 hour the dose size required to be incorporated for a 12 hour or 24 hour duration dosage
form may be too large. If the t ½ is very long there is usually no need for a CRDDS, unless it is simply
intended for a reduction in fluctuation of steady state blood levels. Total clearance (CL) CL is a measure
of the volume of distribution cleared of drug per unit of time. It is the key parameter in estimating the
required dose rate for CRDDS, and predicting the steady state concentration. Terminal disposition rate
constant (Ke or λz) The terminal disposition rate constant or elimination rate constant can be obtained
from the t ½ and is required to predict a blood level time profile. Apparent volume of distribution (Vz)
The Vz is the hypothetical volume of a drug would occupy if it were dissolved at the same concentration
as that found in blood. It is the proportionality constant relating the amount of drug in the body to the
measured concentration in the blood. Among the trio CL, Vz, and t ½, the former two parameters are
the independent variables and the last one is the dependent variable. The Vz or CL is required to predict
the concentration time profile. Absolute bioavailability (F) The absolute bioavailability is the percentage
of drug taken up into systemic circulation upon extravascular administration. For drugs to be suitable for
CRDDS one wants an F value to be close to 100%. Intrinsic absorption rate constant (Ka) The intrinsic
absorption rate constant of the drug administered peroral in the form of a solution should be high,
generally by an order of magnitude higher than the desired release rate constant of the drug from the
dosage form, in order to insure that release process is the rate controlling step. Therapeutic
concentration (Css) The therapeutic concentrations are the desired or target steady state peak
concentrations (Css max), the desired or target steady state minimum concentrations (Css min), and the
mean steady state concentration (Css avg). The difference between Css max and Css min is the
fluctuation. The smaller the desired fluctuation the greater must be the precision of the dosage form
performance. The lower Css, the smaller Vz, the longer t ½, the higher F and The less amount of drug is
required to be incorporated into a CRDDS. Approaches to design controlled release formulations 1.
Dissolution controlled release  Encapsulation Dissolution control  Seed or granule coated  Micro
encapsulation  Matrix Dissolution control 2. Diffusion controlled release  Reservoir type devices 
Matrix type devices 3. Diffusion and Dissolution controlled systems 4. Ion exchange resins 5.
Osmotically controlled release MECHANISTIC ASPECTS FOR ORAL CONTROLLED RELEASE DRUG
DELIVERY FORMULATION Dissolution controlled release Dissolution is defined as solid substance
solubilized in a given solvent. It is a rate determining step when liquid is diffusing from solid. Several
theories explain dissolution: Diffusion layer theory, Surface renewal theory, Limited solvation theory.
Noyes Whitney Equation dc/dt = kD.A (Cs – C) dc/dt = D/h A. (Cs – C) dc/dt = Dissolution rate, k=
Dissolution rate constant (1st order), D = Diffusion coefficient/diffusivity, Cs = Saturation/maximum drug
solubility, C =Conc. Of drug in bulk solution, Cs-C=concentration gradient, h =Thickness of diffusion layer.
Two common formulation system rely on dissolution to determine release rate of drugs are:
Encapsulated dissolution system (ii) Matrix dissolution system Encapsulated dissolution system This is
also known as Coating dissolution controlled system. Dissolution rate of coat depends upon stability &
thickness of coating. It masks color, odor, taste and minimize GI irritation. Controlled release products
by decreasing the dissolution rate of drugs which are highly water soluble can be formulated by
preparing appropriate salt or derivatives, by coating the drug with a slowly dissolving material, or by
incorporating the drug into a slowly dissolving carrier. Examples: Ornade spansules, Chlortrimeto
Repetabs. Matrix dissolution system It is also known as monolithic dissolution controlled system. In this
dissolution IS controlled by: Altering porosity of tablet, decreasing its wet ability, dissolving at slower
rate. It follows first order drug release. The drug release can be determined by dissolution rate of
polymer. Examples: Demeaned extencaps, Dimetapp extentabs. Diffusion controlled system It is a major
process for absorption in which no energy required. In this drug molecules diffuse from a region of
higher concentration to lower concentration until equilibrium is attained and it is directly proportional
to the concentration gradient across the membrane. In this system release rate is determined by its
diffusion through a water-insoluble polymer. There are two types of diffusion devices: - Reservoir
diffusion system - Matrix diffusion system Reservoir diffusion system It is also called as laminated matrix
device. It is a hollow system containing an inner core surrounded by water insoluble membrane and
polymer can be applied by coating or micro encapsulation. The Rate controlling mechanism is that drug
will partition into membrane and exchange with the fluid surrounding the drug by diffusion. Commonly
used polymers are HPC, ethyl cellulose & polyvinyl acetate. Examples: Nico-400, Nitro-Bid. Rate
controlling steps: Polymeric content in coating, thickness of coating, hardness of microcapsule. Matrix
dissolution system (a) Rigid Matrix Diffusion: Materials used are insoluble plastics such as PVP & fatty
acids. (b) Swellable Matrix Diffusion: it is also called as Glassy hydro gels and popular for sustaining the
release of highly water soluble drugs. Materials used are hydrophilic gums[19]. Examples: Natural- Guar
gum, Tragacanth. Semi synthetic -HPMC, CMC, Xanthum gum. Synthetic -Polyacrilamides. Examples:
Glucotrol XL, Procardia XL The Higuchi Equation describing the drug release from this system [1] : Q =
[DƐ/T (2A-Ɛ Cs.t)] 1/2 Where Q=amt of drug release per unit surface area at time t, D=diffusion
coefficient of drug in the release medium, Ɛ=porosity of the matrix, Cs=solubility of drug in release
medium, T=tortuosity of matrix, A=concentration of drug present in matrix per unit volume. Rate
controlling step: Diffusion of dissolved drug in matrix. Dissolution & Diffusion Controlled Release system
In this drug is encased in a partially soluble membrane and pores are created due to dissolution of parts
of membrane. It permits entry of aqueous medium into core & drug is dissolved or diffused out of the
system. Ex- Ethyl cellulose & PVP mixture dissolves in water & creates pores of insoluble ethyl cellulose
Ion exchange resins controlled release system Ion exchange resins are cross-linked water insoluble
polymers carrying ionizable functional groups. These resins are used for taste masking and controlled
release system. The formulations are developed by embedding the drug molecules in the ion-exchange
resin matrix and this core is then coated with a semi permeable coating material such as Ethyl Cellulose.
This system reduced the degradation of drug in GIT. The most widely used and safe ion-exchange resin is
divinylbenzene sulphonate. In tablet formulations ion-exchange resins have been used as disintegrant.
TABLE 1: Marketed drug products with their mechanism based classification Principle: Is based on
preparation of totally insoluble ionic material • Resins are insoluble in acidic and alkaline media •They
contain ionizable groups which can be exchanged for drug molecules IER are capable of exchanging
positively or negatively charged drug molecules to form insoluble poly salt resinates. Types: There are
two types of IER Cationic Exchange resins - RSO3-H+ Resins functional groups Anionic Exchange resins –
RNH3 + OH Mechanism of action IER combine with drug to form insoluble ion complexes 1. R-SO3– H+
+ H2N – A R-SO3 – NH3 + - A R-NH3 + OH- + HOOC – B RNH3 + -OOC-B + H2O Where A- NH2
is basic drug B-COOH is acidic drug These resinates are administered orally 2 hrs in stomach in contact
with acidic fluid at pH 1.2 Intestinal fluid, remain in contact with slightly basic pH for 6hrs. Drug can be
slowly liberated by exchange with ions present in G.I.T In the stomach ®- SO3 - NH3 + - A + HCl ®-
SO3 - H+ + A-NH3 + Cl- ®-NH3 +Cl- + HOOC-B ®-NH3 +Cl- + HOOC-B Un dissociated Thus
carboxylic acid will be poorly dissociated in stomach and thus absorbed. In the Intestine ® - - SO3 - NH3
+ - A + NaCl ®- -SO3 - Na+ + A-NH3 + Cl- Basic pH un dissociated ®-NH3 + -OOC – B + NaCl ®-
NH3 +Cl- + Na+ -OOCB Sodium salt of acid (dissociation of acid salt unabsorbed) Amine salt will be
poorly dissociated in intestine and thus absorbed. (3) CLASSIFICATION OF CONTROLLED RELEASE
SYSTEM The controlled release system divided into following major classes based on release pattern.
(1) Rate pre-programmed drug delivery system (2) Activated modulated drug delivery system (3)
Feedback regulated drug delivery system (4) Site targeting drug delivery system (1) Rate pre-
programmed drug delivery system: In this, the release of drug molecule from the delivery system is pre-
planed with particular flow rate profile of medicine. The system controls the molecular diffusion of drug
molecules in or across the barrier medium within or surrounding the delivery system. (1) Polymer
membrane permeation controlled system In this system, the drug is completely or partially
encapsulated in a drug reservoir cubicle whose drug-releasing surface is covered by flow rate controlling
polymeric membrane. In drug reservoir, the drug can be solid or dispersion of solid drug particle or
concentrated drug solution in a liquid or in a solid type dispersion medium. The polymeric membrane
may be made-up of the fabricated form of homogeneous or heterogeneous non-porous or partial
microporous or semipermeable membrane. (2) Polymer matrix diffusion-controlled system In this drug,
the reservoir is prepared by the homogeneously dispersing drug particles in the rate controlling
hydrophilic or lipophilic polymer matrix. The resultant medicated polymer matrix provides the
medicated disk with defined surface area and controlled thickness. (3) Micro reservoir partition
controlled system The drug reservoirs are a suspension of solid particle in the aqueous solution of the
water- miscible polymer. Micro-dispersion partition controlled system is prepared by the applying high
dispersion techniques. In short reservoir and matrix dispersion forms micro-reservoir Fig. 3-Matrix and
membrane type delivery systems FACTORS INFLUENCING THE DESIGN AND ACT OF CONTROLLED
RELEASE PRODUCTS (1) Physiological properties (1) Aqueous Solubility’s: Most of the active
pharmaceutical moiety (API) are weakly acidic or basic in nature that affect the water solubility of API.
Weak water soluble drugs are difficult to design the controlled release formulations. High aqueous
solubility drug show burst release followed by a rapid increment in plasma drug concentration. These
types of drugs are a good candidate for CRDDS. The pH dependent solubility also creates a problem in
formulating CRDDS. BCS class-III & IV drugs are not a suitable candidate for this type of formulations. (2)
Partition coefficient (P-value): P-value denotes the fraction of the drug into oil & aqueous phase that is a
significant factor that affects the passive diffusion of the drug across the biological membrane. The drugs
are having high or low P value not suitable for CR, it should be appropriate to dissolve in both phases.
(3) Drug pKa: pKa is the factor that determined the ionization of drug at physiological pH in GIT.
Generally, the high ionized drugs are poor candidates for CRDDS. The absorption of the unionized drug
occurs rapidly as compared to ionized drugs from the biological membranes. The pKa range for an acidic
drug that ionization depends on the pH is 3.0 to 7.5 and for a basic drug it lay between 7 and 11. (4)
Drug stability: Drugs that are stable in acid/base, enzymatic degradation, and other gastric fluids are
good candidates for CRDDS. If drug degraded in the stomach and small intestine, it not suitable for
controlled release formulations because it will decrease in bioavailability of concern drug. (5) Molecular
size & molecular weight: The molecular size & molecular weight are two important factors which affect
the molecular diffusibility across a biological membrane. The molecular size less than 400D is easily
diffuse but greater than 400D create a problem in drug diffusion. (6) Protein binding: The drug-protein
complex act as a reservoir in plasma for the drug. Drug showing high plasma protein binding are not a
good candidate for CRDDS because Protein binding increases the biological half-life. So there is no need
to sustain the drug release. (2) Biological factors (1) Absorption: Uniformity in rate and extent of
absorption is an important factor in formulating the CRDDS. However, the rate limiting step is drugged
release from the dosage form. The absorption rate should rapid then release rate to prevent the dose
dumping. The various factors like aqueous solubility, log P, acid hydrolysis, which affect the absorption
of drugs. (2) Biological half-life (t1/2): In general the drug is having short half-life required frequent
dosing and suitable candidate for controlled release system. A drug with long half-life required dosing
after a long time interval. Ideally, the drugs having t1/2 2-3 hrs are a suitable candidate for CRDDS.
Drugs have t1/2 more than 7-8 hrs not used for controlled release system. (3) Dose size: The CRDDS
formulated to eliminate the repetitive dosing, so it must contain the large dose than conventional
dosage form. But the dose used in conventional dosage form give an indication of the dose to be used in
CRDDS. The volume of sustained dose should be as large as it comes under acceptance criteria. (4)
Therapeutic window: The drugs with narrow therapeutic index are not suitable for CRDDS. If the delivery
system failed to control release, it would cause dose dumping and ultimate toxicity. (5) Absorption
window: The drugs which show absorption from the specific segment in GIT, are a poor candidate for
CRDDS. Drugs which absorbed throughout the GIT are good candidates for controlled release. (6)
Patient physiology: The Physiological condition of the patient like gastric emptying rate, residential time,
and GI diseases influence the release of the drug from the dosage form directly or indirectly.
Pharmacokinetic parameters consider during the drug selection listed as follow. Table. 1-
Pharmacokinetic parameters for drug selection Parameter Comment Biological or elimination half-life
Elimination rate constant(KE) Should be between 2 to 6 hrs Required for design Total clearance(CLT)
Intrinsic absorption rate dose independent should be greater than the release rate Apparent volume
of distribution (Vd) Vd effect the required amount of the drug Absolute bioavailability Steady state
concentration (Css) Should be 75% or more lower Css and smaller Vd Toxic concentration The
therapeutic window should be broader POLYMER USED IN CONTROL DRUG DELIVERY SYSTEM Polymers
are becoming increasingly important in the field of drug delivery. The pharmaceutical applications of
polymers range from their use as binders in tablets to viscosity and flow controlling agents in liquids,
suspensions and emulsions. Polymers can be used as film coatings to disguise the unpleasant taste of a
drug, to enhance drug stability and to modify drug release characteristics. The review focuses on the
significance of pharmaceutical polymer for controlled drug delivery [Link] million patients
benefit from advanced drug delivery systems today, receiving safer and more effective doses of the
medicines they need to fight a variety of human ailments, including cancer. Controlled Drug Delivery
(CDD) occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other
active agent in such a way that the active agent is released from the material in a predesigned manner.
The release of the active agent may be constant over a long period, it may be cyclic over a long period,
or it may be triggered by the environment or other external events. In any case, the purpose behind
controlling the drug delivery is to achieve more effective therapies while eliminating the potential for
both under and overdosing. POLYMERS AS BIOMATERIALS FOR DELIVERY-SYSTEMS A range of materials
have been employed to control the release of drugs and other active agents. The earliest of these
polymers were originally intended for other, nonbiological uses, and were selected because of their
desirable physical properties, for example:  Poly(urethanes) for elasticity.  Poly(siloxanes) or silicones
for insulating ability.  Poly(methyl methacrylate) for physical strength and transparency.  Poly(vinyl
alcohol) for hydrophilicity and strength.  Poly(ethylene) for toughness and lack of swelling.  Poly(vinyl
pyrrolidone) for suspension capabilities. To be successfully used in controlled drug delivery
formulations, a material must be chemically inert and free of leachable impurities. It must also have an
appropriate physical structure, with minimal undesired aging, and be readily processable. Some of the
materials that are currently being used for controlled drug delivery include  Poly(2-hydroxy ethyl
methacrylate)  Poly(N-vinyl pyrrolidone).  Poly(methyl methacrylate).  Poly(vinyl alcohol). 
Poly(acrylic acid).  Polyacrylamide.  Poly(ethylene-co-vinyl acetate).  Poly(ethylene glycol). 
Poly(methacrylic acid). Polymers:- • Insoluble, inert - polyethylene, polyvinyl chloride, methyl acrilate,
ethylcellulose. •Insoluble, erodible – carnauba wax, stearyl alcohol, castor wax. •Hydrophilic – methyl
cellulose, hydroxyl ethyl cellulose, sodium carboxymethyl cellulose, sodium alginate. In a matrix system
the drug is dispersed as solid particle within a porous matrix formed of a water insoluble polymer, such
as polyvinyl chloride. Initially, drug particle located at the surface of the release unit will be dissolved
and the drug released rapidly. Thereafter, drug partical at successively increasing distance from the
surface of the release unit will be dissolved and release by diffusion in the pores to the exterior of the
release unit. The main formulation factor by which the release rate from matrix system can be
controlled are; the amount of the drug in the matrix, the porosity of the release unit & the solubility of
the drug. However, in recent years additional polymers designed primarily for medical applications have
entered the arena of controlled release. Many of these materials are designed to degrade within the
body, few of them among these include:  Polylactides (PLA).  Polyglycolides (PGA).  Poly(lactide-co-
glycolides) (PLGA).  Polyanhydrides.  Polyorthoesters. Originally, polylactides and polyglycolides
were used as absorbable suture material, and it was a natural step to work with these polymers in
controlled drug delivery systems. The greatest advantage of these degradable polymers is that they are
broken down into biologically acceptable molecules that are metabolized and removed from the body
via normal metabolic pathways. However, biodegradable materials do produce degradation by-products
that must be tolerated with little or no adverse reactions within the biological environment. These
degradation products both desirable and potentially nondesirable must be tested thoroughly, since
there are a number of factors that will affect the biodegradation of the original materials. The various
important factors indicating the breadth of structural, chemical, and processing properties that can
affect biodegradable drug delivery systems are listed below:  Chemical structure  Chemical
composition  Distribution of repeat units in multimers  Presence of ionic groups  Presence of
unexpected units or chain defects.  Configuration structure.  Molecular weight.  Molecular-weight
distribution.  Morphology (amorphous/semi crystalline, microstructures, residual stresses).  Presence
of low-molecular-weight compounds.  Processing conditions.  Annealing.  Sterilization process. 
Storage history.  Shape.  Site of implantation.  Adsorbed and absorbed compounds (water, lipids,
ions, etc.).  Physicochemical factors (ion exchange, ionic strength, pH). Physical factors (shape and size
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