Presented by ;
Aakash N S
M.Pharm I Semester,
Department of Pharmaceutics
College of Pharmacy,
Madras Medical college.
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CONVENTIONAL DOSAGE FORMS :
Traditional drug delivery system has been characterised by immediate release
and repeated dosing of the drug.
DRAWBACKS OF CONVENTIONAL DOSAGE FORMS:
• Poor patient compliance
• Fluctuations of drug concentration(over or under medication)
• Precipitations of adverse effects
• Difficult in attaining steady state effect
• The newer drug delivery system are being investigated so as to alter the body
distribution of drugs with a view to reduce the toxicity of drugs and/or deliver
them more efficiently to their site of action
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CONCEPTS :
Extended release
USP defines the extended release (ER) dosage form as the one that allows at least
a 2-fold reduction in dosing frequency or significant increase in patient compliance
or therapeutic performance when compared with as conventional dosage form.
Sustained release
• These are DDS that are designed to achieve a prolonged therapeutic effect by
continuously releasing medication over an extended period of time after
administration of single-dose of drug.
• The basic goal of therapy is to achieve steady state blood level that is
therapeutically effective and non toxic for an extended period of time
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Controlled-release dosage forms
They are the class of pharmaceuticals or other biologically active products from
which a drug is released from the delivery system in a planned, predictable, and
slower-than-normal manner for a longer period of time
Plasma drug concentration profile for conventional release, a sustained release
and zero order controlled release formulation
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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(maintanance 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.
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ADVANTAGES OF SR DDS OVER THE CONVENTIONAL DOSAGE FORM :
• Reduced dosing frequency
• Dose reduction
• Improved patient compliance
• A constant level of drug concentration in blood plasma
• Reduced toxicity due to overdose
• Reduces the fluctuation of peak-valley concentration
• Night time dosing can be avoided
• Economic
• The total amount of drug administered can be reduced, thus:
Maximizing availability with minimum dose
Minimize or eliminate local side effects
Minimize or eliminate systemic side effects
Minimize drug accumulation with chronic dosing
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DISADVANTAGES OF SR DDS :
• Probability of dose dumping
• Reduced potential for dose adjustment
• Cost of single unit higher than conventional dosage forms
• Increase potential for first-pass metabolism
• The requirement for additional patient education for proper medication
• Poor in vitro and in vivo correlations.
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RATIONALE OF DEVELOPING SR DDS :
• To extend the duration of action of the drug
• To reduce the frequency of dosing
• To minimize the fluctuations in plasma level
• Improved drug utilization
• Less adverse effects.
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CHARACTERISTIC THAT MAKES A DRUG UNSUITABLE FOR SR
FORMULATION :
• Short elimination half-life, i.e., t1/2 <2 hrs
• Long elimination half-life, i.e., t1/2 >8 hrs
• Narrow therapeutic index
• Large doses
• Poor absorption
• Low or slow solubility
• Extensive first-pass clearance.
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Physicochemical parameters for drug selection
Parameter Preferred value
Molecular weight/size <1000 Dalton
Solubility >0.1 mg/ml for pH 1-7.8
Apparent partition coefficient High
Absorption mechanism Diffusion
General absorbability From all GI segments
Release Should not be influenced by pH and
enzymes
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Pharmacokinetic parameters :
Elimination Total clearance
Preferably between 2 and 8 hrs
half-life Should not be dose dependent
Elimination rate constant Required for design
Apparent volume of distribution (Vd) The larger Vd and MEC, the larger will be the
required dose size
Absolute bioavailability Should be 75% or more
Intrinsic absorption rate Must be greater than release rate
Therapeutic concentrationCss The lower Css and smaller Vd, the loss among
of drug required
Toxic concentration Apart the values of MTC and MEC, safer the
dosage form. Also suitable for drugs with very
short half-life
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FACTORS GOVERNING
THE DESIGN AND
PERFORMANCE OF SR
PRODUCTS
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Physico-chemical Factors: Biological Factors :
• Aqueous solubility • Absorption
• Molecular size and Diffusivity • Distribution
• Partition Coefficient • Metabolism
• Drug Stability • Elimination Half life
• Protein binding • Margin of safety
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PYSICO-CHEMICAL FACTORS :
Aqueous solubility :
• The aqueous solubility of a drug influences its dissolution rate which establishes it
concentration in solution.
• Dissolution rate is given by Noyes-Whitney equation given below:
dC/dt = kD.A.Cs
where dC/dt is the dissolution rate
kD is the dissolution rate constant
A is the total surface area of drug particles
Cs is the aqueous saturation solubility of the drug
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• Drugs with low aqueous solubility and drugs with extensive solubility in the
stomach and intestine are poor candidates for sustained released system.
• This can be overcome by encapsulating the drug with an acid or a base in a
membrane system or incorporated in matrix system.
Molecular size and Diffusivity :
• A drug in SR formulation must diffuse through various biological membranes via
its rate controlling polymeric membrane or matrix.
• The ability of a drug to diffuse through the rate controlling polymeric membrane
is called diffusivity or diffusion coefficient D. Diffusivity is the function of
molecular size.
• Generally values of diffusion coefficient for drugs of molecular weight ranging
from 150 to 400 daltons ranges from 10-6 to 10-9 cm2 /sec
• Drugs with larger molecular size are poor candidates for SR formulation.
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Partition Coefficient :
• Partition coefficient influences both permeation of the drug across
the biological membrane and diffusion across the rate controlling
membrane.
• Drugs with high partition coefficient ie. very oil soluble readily
penetrates the membranes but unable to proceed further.
• Drugs with excessive aqueous solubility ie. low oil/water partition
coefficient cannot penetrate the membrane.
• So a balance in the partition coefficient is needed to give an optimum
flux for permeation through biological and rate controlling
membrane.
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Oil/water partition coefficient is given by the formula,
K= CO / CW
where,
K is the partition coefficient
CO is the concentration of the drug in organic phase
CW is the concentration of the drug in aqueous phase
Drug Stability :
• Drug undergo both acid /base hydrolysis and enzymatic degradation when
administered oral route.
• For drugs that are unstable in GI tract the most appropriate controlling unit will be
releasing its contents only in the intestine by placing it in a slowly available
sustained release form.
• When drugs are unstable in both stomach and intestine a different route of
administration should be chosen. Controlled release of Nitro Glycerin is a good
example.
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Protein binding :
If a high degree of protein binding occurs , it serves as a depot for a drug producing
prolonged drug effect.
BIOLOGICAL FACTORS :
Absorption :
• To maintain constant blood level of drug, it must be uniformly released from the
sustained released system and then uniformly absorbed.
• It would be desirable to have release dose completely absorbed as well but it is not a
prohibitive consideration.
• When considering orally administered drugs, significant clause can occur by
hydrolytic degradation in the contents of the GI tract and metabolism by the industrial
flora.
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• . So the drug selected should have higher absorption rate constant than the releasing rate.
Distribution :
• The distribution of drug molecules into tissues and cells can be the primary factor for the
drug elimination kinetics.
• It not only lowers the concentration of the circulating drug, but it also can be the rate
limiting in its equilibrium with blood and extravascular tissue.
Metabolism :
Drugs that are capable for inducing or inhibiting enzyme synthesis, are poor
candidates for SR delivery system due to difficulty in maintain uniform blood levels.
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Elimination Half life :
Half life is the time taken for amount of drug in the body to fall by half and is
determined by both clearance and volume of distribution.
t1/2 = 0.693.Vd /Cl
Drugs with t1/2 less than 2 Hours : poor candidate for SR formulation
Drugs with long t1/2 more than 8 Hours : Not used in sustained form.
Drugs with very short t1/2 :Require faster rate of release.
Margin of safety :
Larger volume of therapeutic index is safer the drug.
Drugs with less therapeutic index is not suitable for SR.
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CLASSIFICATION OF SR DDS
A. Diffusion sustained system
a. Reservoir type
b. Matrix type
B. Dissolution sustained system
a. Reservoir type
b. Matrix type
C. Methods using Ion-exchange
D. Methods using osmotic pressure
E. pH-independent formulation
F. pH-dependent formulation
G. Altered density formulation
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DIFFUSION SUSTAINED SYSTEM :
Diffusion systems are characterized by the release rate of a drug being dependent on
its diffusion through an inert membrane barrier.
Basically, diffusion process shows the movement of drug molecules from a region of
a higher concentration to one of the lower concentration.
The flux of the drug J (in amount/area−time), across a membrane in the direction of
decreasing concentration is given by Fick’s law.
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Reservoir types :
In the system, water insoluble polymeric material encases a core of drug.
The drug will partition into the membrane and exchange with the fluid surrounding the
particle or tablet.
The additional drug will enter the polymer, diffuse to the periphery and exchange with
the surrounding media.
Drug core surrounded by polymer membrane that controls release rate
Advantages :
• Zero-order delivery is possible.
• Release rate variable with polymer type.
Disadvantages :
• System must be physically removed from implants site.
• Difficult to deliver high molecular weight compound.
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Matrix types :
In a matrix system, the drug is dispersed as solid particles within a porous matrix formed
of a water-insoluble polymer.
The drug particles located at the surface of the release unit will be dissolved first and drug
release rapidly.
Thereafter, drug particles at a successively increasing distance from the surface of the
release unit will be dissolved and release by the diffusion in the pores to the exterior of the
release unit.
Thus, the diffusion distance of dissolve drug will increase as the release process proceeds
Homogeneous dispersion of solid drug in a polymer mix.
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Advantages :
• Easier to produce than reservoir devices
• Can deliver high molecular weight compounds.
Disadvantages
• Cannot obtain zero-order release
• Removal of remaining matrix is necessary for implanted system.
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Schematic representation of Schematic representation of diffusion
diffusion sustained drug sustained drug
release: Reservoir system release: Matrix system
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DISSOLUTION SUSTAINED SYSTEM :
A drug with a slow dissolution rate will demonstrate sustaining properties,
since the release of the drug will be limited by the rate of dissolution.
SR preparation of drugs could be made by decreasing their rate of dissolution.
The approaches to achieve this include preparing appropriate salts or derivatives,
coating the drugs with slowly dissolving materials or incorporating it into a tablet with
a slowly dissolving carrier.
Reservoir type :
The drug is coated with a given thickness coating, which is slowly dissolved in the
contents of GI tract. By alternating layers of the drug with the rate controlling coats, a
pulsed delivery can be achieved.
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Matrix type :
The more common type of dissolution sustained dosage form as it can be either a
drug impregnated sphere or a drug impregnated tablet, which will be subjected to
slow erosion .
Single bead-type device with alternating drug and rate-
controlling layers;
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pH-DEPENDENT FORMULATION :
For a drug labile to gastric fluid pH/ irritating to gastric mucosa, system can be developed.
Core tablet of gastric fluid-sensitive drug + Intestinal fluid insoluble
polymers –HMC phthalate and ethyl
cellulose
In stomach , coating membrane resists the degradation of the drug to the gastric fluid
Gastric Emptying
The drug reaches the small intestine ; coating membrane is dissolved away by the intestinal
fluid (pH> 7.5)
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Drug is delivered in a controlled mode in the intestine by a combination of drug
dissolution in the core and diffusion through pore channels.
pH-INDEPENDENT FORMULATION :
most drugs are either weak acids or weak bases, the release from SR formulations is
pH-dependent.
Buffers such as salts of amino acids, citric acid, phthalic acid, phosphoric acid or
tartaric acid can be added to the formulation, to help to maintain a constant pH thereby
rendering pH-independent drug release.
A buffered SR formulation is prepared by mixing a basic or acidic drug with one or
more buffering agent, granulating with appropriate pharmaceutical excipients and
coating with GI fluid permeable film forming a polymer.
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Methods using ion-exchange :
• Ion-exchange systems generally use resins composed of water-insoluble cross-
linked polymers. These polymers contain salt-forming functional groups in repeating
positions on the polymer chain.
• The drug is bound to the resin and released by exchanging with appropriately
charged ions in contact with the ion-exchange groups.
For the better release in this system is to coat the ion-exchange resin with
hydrophobic rate-limiting polymer.
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Hydrogels :
▪ Hydrogels are water swollen three dimensional structures composed of primarily
hydrophilic polymers
▪ They are insoluble because of chemical or physical cross-links
▪ The physical crosslinks includes crystallites, entanglements or weak association
like H-bond Vanderwaal ’s force
▪ Provide desirable protection of labile drugs peptides and proteins.
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Altered density formulations :
It is reasonable to expect that unless a delivery system remains in the vicinity of the
absorption site until most, if not all of its drug contents is released, it would have limited
utility.
To this end, several approaches have been developed to prolong the residence time of
DDS in the GI tract.
High-density approach
In this approach, the density of the pellets must exceed that of normal stomach content
and should therefore, be at least 1-4 g/cm3.
Low-density approach
Globular shells which have an apparent density lower than that of gastric fluid can be
used as a carrier of the drug for SR purpose.
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Delayed transit and continuous release system:
• Designed to prolong their residence in the GI tract along with their release.
They are fabricated to detain in the stomach.
• The drug present therein should be stable to gastric pH.
• Includes muco-adhesive system and size based systems
• They release drug only at specific site in the GIT.
The drugs contained in the system are:
1. Known to cause gastric distress.
2. Destroyed in the stomach or by intestinal enzymes
3. Meant to extent local effect at a specific GI site.
4. Absorbed from a specific intestinal site.
Two types are:
1. Intestinal release systems
2. Colonic release systems
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Colonic Release Systems
• Drugs are poorly absorbed through colon, but may be delivered to this site for two reasons,
i.e. local action as needed in treatment of ulcerative colitis, infection or diarrhoea and
systemic absorption of proteins and peptides (insulin and vasopressin). Design principles
for these delivery systems take advantages of:
• The specific pH of colon – pH sensitive bioerodible polymers like polymethacrylates
(e.g. combination of Eudragit 10055 and Eudragit S) release the medicament only at the
alkaline pH of the colon.
• The colonic microflora – coating of drug delivery system with polymers, which can be
cleaved only by the azoreductase of colonic bacteria to release the medicament.
• The small intestine transit time – swelling-induced time-controlled drug delivery systems
lead to a delay in drug release. Polymers used are poly(ethyl-acrylate-methylmethacrylate)
i.e. Eudragit NE 30 D or Eudragit RS.
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CONTROLLED RELEASE FORMULATION :
OSMOTIC PRESSURE ACTIVATED SYSTEM :
• These types are also known as oros.
• A semi permeable membrane is placed around the tablet, particle or drug solution
that allows transport of water into tablet with eventual pumping of drug solution
out of the tablet through the small delivery aperture in tablet core.
Two types are:
• 1. osmotic core with drug.
• 2. drug in flexible bag with osmotic core surrounding.
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• The drug is released at constant zero-order rate.
• The reservoir is made up of drug and osmotic agent like mannitol or KCL.
• The release of drug from the reservoir is unaffected by the conditions of GIT.
• The release of drug is depended on factors like size of orifice, thickness of
semipermeable membrane, permeability of membrane, osmotic properties of core
and stability of the drug.
• By optimizing formulation and processing factor, the osmotic system can deliver
the drug of diverse nature at pre-programmed rate.
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Mechanism of drug release in SR Formulation :
Diffusion is rate limiting:
• Diffusion is driving force where movement of drug molecules occurs
from high concentration in the tablet to lower concentration in the
gastrointestinal fluids.
• It depends on surface area exposed to gastric fluid, diffusion pathway,
drug concentration gradient, and diffusion coefficient of the system
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It can follow two methods,
1. The drug is formulated in an insoluble matrix: the gastric fluid penetrates the
dosage form and dissolves the medicament and release the drug through
diffusion.
2. The drug particles are coated with polymer of defined thickness, the portion of
the drug slowly diffuse through the polymer to maintain constant level in blood.
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Dissolution is rate limiting:
• The drugs of poor solubility(BCS class2 and 4) are inherently sustained release
forms. Water soluble drugs are coated with polymeric material
eg., Polyethylene glycol or incorporate a water insoluble carrier to reduce
dissolution of the drug.
• Avoid the use of disintegrating agent to promote delayed release.
Rate dissolution = ks (Solubility)(Surface area) particle size control
selection of complexing agent
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Both depends upon pH and composition of gastric and intestinal fluids.
Eg : Tannate (salt / esters of Tannic acid ) are complexes of bases are Hydrolysed in
both acidic and basic media.
Release is controlled by ion exchange:
• Ion exchangers are water insoluble resinous material containing salt forming anionic
and cationic groups.
• The drug solution is mixed with resin and dried to form beads which are tableted.
• The drug release depends on high concentration of charged ions in gastrointestinal
tract where, the drug are exchanged and diffused out of the resin into the surrounding
fluid.
• It relies upon the environment of resin and not pH or enzyme on absorption site.
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Osmotic pressure is rate limiting:
• Osmosis is the phenomenon in which the flow of liquid occurs from lower
concentration to higher concentration through a semi permeable membrane which
allows the transfer of liquid only.
• The whole drug is coated with a semi permeable membrane with a hole on one end of
the tablet made by a laser beam.
• The GF penetrates through the membrane, solubilises the drug and increases the
internal pressure which pumps the drug solution out of the aperture.
• The delivery rate is constant provided that the excess of drug present inside the tablet.
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Drug release from the Matrix Embedded system:
• Permeation of matrix by water / body fluids
erosion of matrix drug release
• Drug dissolves in matrix
release by diffusion.
Drug release from planar surface of insoluble matrix can be found out by Higuchi
equation :
Q = K D Cs t/h
Eg: Chlorpheniramine maleate in MC matrices.
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Evaluation:
1.Thickness:
The thickness of a tablet is the only dimensional variable related to the
process. Thickness of individual tablets may be measured by a micrometer. Other
techniques involve placing 5 or 10 tablets in a holding tray, where their total
thickness may be measured by a sliding caliper scale. Tablet thickness should be
controlled within a ± 5 % variation of a standard. Thickness must be controlled to
facilitate packaging. It is expressed in mm.
Measured by;
-Micrometer
-Studying caliber scale method
-Digital read out calibar
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2.Uniformity of content:
A physically sound tablet may not produce the desired effects. To evaluate a tablet
potential for efficacy, the amount of drug per tablet needs to be monitored from tablet to
tablet and batch to batch. For this test according to BP using a suitable analytical method,
determine the individual contents of active substance(s) of 10 tablets taken at random.
The tablet complies with the test according to BP, if each individual content is between 85%
and 115% of the average content. The tablet fails to comply with the test if more than one
individual contents are outside these limits or if one individual content is outside the limits of
75% to 125% of the average content.
If one individual content is outside the limits of 85% to 115%, but within the limits of 75%
to 125%, determine the individual contents of another 20 tablets taken at random.
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3.Uniformity of weight test:
According to the USP weight variation test is run by weighting 20 tablets
individually calculating the average weights and comparing the individual tablet
weights to the average. The value of weight variation test is expressed in
percentage.
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4.Hardness Test or Tablet Crushing Strength or Fracture resistance Method :
The force required to break the tablet in a diametric compression test.
The tester consists of a barrel containing a compressible spring held between two
plungers.
The lower plunger is placed in contact with the tablet and zero reading is taken.
The upper plunger is then forced against a spring by turning a threaded bolt until the
tablet fractures.
As the spring is compressed, a pointer rides along a gauge in the barrel to indicate the
force. The force of fracture is recorded in kilogram.
Ex; Monsonto tester ; Pfizer tester; Erweka tester
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5.Frailability test :
also called Attrition Resistance Method
measures tablet strength
Used to measure the tablet strength by mimicking the kind of forces to tablet is subjected
during handling between its production and administration.
Ex; Roche friabilator
6.Dissolution Test : (In vitro drug release studies )
Drug release studies were conducted using USP dissolution apparatus-2 paddle type at
a rpm of 50 at 37±0.5·C .The dissolution media was 900ml of 0.1M Phosphate buffer and
sink conditions was maintained for whole experiment. Samples are withdrawn at regular
intervals and drug contents was analysed after suitable dilution with a UV
spectrophotometer.
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Drug dissolved at specific time periods was plotted as cumulative percent rrelease
versus time.
7.Stability Test :
Testing at normal and exaggerated conditions of comparative light and humidity.
Physical , Chemical stability and release profile measured at different time
intervals.
8.In vivo test :
To determine ;
fraction of drug administered
influence of food on drug absorption
duration of action
Cmax/Cmin ratio of steady state.
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List of some marketed sustained release formulations :
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POLYMERS
• Polymer science has been the backbone for the development of new formulations for
the past few years and its advances have led to the development of several applications
in pharmaceutical sciences.
• These are widely used as pharmaceutical aids(suspending agent, emulsifying agent,
adhesives, coating agents, adjuvants etc.), packaging materials and medical devices
both in conventional and controlled drug- delivery systems.
• The word polymer is derived from Greek words
“Poly” means Many,
“Mers” means Parts / Units.
• A polymer is a large molecule made up of many small repeating units and are
formed by a process called Polymerization.
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POLYMERS USED I0N SR/CR FORMULATION :
Polymers Example
1. Hydrophilic Polymers Hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl
cellulose(HPC), hydroxyl ethyl cellulose (HEC), Xanthan gum,
Sodium alginate, poly(ethylene oxide), and cross linked
homopolymers and co-polymers of acrylic acid
2. Hydrophobic Polymers Includes waxes and water insoluble polymers in their
formulation
3. Waxes Carnauba wax, bees wax, candelilla wax, micro crystalline wax,
ozokerite wax, paraffin waxes and low molecular weight
polyethylene.
4. Insoluble polymers Ammoniomethacrylate co-polymers (Eudragit RL100, PO,
RS100, PO), ethyl cellulose, cellulose acetate butyrate, cellulose
acetate propionate and latex dispersion of methacrylic ester
copolymers.
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Classifications :
BASED ON BACKBONE :
• Polymers With Carbon Chain Backbone:
Polyethylene, polypropylene, polystyrene, poly(vinyl chloride),
polytetrafluoroethylene, polyacrylonitrile, poly(vinyl alcohol), poly(vinyl acetate),
polyacrylamide, poly(methylmethacrylate), polyvinylpyrrolidone etc.
• Polymers With Hetero chain Backbone:
Poly(ethylene oxide), poly(propylene oxide), cellulose, amylose, pectinic acid,
polyethylene glycol terephthalate, polydimethylsiloxane etc.
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BASED ON STRUCTURE:
Linear Polymers:
• In these polymers monomers are linked with each other and form a long straight
chain.
• These chain have no any side chains.
• Ex: Polythene, PVC, Nylon, Polyesters etc.
• Their molecules are closely packed and have high density, tensile strength and
melting point
Branched Polymers:
They have a straight long chain with different side chains.
Their molecules are irregularly packed hence they have low density, tensile
strength and melting point.
Ex: Polypropylene (side chain –CH3), amylopectin and glycogen.
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Network or cross linked Polymers:
In these monomeric units are linked together to constitute a three dimensional
network.
They are hard, rigid and brittle due to their network structure
Ex: Bakelite, Maia mine, Formaldehyde resin, Vulcanized rubber etc.
BASED ON POLYMERISATION
Addition Polymers:
• The polymers formed by the addition of monomers repeatedly without removal
of by-products are called addition Polymers.
• These Polymers contain all the atoms of monomers.
Ex: Orion, Teflon, Polypropylene, PVC.
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Condensation Polymers:
• They are formed by the combination of two monomers by removal of small
molecules like water, alcohol or NH3.
• They have ester and amide linkage in their molecules.
• Ex: Polyamides(Nylons), Polyesters, Polyurethanes
BASED ON MOLECULAR FORCES
Elastomers:
• These are the polymers in which polymer chains are held up by weak attractive
forces.
• They contains randomly coiled molecular chains having few cross links.
• As the strain is applied polymer get stretched and as the force is released
polymer regain its original position.
• Ex: Neoprene, Vulcanized rubber.
Fibers:
• They have high intermolecular attractive force like H-Bonding.
• They have high tensile strength and used in textile industries
• Ex: Nylon-6, Nylon-66 and TerMywylwPehwan.rDmuealoGMuiidxe.c.Coomm
BASED ON SOURCE OF ORIGIN :
Natural Polymers:
• Polymers either obtained from plants or animals are called Natural polymers.
Ex: Cellulose, Jute, Lihen, Silk, Wool, Leather, RNA, DNA, Natural Rubber.
Semisynthetic Polymer:
• The Polymers obtained by simple chemical treatment of natural fibers to improve
their physical properties like lastrus nature, tensile strength are called semisynthetic
fibers.
• Ex: Acetate rayon, Cupra Ammonium silk, Viscous rayon.
Synthetic Polymer:
• The fibers obtained by polymerization of simple chemical molecules in laboratory
are synthetic fibers.
• Ex: Nylon, Terylene, Polythene, polystyrene, Synthetic rubber, PVC, Bakelite,
Teflon, Orion etc.
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BASED ON POLYMERIZATION MECHANISM :
Chain Polymerization:
• These polymerizations are also known as Vinyl Polymerizations, because most of
the monomers of interest are compounds that contain a vinyl group.
• Chain Polymerization can be divided into 4 types according to the nature of active
center.
1) Free Radical
2) Anionic
3) Cationic
4) Ziegler- Natta
Free Radical Polymerization:
A free radical is a species bearing an odd number of electrons and hence has an
unpaired electron
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Occurs by three stages :
Initiation , Propagation and termination.
Anionic polymerization:
• In anionic polymerizations the growing chain end is an anion and is thus
associated with a positive counter ion.
• Only monomers that contain an electron-withdrawing substituent on the
double bond and can stabilize an anion will undergo anionic polymerizations.
Cationic Polymerization:
• These are also ionic polymerizations, in that the active chain end is a cation
and the associated counterion is a negative species.
• Only monomer that contain an electron-donating substituent on the double
bond that is capable of stabilizing a cation will undergo cationic
polymerizations.
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Ziegler-Natta Polymerization:
• The combination of metal alkyls and transition metal compounds are known as
Ziegler-Natta catalyst system.
• Of particular importance are aluminium alkyls such as aluminium triisobutyl
and titanium or vanadium halides such as Ticl4, Vcl4, Ticl3 or Vcl3.
• These catalyst systems are not only capable of polymerizing olefins such as
ethylene or propylene, at essentially atmospheric pressure to very high
molecular weight polymers, but are also capable of producing stereoregular
polymer.
• For this reasons, these catalysts are of enormous industrial importance.
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Polymer properties
• Polymers display different thermal, physical and mechanical
properties depending on their structure, molecular weight, linearity,
intra- and intermolecular interactions.
Mechanical properties:
• Depending on their structure, molecular weight and intermolecular
forces, polymers resist differently when they are stressed.
• They can resist against stretching (tensile strength),
compression(compressive strength), bending (flexural strength),
sudden stress(impact strength) and dynamic loading.
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Chemical properties:
• The attractive forces between polymer chain play a large part in
determining polymer’s properties.
• Because polymer chains are so long, these inter chain forces are amplified
far beyond the attractions between conventional molecules.
• These strongest forces typically result in higher tensile strength and higher
crystalline melting points
Viscoelastic properties:
• Polymer are neither a pure elastic nor a pure fluid material.
• They have the ability to store the energy(elastic behavior) and dissipate
it(viscous behavior).
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Thermal transitions:
• The volume of a polymer can change with temperature as a first or
second order transition.
• When a crystal melts, the polymer volume increases significantly as the
solid turns into liquids. The melting temperature(Tm) represents a first-
order thermal transition in polymers.
• The volume of an amorphous polymer gradually changes over a wide
temperature range or so called Glass transition temperature. This
behavior represents a Second-order thermal transition in polymers.
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Applications In Drug Delivery:
Cationic Polymers :
• coating applications : Dimethyl amino ethyl methacrylate for a functional
group.
• Butyl methacrylate, methyl methacrylate, dimethyl aminoethyl methacrylate
Used as pH dependent drug delivery platforms to protect sensitive drugs, to
mask unpleasant taste and odour, to protect the active ingredient from moisture
and also to improve drug storage stability.
Anionic Polymers:
• Eudragit L and S and are generally used for delivery into the duodenum,
jejunum, ileum or colon.
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Neutral polymers:
• Acrylate or methacrylate polymers with or without aminoethyl
functionality are generally insoluble or have pH-independent swelling
property.
• These are neutral acrylic polymers which are used for sustained release
applications where insolubility of the polymeric drug carrier is very much
desirable.
• Neutral polymers with added functionality are supplied as powder (e.g.,
Eudragit RS PO)
granule (e.g., Eudragit RS 100), and
aqueous dispersions (e.g., Eudragit RS 30 D).
• Neutral polymers with no added functionality are supplied as aqueous
dispersions (Eudragit NE30D, NM30D, and NE40D).
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• Polymers used in sustain by preparing biodegradable microspheres.
• Polymers protects the drug from degradation or release in the stomach and
small intestine. It also ensures or abrupt or controlled release of the drug
in the proximal colon,.
• To target the delivery of drug to a specific region in the gastrointestinal
tract i.e. Stomach.
• Pharmaceutical polymers are widely used to achieve taste masking,
controlled release(eg., Extended, pulsative & targeted), enhanced stability
and improve bioavailability.
• polymers have found application in liquid dosage forms as rheology
modifiers
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BIODEGRADABLE POLYMERS:
• Biodegradable polymers have properties of degrading in biological fluids
with progressive release of dissolved or dispersed drug.
• The most promising area of application involves drug-composites which
are implanted injected or inserted.
TYPES :
Natural :
Polysaccharides and protein- based polymers
Synthetic :
Polyesters or copolyesters of lactic acid and glycolic acid,
polycaprolactone, polyanhydrides, and polyethylene glycol .
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Mechanism of Release :
• the drug can be released from a dosage form as a result of polymer erosion. Erosion
occurs because of biodegradation or swelling and might happen within the bulk of the
polymer or may be limited to the polymer surface at a time. Porous and nonporous
platforms can provide bulk and surface erosion, respectively.
• Polymers with ester and amide functional groups are susceptible to a hydrolytic
degradation in strong acidic and basic environment.
• When a polymer starts to erode from its surface, the drug imbedded within the polymer
matrix will be released at a rate depending on the erosion rate of the polymer. If erosion
happens in bulk, a much faster release is expected as an enormous number of
hydrolysable sites are simultaneously cleaved up in water.
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• Alternatively, a drug may be released as a result of matrix swelling. The matrix is
made of non biodegradable but erodible polymers, which control the drug delivery
due to its swelling. A polymer in its swollen form is mechanically weak and can be
eroded at different rates depending on the swelling feature of the matrix.
• A fast swelling hydrogel may undergo faster erosion and provide faster drug release
compared with a slow swelling hydrogel. The release kinetics from a swellable matrix
is generally zero-order.
Example :
Leuprolide(Eligard), a delivery system for prostate cancer, is supplied as an injectable
suspension that utilizes the Atrigel technology for delivering the hormone Leuprolide
acetate. The delivery system consists of a biodegradable (Lactide- Co-Glycolide)
Copolymer dissolved in biocompatible solvent.
Doxycycline(Atridox), a bio-absorbable delivery system for the treatment of
periodontal disease, also uses Atrigel technology to deliver an antibiotic, doxycycline
hyclate.
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PHARMACEUTICAL APPLICATION :
Water-Soluble Synthetic Polymers
Poly (acrylic acid) Cosmetic, pharmaceuticals, immobilization of cationic drugs, base for
Carbopol polymers
Poly (ethylene oxide) Coagulant, flocculent, very high molecular- weight up to a few millions,
swelling agent
Poly (ethylene glycol) Mw <10,000; liquid (Mw <1000) and wax (Mw >1000), plasticizer, base for
suppositories
Poly (vinyl pyrrolidone) Used to make betadine (iodine complex of PVP) with less toxicity than
iodine, plasma replacement, tablet granulation.
Poly (vinyl alcohol) Water-soluble packaging, tablet binder, tablet coating
Polyacrylamide Gel electrophoresis to separate proteins based on their molecular weights,
coagulant, absorbent
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Cellulose-Based Polymers :
Ethyl cellulose Insoluble but dispersible in water, aqueous coating system for sustained release
Carboxymethyl cellulose Superdisintegrant, emulsion stabilizer
Hydroxyethyl and Soluble in water and in alcohol, tablet coating
hydroxypropyl celluloses
Hydroxypropyl methyl Binder for tablet matrix and tablet coating, gelatin alternative as capsule material
cellulose
Cellulose acetate phthalate Enteric coating
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Hydrocolloids :
Carrageenan Modified release , viscosifier
Alginic acid Oral and topical pharmaceutical products; thickening and suspending agent in a
variety of pastes, creams, and gels, as well as a stabilizing agent for oil-in-water
emulsions; binder and disintegrant
Chitosan Cosmetics and controlled drug delivery applications, mucoadhesive dosage
forms, rapid release dosage forms
Hyaluronic acid Reduction of scar tissue, cosmetics
Pectinic acid Drug delivery
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Water-Insoluble Biodegradable Polymers :
Lactide(-co-glycolide) polymers Microparticle–nanoparticle for protein
delivery
Starch-Based Polymers :
Starch Glidant, a diluent in tablets and capsules, a
disintegrant in tablets and capsules, a tablet
binder
Sodium starch glycolate Superdisintegrant for tablets and capsules in
oral delivery
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Plastics and Rubbers :
Polyurethane Transdermal patch backing (soft, comfortable,
moderate moisture transmission), blood pump,
artificial heart, and vascular grafts, foam in
biomedical and industrial products
Silicones Pacifier, therapeutic devices, implants, medical grade
adhesive for transdermal delivery
Polycarbonate Case for biomedical and pharmaceutical products
polyisobutylene Pressure sensitive adhesives for transdermal delivery
Polycyanoacrylate Biodegradable tissue adhesives in surgery, a drug
carrier in nano- and microparticles
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Polyethylene Transdermal patch backing for drug in adhesive design, wrap, packaging,
containers
Poly (methyl Hard contact lenses
methacrylate)
Poly (hydroxyethyl Soft contact lenses
methacrylate)
Polyethylene and Transdermal patch backing (when ethylene vinyl acetate copolymer is
polyethylene incompatible with the drug)
terephthalate
Acrylic acid and butyl High Tg pressure–sensitive adhesive for transdermal patches
acrylate copolymer
2-Ethylhexyl acrylate Low Tg pressure–sensitive adhesive for transdermal patches
and butyl acrylate
copolymer
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References :
1. Joseph R.Robinson ,VincentH.L.Lee(eds) ,Controlled Drug
Delivery Fundamentals and Application , Drugs and Pharmaceutical
Sciences,Vol29,Second Edition, revised and expanded, New york,
Marcel Dekker, 1987;140-178
2. Martin’s physical pharmacy and pharmaceutical sciences sixth
edition.
3.The Theory and Practice of Industrial Pharmacy by Lachman and
Liberman ; 4th Edition; 597-621
4.Sustained and controlled drug delivery system: A review.Rakesh
Rosahn mali, Vaishali Goel, Sparsh Gupta , International Journal of
Research in Pharmaceutical and Nano Science.
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5. Formulation Appproaches for Sustained release dosage forms; A
review ; sudhir karna , Shashank Chaturvedi, Vipin Agarwal
,Mohammed Alim ; Asian Journal of Pharmaceutical and Clinical
Research.
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