NOVEL DRUG DELIVERY SYSTEM (BP704T)

UNIT-I
SYLLABUS
Controlled drugdelivery 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.

CONTROLLED DRUG DELIVERY SYSTEMS

Introduction

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 anti-
foulants (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 the 10 th 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
in1952.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
to1970 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.
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 controlled-
release 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 Definitions of Controlled Release Dosage Forms

The United States Pharmacopoeia (USP) defines 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
2-fold 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 “extendedrelease”. 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 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 with in the body.

RATIONALE
Thebasicrationaleofacontrolledreleasedrugdeliverysystemistooptimizethebiopharmaceutics,ph
armacokinetics, and pharmacodynamics properties of a drug in such a waythat its utility
ismaximized through reduction inside effects and cure or control of diseasecondition in the
shortest possible time by using smallest quantity of drug, administered by
mostsuitableroute.Theimmediatereleasedrugdeliverysystemlackssomefeatureslikedosemainten
ance, controlled release rate and site targeting. An ideal drug delivery system shoulddeliver
thedrugataratedictatedbytheneedofbody overaspecifiedperiodoftreatment.

Fig.1-Plasmadrugconcentration-timeprofile

AdvantagesofControlReleaseDosageFormsClinical

Advantages
□ Reductioninfrequencyofdrugadministration
□ Improvedpatientcompliance
□ Reductionindruglevelfluctuationinblood
□ Reductionintotaldrugusagewhencomparedwithconventionaltherapy
□ Reductionindrugaccumulationwithchronictherapy
□ Reductionindrugtoxicity(local/systemic)
□ Stabilizationofmedicalcondition(becauseofmoreuniformdruglevels)
□ Improvementinbioavailability ofsomedrugsbecauseofspatialcontrol
□ Economicaltothehealthcareprovidersandthepatient

Commercial/IndustrialAdvantages
□ Illustrationofinnovative/technologicalleadership
□ Productlife-cycleextension
□ Productdifferentiation
□ Marketexpansion
□ Patentextension
DisadvantagesofCRDDS

□ Delayinonsetofdrugaction
□ Possibilityofdosedumpinginthecaseofapoorformulationstrategy
□ Increasedpotentialforfirstpassmetabolism
□ GreaterdependenceonGIresidencetimeofdosageform
□ Possibilityoflessaccuratedoseadjustmentinsomecases
□ Costperunitdoseishigherwhencomparedwithconventionaldoses
□ NotalldrugsaresuitableforformulatingintoERdosageform

Selectionofdrugforformulationintoextendedreleasedosageformisthekeystep.Followingcandidates
aregenerallynotsuitableforERdosageforms

Selectionofdrugcandidatesor
characteristicsthatmaymakeadrugunsuitableforControlreleasedosageform

□ Shorteliminationhalf-life
□ Longeliminationhalf-life
□ Narrowtherapeuticindex
□ Poorabsorption
□ Activeabsorption
□ Loworslowabsorption
□ Extensivefirstpasseffect

Parametersfordrugselection

Parameter: Preferred values/property

Molecularweight/size: <1000

Solubility: >0.1µg/mlforpH1topH7.8

pKaNonionizedmoiety: >0.1%atpH1topH7.8

Apparent partitioncoefficient:High

Absorptionmechanism: Diffusion

Generalabsorbability: FromallGIsegments

Release: ShouldnotbeinfluencedbypHandenzymes
BIOPHARMACEUTICANDPHARMACOKINETICASPECTSINTHEDESIGNOFCONT
ROLLEDRELEASEPERORALDRUGDELIVERYSYSTEMS

Controlled release drug delivery systems are dosage forms from which the drug is released by
apredeterminedratewhichisbasedonadesiredtherapeuticconcentrationandthedrug’spharmacokin
eticcharacteristics
Biologicalhalf-life(t½)
The shorterthe t½ ofadrug thelarger will be the fluctuations betweenthemaximum steadystate
concentration and maximum steady state concentration upon repetitive dosing. Thus
drugproductneedstobeadministeredmorefrequently.
Minimumeffectiveconcentration(MEC)
If a minimum effective concentration, MEC is required either frequent dosing of a
conventionaldrug productisnecessary or acontrolledrelease preparationmaybechosen.
DosesizeandExtentofduration
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 asystem.
Relativelylongt1/2orfluctuationdesiredatsteadystate
ItisthebeliefofsomethatneitheraSRnoraCRDDSisneededorusefulfordrugshavingat
½ of 12 hours or more. This is not so because there are two cases for which a 12 or 24
CRDDSseems to beindicated:
1. A drug having a t ½ between 12 and 72 hours may be designed for a CRDDS
permittingapplication for every two to three days. The decline of the blood level time curve
after release ofthe drug from the system will depend on the drug’s t ½. Naturally, fluctuation
between Css maxand Css min may accordingly be relatively large in other words on adds slow
release to the slowelimination process.

Forsomedrugshavingat1/2between20and100hrs,
andwhichareintendedforlongtermuse,onemaydesiresmallfluctuationsbetweenpeaksandtroughsats
teady
2. stateseithertoachieveacertaintherapeuticeffectorbecausethetherapeuticrangeisnarrow.

DESIREDBIOPHARMACEUTICCHARACTERISTICSOFDRUGTOQUALIFYFORC
RDDS

Molecularweightorsize
Small molecules may pass through pores of a membrane by convective transport. This applies
toboth, the drug release from the dosage form and the transport across a biologic membrane.
Forbiologicmembranesthelimitmaybeamolecularweightof150and400respectivelyforsphericalm
oleculesandchainlikecompoundsrespectively.
Solubility
For all mechanisms of absorption the drug must be present at the site of absorption in the form
ofsolution. During the Preformulation study it is necessary to determine the solubility of the
drug atvariouspHvalues. Ifthesolubilityisless
than0.1μg/ml(inacidicmedium)onemayexpectvariableandreducedbioavailability.

Ifthesolubility islessthan0.01μg/mlabsorptionand availabilitymostlikely

becomedissolutionlimiteddissolutionlimited.Hence drivingforcefordiffusionmaybe inadequate.
It seems that drugs are well absorbed by passive diffusion from the small intestine upon per
oraladministration ifat least0.1to1%is nonionisedform.

Apparentpartitioncoefficient(APC)
Drugsbeing absorbedby passive diffusionmusthave a certainminimalAPC.The highertheAPC
in an n-octanol/buffer system the higher is the flux across a membrane for many drugs.
TheAPC should be determined for the entire pH range in the GI tract. The APC must also be
appliedforpartitionofthedrugbetweenCRDDSandthebiologicalfluid.

Generalabsorptionmechanism
For a drug to be a variable candidate for per oral CRDDS, its absorption mechanism must be
bydiffusion throughout the entire GI tract. The term diffusion here refers to the dual pathway
ofabsorption either by partitioning into the lipid membrane (across the cells) or by passing
throughwater filled channels (between the cells). It is also important that absorption occurs
from allsegments of the GI tract which may depend on the drug’s pKa, the pH in the segment,
binding ofdrug to mucus, blood flow rate, etc. The absorption process seems to be highly
dependent on thehydrodynamics in theGIlumen.
Even though that first order and square root of time release can result in highly effective
drugdeliverysystemsitiswidelybelievedthattheultimategoaliszeroorderreleaseprofile.
Zero order release invitro release will produce zero order in vivo release and zero order in
vivoabsorption only if; (1) the entire GI tract behaves as a one compartment model, i.e. the
varioussegmentsthroughout theGI tract are homogeneous with respectto absorption, and (2)
drugreleaserateistheratelimitingstepintheabsorptionprocess.
With firstorder releaseon the other hand, smaller andsmaller amountsare released per unit
oftimewithincreasingtime.Assumingthatrateofabsorptiongetsslowerpastthesmallintestinedue to
increased viscosity, decreased mixing, and decreased intestinal surface area, less drug
isabsorbed.
Inanycase,thedrugreleasefromtheCRDDSshouldnotbeinfluencedbypHchangeswithintheGItract
,byenzymespresentinthelumen,peristalsis,etc.
For all practicality, the one compartment open model is quite suitable to design CRDDS for
mostdrugs.

PharmacokineticparametersEliminationhalflife(t½)
Drugs having a t ½ and 8 hours are ideally suited for CRDDS.If the t½ is lessthan 1 hour
thedose size required to be incorporated for a 12 hour or 24 hour duration dosage form may be
toolarge.Ifthet½isverylongthereisusuallynoneedforaCRDDS,unlessitissimplyintendedforaredu
ctioninfluctuationofsteadystatebloodlevels.

Totalclearance(CL)
CL is a measure of the volume of distribution cleared of drug per unit of time. It is the
keyparameterinestimatingtherequireddoserateforCRDDS,andpredictingthesteadystateconcentr
ation.

Terminaldispositionrateconstant(Keorλz)Theterminaldispositionrateconstantoreliminationr
ateconstantcanbeobtainedfromthet½andisrequiredtopredictabloodleveltime profile.

Apparentvolumeofdistribution(Vz)
The Vz is the hypothetical volume of a drug would occupy if it were dissolved at the
sameconcentration as that found in blood. It is the proportionality constant relating the amount
of drugin thebodytothemeasuredconcentrationintheblood.
Among the trio CL, Vz, and t ½, the former two parameters are the independent variables and
thelastone isthedependentvariable.
TheVzorCLisrequiredtopredicttheconcentrationtimeprofile.

Absolutebioavailability(F)
The absolute bioavailability is the percentage of drug taken up into systemic circulation
uponextravascular administration.For drugs to be suitable for CRDDS one wantsanF value
tobeclose to 100%.

Intrinsicabsorptionrateconstant(Ka)
The intrinsic absorption rate constant of the drug administered peroral in the form of a
solutionshould be high,generally by an orderofmagnitude higher than the desired release rate
constantof the drugfrom the dosage form,inorder toinsure thatrelease processis the
ratecontrollingstep.

Therapeuticconcentration(Css)
The therapeuticconcentrations are thedesiredortargetsteady state peak concentrations
(Cssmax), the desired or target steady state minimum concentrations (Css min), and the mean
steadystateconcentration(Cssavg).ThedifferencebetweenCssmaxandCssministhefluctuation.Th
esmallerthedesiredfluctuationthegreatermustbetheprecisionofthedosageformperformance.
ThelowerCss,thesmallerVz,thelongert½,thehigherFandThelessamountofdrugisrequiredto
beincorporated intoa CRDDS.

Approachestodesigncontrolledreleaseformulations

1. Dissolutioncontrolledrelease
□ EncapsulationDissolutioncontrol
□ Seedorgranulecoated
□ Microencapsulation
□ MatrixDissolutioncontrol

2. Diffusioncontrolledrelease
□ Reservoirtypedevices
□ Matrixtypedevices

3. DiffusionandDissolutioncontrolledsystems
4. Ionexchangeresins
5. Osmoticallycontrolledrelease
MECHANISTICASPECTSFOR ORAL CONTROLLED RELEASE DRUG
DELIVERYFORMULATION

Dissolutioncontrolledrelease
Dissolutionisdefinedassolidsubstancesolubilizedinagivensolvent.Itisaratedeterminingstepwhenli
quidisdiffusingfromsolid.Severaltheoriesexplaindissolution:
Diffusionlayertheory,Surfacerenewaltheory,Limitedsolvationtheory.
NoyesWhitneyEquationd
c/dt=kD.A(Cs–C)dc/
dt=D/hA.(Cs–C)
dc/dt=Dissolutionrate,k=Dissolutionrateconstant(1storder),D=Diffusioncoefficient/
diffusivity,Cs=Saturation/maximumdrugsolubility,C=Conc.Ofdruginbulksolution,Cs-
C=concentrationgradient,h=Thicknessofdiffusionlayer.
Twocommonformulationsystemrelyondissolutiontodeterminereleaserateofdrugsare:
Encapsulateddissolutionsystem(ii)Matrixdissolutionsystem

Encapsulateddissolutionsystem
ThisisalsoknownasCoating
dissolutioncontrolledsystem.Dissolutionrateofcoatdependsuponstability&thicknessofcoat
ing.Itmaskscolor,odor,tasteandminimizeGIirritation.Controlledreleaseproductsbydecreasi
ngthedissolutionrateofdrugswhicharehighlywatersolublecanbeformulatedbypreparingapp
ropriatesaltorderivatives,bycoatingthedrugwithaslowlydissolvingmaterial,orbyincorporati
ngthedrugintoaslowlydissolving
carrier.Examples:Ornadespansules,ChlortrimetoRepetabs.

Matrixdissolutionsystem
Itisalsoknownasmonolithicdissolutioncontrolledsystem.InthisdissolutionIScontrolledby:
Alteringporosityoftablet,decreasingitswetability,dissolvingatslowerrate.Itfollowsfirstor
derdrugrelease.Thedrugreleasecanbedeterminedbydissolutionrateofpolymer.Examples:
Demeanedextencaps,Dimetappextentabs.
Diffusioncontrolledsystem
Itisamajorprocessforabsorptioninwhichnoenergyrequired.Inthisdrugmoleculesdiffusefromar
egionofhigherconcentrationtolowerconcentrationuntilequilibriumisattainedanditisdirectlypr
oportionaltotheconcentrationgradientacrossthemembrane.Inthissystemreleaserateisdetermin
edbyitsdiffusionthroughawater-insolublepolymer.Therearetwotypesofdiffusiondevices:
- Reservoirdiffusionsystem
- Matrixdiffusionsystem

Reservoirdiffusionsystem
Itisalsocalledaslaminatedmatrixdevice.Itisahollowsystemcontaininganinnercoresurroundedbywa
terinsolublemembraneandpolymercanbeappliedbycoatingormicroencapsulation.TheRatecontroll
ingmechanismisthatdrugwillpartitionintomembraneandexchangewiththefluidsurroundingthedru
gbydiffusion.CommonlyusedpolymersareHPC,ethylcellulose&polyvinylacetate.
Examples:Nico-400,Nitro-Bid.

Ratecontrollingsteps:Polymericcontentincoating,thicknessofcoating,hardnessofmicrocapsule.
Matrixdissolutionsystem

(a) RigidMatrixDiffusion:MaterialsusedareinsolubleplasticssuchasPVP&fattyacids.
(b) SwellableMatrixDiffusion:itisalsocalledasGlassyhydrogelsandpopularforsustainingther
eleaseofhighlywatersolubledrugs.Materialsusedarehydrophilicgums.Examples:Natural-
Guargum,Tragacanth.
Semisynthetic-HPMC,CMC,Xanthumgum.Synthetic-
Polyacrilamides.Examples:GlucotrolXL,ProcardiaXL
TheHiguchiEquationdescribingthedrugreleasefromthissystem
:Q=[DƐ/T(2A-ƐCs.t)]1/2WhereQ=amtofdrug release
perunitsurfaceareaattimet,D=diffusioncoefficientofdruginthereleasemedium,Ɛ=porosityofthem
atrix,Cs=solubilityofdruginreleasemedium,T=tortuosityofmatrix,A=concentrationofdrugpresen
tinmatrixperunitvolume.
Ratecontrollingstep:Diffusionofdissolveddruginmatrix.
 Dissolution&DiffusionControlledReleasesystem

Inthisdrugisencasedinapartiallysolublemembraneandporesarecreatedduetodissolutionofpartsof
membrane.Itpermitsentryofaqueousmediumintocore&drugisdissolvedordiffusedoutofthesyste
m.Ex-Ethylcellulose&PVPmixturedissolvesinwater&createsporesof insolubleethylcellulose

Ionexchangeresinscontrolledreleasesystem

Ionexchangeresinsarecross-
linkedwaterinsolublepolymerscarryingionizablefunctionalgroups.Theseresinsareusedfortastema
skingandcontrolledreleasesystem.Theformulationsaredevelopedbyembedding
thedrugmoleculesintheion-
exchangeresinmatrixandthiscoreisthencoatedwithasemipermeablecoatingmaterialsuchasEthylC
ellulose.ThissystemreducedthedegradationofdruginGIT.Themostwidelyusedandsafeion-
exchangeresinisdivinylbenzenesulphonate.Intabletformulationsion-

exchangeresinshavebeenusedasdisintegrant.
Principle:
Isbasedonpreparationoftotallyinsolubleionicmaterial
• Resinsareinsolubleinacidicandalkalinemedia
•Theycontainionizablegroupswhichcanbeexchangedfordrugmolecules
IERarecapableofexchangingpositivelyornegativelychargeddrugmoleculestoforminsolublepolysa
ltresinates.

Types:
TherearetwotypesofIER
CationicExchangeresins-RSO3-H+Resinsfunctionalgroups
AnionicExchangeresins–RNH3+OH

Mechanismofaction

IERcombinewithdrugtoforminsolubleioncomplexes
1.R-SO3–H++H2N–A R-SO3–NH3+-A

R-NH3+OH-+HOOC–B RNH3+-OOC-B+H2O

WhereA-
NH2isbasicdrugB-
COOHisacidicdrug
Theseresinatesareadministeredorally

2hrsinstomachincontactwithacidicfluidatpH1.2

Intestinalfluid,remainincontactwithslightlybasicpHfor6hrs.

DrugcanbeslowlyliberatedbyexchangewithionspresentinG.I.T

Inthestomach

®-SO3-NH3+-A+HCl ®-SO3-H++A-NH3+Cl-

®-NH3+Cl-+HOOC-B ®-NH3+Cl-+HOOC-B
 Un-

dissociatedThuscarboxylicacidwillbepoorlydissociatedinstomachandthusabs

orbed.

IntheIntestine
®--SO3-NH3+-A+ NaCl ®--SO3-Na++A-NH3+Cl-
BasicpHundissociated

®-NH3+-OOC–B+NaCl ®-NH3+Cl-+Na+-OOCBSodiumsaltofacid
(dissociationofacidsaltunabsorbed)Amine

saltwillbepoorly dissociatedinintestineandthusabsorbed.

(3)CLASSIFICATIONOFCONTROLLEDRELEASESYSTEM
Thecontrolledreleasesystemdividedintofollowingmajorclassesbasedonreleasepattern.
(1) Ratepre-programmeddrugdeliverysystem
(2) Activatedmodulateddrugdeliverysystem
(3) Feedbackregulateddrugdeliverysystem
(4) Sitetargetingdrugdeliverysystem

(1)Ratepre-programmeddrugdeliverysystem:
In this, the release of drug molecule from the delivery system is pre-planed with particular
flowrate profile ofmedicine. The system controls the molecular diffusion of drug molecules in
oracrossthebarriermediumwithinorsurroundingthedeliverysystem.

(1) Polymermembranepermeationcontrolledsystem
In this system, the drug is completely or partially encapsulated in a drug reservoir cubicle
whosedrug-
releasingsurfaceiscoveredbyflowratecontrollingpolymericmembrane.Indrugreservoir, the
drugcan be solid or dispersion of solid drug particle orconcentrateddrug solutionina liquidor
ina solid type dispersion medium.The polymeric membrane may be made-
upofthefabricatedformofhomogeneousorheterogeneousnon-
porousorpartialmicroporousorsemipermeablemembrane.

(2) Polymermatrixdiffusion-controlledsystem
In this drug, the reservoir is prepared by the homogeneously dispersing drug particles in the
ratecontrolling hydrophilic or lipophilic polymer matrix. The resultant medicated polymer
matrixprovidesthemedicateddiskwithdefinedsurfaceareaandcontrolledthickness.

(3) Microreservoirpartitioncontrolledsystem
The drug reservoirsarea suspensionof solidparticleinthe aqueoussolutionof the water-miscible
polymer. Micro-dispersion partition controlled system is prepared by the applying
highdispersiontechniques.Inshortreservoirandmatrixdispersionformsmicro-reservoir
 Fig.3-Matrixandmembranetypedeliverysystems

FACTORSINFLUENCINGTHEDESIGNANDACTOFCONTROLLEDRELEASEPROD
UCTS

(1)Physiologicalproperties

(1) Aqueous Solubility’s: Most of the active pharmaceutical moiety (API) are weakly acidic
orbasic in nature that affect the water solubility of API. Weak water soluble drugs are difficult
todesignthecontrolledreleaseformulations.Highaqueoussolubilitydrugshowburstreleasefollowe
d by a rapid increment in plasma drug concentration. These types of drugs are a
goodcandidateforCRDDS.ThepHdependentsolubilityalsocreatesaprobleminformulatingCRDD
S.BCSclass-III&IVdrugsarenotasuitablecandidateforthistypeofformulations.

(2) Partition coefficient (P-value): P-value denotes the fraction of the drug into oil &
aqueousphase that is a significant factor that affects the passive diffusion of the drug across
the
biologicalmembrane.ThedrugsarehavinghighorlowPvaluenotsuitableforCR,itshouldbeappropri
ateto dissolveinbothphases.

(3) DrugpKa:pKaisthefactorthatdeterminedtheionizationofdrugatphysiologicalpHinGIT.
Generally, the high ionized drugs are poor candidates for CRDDS. The absorption of
theunionized drug occurs rapidly as compared to ionized drugs from the biological
membranes.
ThepKarangeforanacidicdrugthationizationdependsonthepHis3.0to7.5andforabasicdrugitlaybet
ween 7 and11.

(4) Drug stability: Drugs that are stable in acid/base, enzymatic degradation, and other
gastricfluidsaregoodcandidatesforCRDDS.Ifdrugdegradedinthestomachandsmallintestine,itnot
suitableforcontrolledreleaseformulationsbecauseitwilldecreaseinbioavailability ofconcern
drug.
(5) Molecularsize&molecularweight:Themolecularsize&molecularweightaretwoimportantfa
ctorswhich affect themoleculardiffusibility across abiological membrane. Themolecular size
less than 400D is easily diffuse but greater than 400D create a problem in drugdiffusion.

(6) Protein binding: The drug-protein complex act as a reservoir in plasma for the drug.
Drugshowing highplasmaprotein binding arenotagood candidatefor CRDDS
becauseProteinbindingincreasesthebiologicalhalf-life.Sothereisnoneedtosustainthedrugrelease.

(2)Biologicalfactors
(1) Absorption: Uniformity in rate and extent of absorption is an important factor in
formulatingthe CRDDS.However,theratelimiting
stepisdruggedreleasefromthedosageform.Theabsorptionrateshouldrapidthenreleaseratetopreven
tthedosedumping.Thevariousfactorslikeaqueoussolubility,log
P,acidhydrolysis,whichaffecttheabsorptionofdrugs.

(2) Biologicalhalf-life (t1/2):Ingeneralthe drug ishaving shorthalf-life requiredfrequentdosing

and suitable candidate for controlled release system. A drug with long half-life
requireddosingafteralongtimeinterval.Ideally,thedrugshavingt1/22-
3hrsareasuitablecandidateforCRDDS.Drugshavet1/2morethan7-
8hrsnotusedforcontrolledreleasesystem.

(3) Dose size: The CRDDS formulated to eliminate the repetitive dosing, so it must contain
thelargedosethanconventionaldosageform.Butthedoseusedinconventionaldosageformgiveanind
icationofthedosetobeusedinCRDDS.Thevolumeofsustaineddoseshouldbeaslargeasitcomesunde
r acceptancecriteria.

(4) Therapeuticwindow:ThedrugswithnarrowtherapeuticindexarenotsuitableforCRDDS.Ifthe
deliverysystemfailedtocontrolrelease,itwouldcausedosedumpingandultimatetoxicity.

(5) Absorptionwindow:ThedrugswhichshowabsorptionfromthespecificsegmentinGIT,are a
poor candidate for CRDDS. Drugs which absorbed throughout the GIT are good candidatesfor
controlled release.
(6) Patient physiology: The Physiological condition of the patient like gastric emptying
rate,residentialtime,andGIdiseasesinfluencethereleaseofthedrugfromthedosageformdirectlyor
indirectly.

Pharmacokineticparametersconsiderduringthedrugselectionlistedasfollow.

Table.1-Pharmacokineticparametersfordrugselection
Parameter Comment
Biologicaloreliminationhalf-life Shouldbebetween2to6hrs
Eliminationrateconstant(KE) Requiredfordesign
Totalclearance(CLT) doseindependent
Intrinsicabsorptionrate shouldbegreaterthanthereleaserate
Apparentvolumeofdistribution(Vd) Vdeffecttherequiredamountofthedrug

Absolutebioavailability Shouldbe75%ormore
Steadystateconcentration(Css) lowerCssandsmallerVd
Toxicconcentration Thetherapeutic window should be
Broader
 POLYMERS

Polymers are becoming increasingly important in the field of drug delivery. The
pharmaceuticalapplicationsofpolymersrangefromtheiruseasbindersintabletstoviscosityandflow
controllingagentsinliquids,suspensionsandemulsions.Polymerscanbeusedasfilmcoatingsto
disguise the unpleasant taste of a drug, to enhance drug stability and to modify drug
releasecharacteristics. The review focuses on the significance of pharmaceutical polymer for
controlleddrug delivery applications.Sixty million patients benefit from advanced drug
delivery systemstoday, receiving safer and more effective doses of the medicines they need to
fight a variety ofhuman 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 away that the active agentis released fromthe materialin a predesigned
manner. The release
oftheactiveagentmaybeconstantoveralongperiod,itmaybecyclicoveralongperiod,oritmay be
triggered by the environment or other external events. In any case, the purpose
behindcontrollingthedrugdeliveryistoachievemoreeffectivetherapieswhileeliminatingthepotenti
alforbothunderandoverdosing.

POLYMERSASBIOMATERIALSFORDELIVERY-SYSTEMS

Arangeofmaterialshavebeenemployedtocontrolthereleaseofdrugsandotheractiveagents.Theearlie
stofthesepolymerswereoriginallyintendedforother,nonbiologicaluses,andwereselectedbecauseoft
heirdesirable physicalproperties,forexample:
□ Poly(urethanes)forelasticity.
□ Poly(siloxanes)orsiliconesforinsulatingability.
□ Poly(methylmethacrylate)forphysicalstrengthandtransparency.
□ Poly(vinylalcohol)forhydrophilicityandstrength.
□ Poly(ethylene)fortoughnessandlackofswelling.
□ Poly(vinylpyrrolidone)forsuspensioncapabilities.

Tobesuccessfullyusedincontrolleddrugdeliveryformulations,amaterialmustbechemicallyinertan
dfreeofleachableimpurities.Itmustalsohaveanappropriatephysicalstructure,withminimalundesire
daging,andbereadilyprocessable.Someofthematerialsthatarecurrentlybeingusedforcontrolleddru
gdeliveryinclude
□ Poly(2-hydroxyethylmethacrylate)
□ Poly(N-vinylpyrrolidone).
□ Poly(methylmethacrylate).
□ Poly(vinylalcohol).
□ Poly(acrylicacid).
□ Polyacrylamide.
 □ Poly(ethylene-co-vinylacetate).
□ Poly(ethyleneglycol).
□ Poly(methacrylicacid).

Polymers
• Insoluble,inert-polyethylene,polyvinylchloride,methylacrilate,ethylcellulose.
• Soluble–
methylcellulose,hydroxylethylcellulose,sodiumcarboxymethylcellulose,sodiumalginate.
Inamatrixsystemthedrugisdispersedassolidparticlewithinaporousmatrixformedofawaterin
solublepolymer,suchaspolyvinyl chloride.

Initially,drugparticlelocatedatthesurfaceofthereleaseunitwillbedissolvedandthedrugreleasedrapid
ly.Thereafter,drugparticalatsuccessivelyincreasingdistancefromthesurfaceofthereleaseunitwillbe
dissolvedandreleaseby diffusionintheporestotheexteriorofthereleaseunit.
Themainformulationfactorbywhichthereleaseratefrommatrixsystemcanbecontrolledare;theamou
ntofthedruginthematrix,theporosityofthereleaseunit&thesolubilityofthedrug.
However, in recent years additional polymers designed primarily for medical applications
haveentered the arena of controlled release. Many of these materials are designed to degrade
withinthe body,fewofthemamongthese 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
anaturalsteptoworkwiththesepolymersincontrolleddrugdeliverysystems.Thegreatestadvantage
of these degradable polymers is that they are broken down into biologically
acceptablemolecules that are metabolized andremovedfrom the body via normal metabolic
pathways.However, biodegradablematerials doproduce degradation by-productsthatmustbe
toleratedwithlittleornoadversereactionswithinthebiologicalenvironment.
 Thesedegradationproductsbothdesirableandpotentiallynondesirablemustbetestedthoroughly,
since there are a number of factors that will affect the biodegradation of the
originalmaterials.Thevariousimportantfactorsindicatingthebreadthofstructural,chemical,andpro
cessingpropertiesthatcanaffectbiodegradabledrugdeliverysystemsarelistedbelow:
□ Chemicalstructure
□ Chemicalcomposition
□ Distributionofrepeatunitsinmultimers
□ Presenceofionicgroups
□ Presenceofunexpectedunitsorchaindefects.
□ Configurationstructure.
□ Molecularweight.
□ Molecular-weightdistribution.
□ Morphology(amorphous/semicrystalline,microstructures,residualstresses).
□ Presenceoflow-molecular-weightcompounds.
□ Processingconditions.
□ Annealing.
□ Sterilizationprocess.
□ Storagehistory.
□ Shape.
□ Siteofimplantation.
□ Adsorbedandabsorbedcompounds(water,lipids,ions,etc.).
□ Physicochemicalfactors(ionexchange,ionicstrength,pH).

Physicalfactors(shapeandsizechanges,variationsofdiffusioncoefficients.

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