it contain general information about ph activated and ion activated controlled drug delivery system..

1. dept of pharmaceutics.dept of pharmaceutics. 11
pH-activated and ion-activatedpH-activated and ion-activated
controlled drug delivery systemcontrolled drug delivery system
Presented by
Chandrika y
1st
m-pharma
Dept of pharmaceutics
Facilited by
Shankar
Ass professor
Dept of pharmaceutics

2. dept of pharmaceutics. 2
Contents…Contents…
☼ pH-activated CDDSpH-activated CDDS
☼ Ion-activated CDDSIon-activated CDDS
☼ ReferencesReferences

3. dept of pharmaceutics. 3
pH-activated CDDSpH-activated CDDS
 This type of DDS permits targeting the delivery of aThis type of DDS permits targeting the delivery of a
drug only in the region with a selected pH range.drug only in the region with a selected pH range.
 Drugs administer orally would encounter a spectrumDrugs administer orally would encounter a spectrum
of pH ranging from 7 in mouth, 1-4 in the stomach,of pH ranging from 7 in mouth, 1-4 in the stomach,
and 5-7 in the small intestine.and 5-7 in the small intestine.
 Since most drugs are either weak acids or weak bases,Since most drugs are either weak acids or weak bases,
their release from formulation is pH dependenttheir release from formulation is pH dependent
 This type of system is designed for the controlledThis type of system is designed for the controlled
release of acidic (or basic) drugs in GIT at a raterelease of acidic (or basic) drugs in GIT at a rate
independent of the variation in GI-pH by formulatingindependent of the variation in GI-pH by formulating
them with sufficient buffering agents.them with sufficient buffering agents.

4. PreparationPreparation
► Procedure 1- using bufferProcedure 1- using buffer
 ItIt is prepared by first blending an acidic (or basic) drug withis prepared by first blending an acidic (or basic) drug with
one or more buffering agents, e.g. a primary, secondary, orone or more buffering agents, e.g. a primary, secondary, or
tertiary salt of citric acid,tertiary salt of citric acid,
 Granulating with appropriate excipients to form smallGranulating with appropriate excipients to form small
granules,granules,
 Then coating the granules with GI fluid-permeable film-Then coating the granules with GI fluid-permeable film-
forming polymer, e.g. cellulose derivatives.forming polymer, e.g. cellulose derivatives.
 The polymer coating controls the permeation of GI fluid. TheThe polymer coating controls the permeation of GI fluid. The
GI fluid permeating into the device is adjusted by theGI fluid permeating into the device is adjusted by the
buffering agents to an appropriate constant pH, at which thebuffering agents to an appropriate constant pH, at which the
drug dissolves and is delivered through the membrane at adrug dissolves and is delivered through the membrane at a
constant rate regardless of the location of the device in theconstant rate regardless of the location of the device in the
alimentary canal.alimentary canal.
dept of pharmaceutics. 4

5.  Procedure 2- using polymerProcedure 2- using polymer
a)a) Making a core tabletMaking a core tablet
b)b) Coating a core tablet with a combination of –Coating a core tablet with a combination of –
 Intestinal fluid-insoluble polymers.Intestinal fluid-insoluble polymers.
• Example- ethyl celluloseExample- ethyl cellulose
 Intestinal fluid soluble polymerIntestinal fluid soluble polymer
• Example- methyl celluloseExample- methyl cellulose
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6. Intestinal pH activated DDSIntestinal pH activated DDS
 It is fabricated by coating the drug containing core withIt is fabricated by coating the drug containing core with
a pH sensitive polymer combination.a pH sensitive polymer combination.
 A gastric fluid labile drug is protected by encapsulatingA gastric fluid labile drug is protected by encapsulating
it inside a polymer membrane that resist theit inside a polymer membrane that resist the
degradation action of gastric pH. such as thedegradation action of gastric pH. such as the
combination of ethyl cellulose and HMC phthalate.combination of ethyl cellulose and HMC phthalate.
 The drug is release by drug dissolution and poreThe drug is release by drug dissolution and pore
channel diffusion mechanism.channel diffusion mechanism.
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 In the stomach, coating membrane resists the action of
gastric fluid (pH<3) & the drug molecule thus
protected from acid degradation.
 After gastric emptying the DDS travels to the small
intestine & intestinal fluid (pH>7.5) activates the
erosion of the intestinal fluid soluble polymer from the
coating membrane.
 This leaves a micro porous membrane constructed
from the intestinal fluid insoluble polymer, which
controls the release of drug from the core tablet.
 The drug solute is thus delivered at a controlled
manner in the intestine by a combination of drug
dissolution & pore-channel diffusion.

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Gastric pH activated DDSGastric pH activated DDS

10. Ion-activated CDDSIon-activated CDDS
IntroductionIntroduction
♦CRDDSCRDDS are gaining the momentum in the recent decades, asare gaining the momentum in the recent decades, as
the rate of delivery of drug, intensity, duration of action havethe rate of delivery of drug, intensity, duration of action have
been the subject of increasing multidisciplinary research.been the subject of increasing multidisciplinary research.
♦After three decades a new era has started in modernAfter three decades a new era has started in modern
therapeutics.therapeutics.
♦One of the attractive methods for modified drug deliveryOne of the attractive methods for modified drug delivery
system preferable controlled type issystem preferable controlled type is ion-exchange resinsion-exchange resins asas
carrierscarriers for such system.for such system.
♦This system is satisfactorily be achieved for zero-order kineticsThis system is satisfactorily be achieved for zero-order kinetics
in drug delivery pattern.in drug delivery pattern.
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♦ Ionic or charged drug can be delivered by an this DDS.Ionic or charged drug can be delivered by an this DDS.
♦ This system are prepared by complexing an ionic drug with anThis system are prepared by complexing an ionic drug with an
ion-exchange resin containing a suitable counter ion.ion-exchange resin containing a suitable counter ion.
♦ Ion-exchange resins have specific properties like availableIon-exchange resins have specific properties like available
capacity, acid base strength, particle size, porosity andcapacity, acid base strength, particle size, porosity and
swelling on which, the release characteristics of drugswelling on which, the release characteristics of drug
resinates are dependent.resinates are dependent.
♦ Types of ion-exchange resins-Types of ion-exchange resins-
Cation-exchangersCation-exchangers: whose functional group can undergo reaction: whose functional group can undergo reaction
with cations of a surrounding solution.with cations of a surrounding solution.
Anion-exchangers:Anion-exchangers: whose functional group can undergo reactionwhose functional group can undergo reaction
with anion of a surrounding solution.with anion of a surrounding solution.

12. Ion-activated CDDSIon-activated CDDS
dept of pharmaceutics. 12

13. ► EXAMPLEEXAMPLE
► By forming a complex between a cationic drug with aBy forming a complex between a cationic drug with a
resin having a Soresin having a So33- group or between an anionic drug- group or between an anionic drug
with a resin having a N(CHwith a resin having a N(CH33))33 group.group.
► The granules of drug-resin complex are first treatedThe granules of drug-resin complex are first treated
with an impregnating agent & then coated with a water-with an impregnating agent & then coated with a water-
insoluble but water-permeable polymeric membrane.insoluble but water-permeable polymeric membrane.
► This membrane serves as a rate-controlling barrier toThis membrane serves as a rate-controlling barrier to
modulate the influx of ions as well as the release of drugmodulate the influx of ions as well as the release of drug
from the system.from the system.
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 Preparations of resinsPreparations of resins
► Cation exchange resinCation exchange resin is prepared by theis prepared by the
copolymerisation of styrene-(l) and divinyl bezene (ll).copolymerisation of styrene-(l) and divinyl bezene (ll).
► Sulfonic acid group (-SOSulfonic acid group (-SO33
--
HH++
) are introduced in to most of) are introduced in to most of
the benzene rings of the styrene-divinyl benzenethe benzene rings of the styrene-divinyl benzene
polymer.polymer.
► Anion exchange resinAnion exchange resin is prepared by firstis prepared by first
chloromethylating the benzene rings of the threechloromethylating the benzene rings of the three
dimensional styrene-divinyl benzene copolymer to attachdimensional styrene-divinyl benzene copolymer to attach
–CH–CH22Cl groups.Cl groups.
► Than causing these to react with a tertiary amine, suchThan causing these to react with a tertiary amine, such
as trimethylamine.as trimethylamine.

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Drug suitable for the resinateDrug suitable for the resinate
preparationpreparation
► Drug should have acidic or basic groups in their chemicalDrug should have acidic or basic groups in their chemical
structure.structure.
► The biological half-life should be 2-6 hrThe biological half-life should be 2-6 hr
► The drug is to be absorbed from all regions of the GIT. InThe drug is to be absorbed from all regions of the GIT. In
the case of limited absorption zone, the bioavailabilitythe case of limited absorption zone, the bioavailability
will be insufficient.will be insufficient.
► Drug should be stable sufficiently in the gastric juice.Drug should be stable sufficiently in the gastric juice.

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Important properties of ion-Important properties of ion-
exchange resinexchange resin

17.  Particle sizeParticle size
☼ The rate of ion-exchange reaction depends on the particle sizeThe rate of ion-exchange reaction depends on the particle size
of the resin particle.of the resin particle.
☼ Decreasing the size of resin particle significantly decrease theDecreasing the size of resin particle significantly decrease the
time required for the reaction to reach equilibrium with thetime required for the reaction to reach equilibrium with the
surrounding medium.surrounding medium.
☼ Most of the ion exchange resin are cold in the form of beads.Most of the ion exchange resin are cold in the form of beads.
When the beads is immersed in water they imbibe a limitedWhen the beads is immersed in water they imbibe a limited
amount of liquid to form homogenous gel like structure.amount of liquid to form homogenous gel like structure.
☼ Cation- exchange resinCation- exchange resin
schematicschematic
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18.  Porosity and swellingPorosity and swelling
♪ PorosityPorosity is defined as ratio of the volume of the material tois defined as ratio of the volume of the material to
its mass. The limiting size of ions, which can penetrate intoits mass. The limiting size of ions, which can penetrate into
a resin matrix depends strongly on the porosity.a resin matrix depends strongly on the porosity.
♪ The porosity of an ion- exchanger depends not only on theThe porosity of an ion- exchanger depends not only on the
polymerization but mainly on thepolymerization but mainly on the polymerizationpolymerization
procedures.procedures.
♪ The structural parameter depend considerably influence theThe structural parameter depend considerably influence the
swelling behaviour of the resin consequently have markedswelling behaviour of the resin consequently have marked
effect on the release characteristics of the drug resinate.effect on the release characteristics of the drug resinate.
♪ The amount of swelling index isThe amount of swelling index is directly proportionaldirectly proportional to theto the
number of hydrophilic functional group attached to thenumber of hydrophilic functional group attached to the
polymer matrix andpolymer matrix and inversely proportionalinversely proportional to the degree ofto the degree of
divinylbenzen cross linking present in the resindivinylbenzen cross linking present in the resin
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19.  Cross linkageCross linkage
♣ The percentage of cross-linking affects the purely physicalThe percentage of cross-linking affects the purely physical
structure of the resin particle.structure of the resin particle.
♣ Resin with low degree of cross-linking can take up aResin with low degree of cross-linking can take up a
considerable amount of water and swell into a structure thatconsiderable amount of water and swell into a structure that
is soft and gelatinous.is soft and gelatinous.
♣ However, resin with a high divinylbenxen content swell veryHowever, resin with a high divinylbenxen content swell very
little, these particle take up only small amount of water andlittle, these particle take up only small amount of water and
consequently are hard and brittleconsequently are hard and brittle
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20.  StabilityStability
♯ The resinous ion-exchangers are remarkably inertThe resinous ion-exchangers are remarkably inert
substance.substance.
♯ At ordinary temperature and excluding the more potentAt ordinary temperature and excluding the more potent
oxidizing agent, vinylbenzen cross-linked resins areoxidizing agent, vinylbenzen cross-linked resins are
resistant to decomposition through chemical attack.resistant to decomposition through chemical attack.
♯ Another limitation of these resins is their degradation andAnother limitation of these resins is their degradation and
degeneration in the presence of strong gamma ray sources.degeneration in the presence of strong gamma ray sources.
dept of pharmaceutics. 20

21.  Acid base strengthAcid base strength
╬ The acid base strength of an ion-exchanger is dependent onThe acid base strength of an ion-exchanger is dependent on
the various ionogenic groups, incorporated into the resin.the various ionogenic groups, incorporated into the resin.
╬ Resin containing sulfonic, phenolic or carboxylic acidResin containing sulfonic, phenolic or carboxylic acid
exchange groups have approximate pKa value of <1,2-3 andexchange groups have approximate pKa value of <1,2-3 and
4-6, respectively.4-6, respectively.
╬ Anionic cxchangers are quarternary, tertiary or secondaryAnionic cxchangers are quarternary, tertiary or secondary
ammnonium group having apparent pKa value 0f >13,7-9 orammnonium group having apparent pKa value 0f >13,7-9 or
5-9, respectively.5-9, respectively.
╬ The pKa value of resin will significant influence on the rate ofThe pKa value of resin will significant influence on the rate of
which the drug will be released from resinate in the gastricwhich the drug will be released from resinate in the gastric
fluid.fluid.
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22. Mechanism and principleMechanism and principle
‡ Anion exchange resins involve basic functional group (usuallyAnion exchange resins involve basic functional group (usually
a polyamin) capable of removing amine from acidic solution.a polyamin) capable of removing amine from acidic solution.
‡ Cationic exchange resin containing acidic functional group.Cationic exchange resin containing acidic functional group.
‡ Although their exact composition may vary, they usuallyAlthough their exact composition may vary, they usually
contain polystyrene polymers either sulfonic, carboxylic orcontain polystyrene polymers either sulfonic, carboxylic or
phenolic groups.phenolic groups.
‡ The use of ion-exchange resins to prolong the effect of theThe use of ion-exchange resins to prolong the effect of the
drugs is based on the principle that positively or negativelydrugs is based on the principle that positively or negatively
charged pharmaceuticals, combined with appropriate resinscharged pharmaceuticals, combined with appropriate resins
yield insoluble polysalt resinates.yield insoluble polysalt resinates.
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‡ Where H2 N-A and HOOC-B respectively and RSO3 H and
R-NH3 OH represent cationic and anionic exchanger resin
respectively.
‡ The slow release of the drug from ion-exchange resin was
recognised by Saunders and Srivastava (1980) as suitable
approach to the design of sustain release preparations.
‡ ion exchange resinates administered orally are likely to
spend about two hours in stomach in contact with an acidic
fluid of pH 1.2 and then move into the intestine where they
will be in contact for more than six hours with a fluid of
slightly alkaline pH

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First
generation
System Ion
Activated
DDS
Second
generation
System Ion
Activated
DDS

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Process involved in the ion-exchange—controlled
release

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General preparation of drugGeneral preparation of drug
resinatesresinates
► PurificationPurification
► Loading of drugLoading of drug
1.1. Column processColumn process : A highly concentrated drug: A highly concentrated drug
solution is eluted through a bed or column of the resinsolution is eluted through a bed or column of the resin
until equilibrium is established.until equilibrium is established.
2.2. Batch processBatch process : The resin particles are stirred with a: The resin particles are stirred with a
large volume of concentrated drug solution.large volume of concentrated drug solution.

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AdvantagesAdvantages
► Ion – exchange resinates of drug can help in reducingIon – exchange resinates of drug can help in reducing
the dose.the dose.
► Reduced fluctuations in blood and tissue concentrationReduced fluctuations in blood and tissue concentration
level can be achieved.level can be achieved.
► Protection of drug form gastric enzymes.Protection of drug form gastric enzymes.
► Sustained or controlled release.Sustained or controlled release.

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LimitationsLimitations
☺ The release rate is proportional to the concentrationThe release rate is proportional to the concentration
of the ions present in the area of administration.of the ions present in the area of administration.
☺ The release rate of drug can be affected byThe release rate of drug can be affected by
variability in diet, water intake and individualvariability in diet, water intake and individual
intestinal content.intestinal content.

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ReferencesReferences
►Novel drug delivery systemsNovel drug delivery systems by Y. W. Chein, 2by Y. W. Chein, 2ndnd
edition,edition,
Dekkar series, pg. no. 195-224.Dekkar series, pg. no. 195-224.
►Controlled and novel drug deliveryControlled and novel drug delivery by N. K. Jain,by N. K. Jain,
C.B.S. Publishers and distributors, 1C.B.S. Publishers and distributors, 1stst
edition, 1997.edition, 1997.
►www.google.comwww.google.com

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