ph activated and ion activated cdds

dept of pharmaceutics.dept of pharmaceutics. 11

pH-activated and ion-activated pH-activated and ion-activated controlled drug delivery systemcontrolled drug delivery system

Presented byChandrika y1st m-pharmaDept of pharmaceutics

Facilited byShankar Ass professorDept of pharmaceutics

dept of pharmaceutics. 2

Contents…Contents…

☼ pH-activated CDDSpH-activated CDDS☼ Ion-activated CDDSIon-activated CDDS☼ ReferencesReferences


pH-activated CDDSpH-activated CDDS This type of DDS permits targeting the delivery of a This 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 spectrum Drugs 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 controlled This type of system is designed for the controlled release of acidic (or basic) drugs in GIT at a rate release of acidic (or basic) drugs in GIT at a rate independent of the variation in GI-pH by formulating independent of the variation in GI-pH by formulating them with sufficient buffering agents.them with sufficient buffering agents.

Preparation Preparation ► Procedure 1- using bufferProcedure 1- using buffer ItIt is prepared by first blending an acidic (or basic) drug with is prepared by first blending an acidic (or basic) drug with

one or more buffering agents, e.g. a primary, secondary, or one 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 small Granulating 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. The The polymer coating controls the permeation of GI fluid. The GI fluid permeating into the device is adjusted by the GI fluid permeating into the device is adjusted by the buffering agents to an appropriate constant pH, at which the buffering agents to an appropriate constant pH, at which the drug dissolves and is delivered through the membrane at a drug dissolves and is delivered through the membrane at a constant rate regardless of the location of the device in the constant rate regardless of the location of the device in the alimentary canal.alimentary canal.


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 cellulose Example- ethyl cellulose

Intestinal fluid soluble polymerIntestinal fluid soluble polymer

• Example- methyl celluloseExample- methyl cellulose


Intestinal pH activated DDSIntestinal pH activated DDS

It is fabricated by coating the drug containing core with It 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 encapsulating A gastric fluid labile drug is protected by encapsulating

it inside a polymer membrane that resist the it inside a polymer membrane that resist the

degradation action of gastric pH. such as the degradation 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 pore The drug is release by drug dissolution and pore

channel diffusion mechanism.channel diffusion mechanism.dept of pharmaceutics. 6


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.


Gastric pH activated DDSGastric pH activated DDS

Ion-activated CDDSIon-activated CDDSIntroductionIntroduction♦CRDDS CRDDS are gaining the momentum in the recent decades, as are gaining the momentum in the recent decades, as the rate of delivery of drug, intensity, duration of action have the 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 modern After three decades a new era has started in modern therapeutics.therapeutics.♦One of the attractive methods for modified drug delivery One of the attractive methods for modified drug delivery system preferable controlled type is system preferable controlled type is ion-exchange resins ion-exchange resins as as carrierscarriers for such system. for such system.♦This system is satisfactorily be achieved for zero-order kinetics This system is satisfactorily be achieved for zero-order kinetics in drug delivery pattern.in drug delivery pattern.



♦ 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 an This 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 available Ion-exchange resins have specific properties like available

capacity, acid base strength, particle size, porosity and capacity, acid base strength, particle size, porosity and

swelling on which, the release characteristics of drug swelling 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 reaction whose functional group can undergo reaction

with anion of a surrounding solution.with anion of a surrounding solution.

Ion-activated CDDSIon-activated CDDS


► EXAMPLEEXAMPLE► By forming a complex between a cationic drug with a By 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 treated The 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 to This membrane serves as a rate-controlling barrier to modulate the influx of ions as well as the release of drug modulate the influx of ions as well as the release of drug from the system. from the system.



Preparations of resinsPreparations of resins► Cation exchange resin Cation exchange resin is prepared by the is 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 benzene the benzene rings of the styrene-divinyl benzene polymer.polymer.

► Anion exchange resin Anion exchange resin is prepared by first is prepared by first chloromethylating the benzene rings of the three chloromethylating the benzene rings of the three dimensional styrene-divinyl benzene copolymer to attach dimensional styrene-divinyl benzene copolymer to attach –CH–CH22Cl groups.Cl groups.

► Than causing these to react with a tertiary amine, such Than causing these to react with a tertiary amine, such as trimethylamine. as trimethylamine.


Drug suitable for the resinate Drug suitable for the resinate preparationpreparation

► Drug should have acidic or basic groups in their chemical Drug 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. In The drug is to be absorbed from all regions of the GIT. In

the case of limited absorption zone, the bioavailability the 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.


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

Particle sizeParticle size☼ The rate of ion-exchange reaction depends on the particle size The 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 the Decreasing the size of resin particle significantly decrease the

time required for the reaction to reach equilibrium with the time 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 limited When 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 resin Cation- exchange resin schematicschematic


Porosity and swellingPorosity and swelling

♪ PorosityPorosity is defined as ratio of the volume of the material to is defined as ratio of the volume of the material to its mass. The limiting size of ions, which can penetrate into its 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 the The porosity of an ion- exchanger depends not only on the polymerization but mainly on the polymerization but mainly on the polymerization polymerization procedures.procedures.

♪ The structural parameter depend considerably influence the The structural parameter depend considerably influence the swelling behaviour of the resin consequently have marked swelling 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 is The amount of swelling index is directly proportional directly proportional to the to the number of hydrophilic functional group attached to the number of hydrophilic functional group attached to the polymer matrix and polymer matrix and inversely proportional inversely proportional to the degree of to the degree of divinylbenzen cross linking present in the resin divinylbenzen cross linking present in the resin


Cross linkageCross linkage

♣ The percentage of cross-linking affects the purely physical The 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 a Resin with low degree of cross-linking can take up a

considerable amount of water and swell into a structure that considerable 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 very However, resin with a high divinylbenxen content swell very

little, these particle take up only small amount of water and little, these particle take up only small amount of water and

consequently are hard and brittleconsequently are hard and brittle


Stability Stability

♯ The resinous ion-exchangers are remarkably inert The resinous ion-exchangers are remarkably inert

substance.substance.

♯ At ordinary temperature and excluding the more potent At ordinary temperature and excluding the more potent

oxidizing agent, vinylbenzen cross-linked resins are oxidizing 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 and Another 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.


Acid base strengthAcid base strength

╬ The acid base strength of an ion-exchanger is dependent on The 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 acid Resin containing sulfonic, phenolic or carboxylic acid exchange groups have approximate pKa value of <1,2-3 and exchange groups have approximate pKa value of <1,2-3 and 4-6, respectively.4-6, respectively.

╬ Anionic cxchangers are quarternary, tertiary or secondary Anionic cxchangers are quarternary, tertiary or secondary ammnonium group having apparent pKa value 0f >13,7-9 or ammnonium 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 of The pKa value of resin will significant influence on the rate of which the drug will be released from resinate in the gastric which the drug will be released from resinate in the gastric fluid. fluid.


Mechanism and principleMechanism and principle‡ Anion exchange resins involve basic functional group (usually Anion 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 usually Although their exact composition may vary, they usually

contain polystyrene polymers either sulfonic, carboxylic or contain polystyrene polymers either sulfonic, carboxylic or phenolic groups.phenolic groups.

‡ The use of ion-exchange resins to prolong the effect of the The use of ion-exchange resins to prolong the effect of the drugs is based on the principle that positively or negatively drugs is based on the principle that positively or negatively charged pharmaceuticals, combined with appropriate resins charged pharmaceuticals, combined with appropriate resins yield insoluble polysalt resinates.yield insoluble polysalt resinates.



‡ 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


First generation System Ion Activated DDS

Second generation System Ion Activated DDS


Process involved in the ion-exchange—controlled release


General preparation of drug General preparation of drug resinatesresinates

► Purification Purification

► Loading of drugLoading of drug

1.1. Column process Column process : A highly concentrated drug : A highly concentrated drug

solution is eluted through a bed or column of the resin solution is eluted through a bed or column of the resin

until equilibrium is established.until equilibrium is established.

2.2. Batch process Batch 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.


Advantages Advantages

► Ion – exchange resinates of drug can help in reducing Ion – exchange resinates of drug can help in reducing

the dose.the dose.

► Reduced fluctuations in blood and tissue concentration Reduced 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.


Limitations Limitations

☺ The release rate is proportional to the concentration The 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 by The release rate of drug can be affected by

variability in diet, water intake and individual variability in diet, water intake and individual

intestinal content.intestinal content.


ReferencesReferences

►Novel drug delivery systems Novel 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 delivery Controlled and novel drug delivery by N. K. Jain, by N. K. Jain, C.B.S. Publishers and distributors, 1C.B.S. Publishers and distributors, 1 stst edition, 1997. edition, 1997.

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