Controlled Drug Delivery

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CONTROLLED DRUG DELIVERY

INTRODUCTION
For many decades treatment of an acute disease or a chronic illness has been mostly
accomplished by delivery of drugs to patients using various pharmaceutical dosage forms, including
tablets, capsules, pills, suppositories, creams, ointments, liquids, aerosols, and injectable as drug
carriers. Even today these conventional drug delivery systems are the primary pharmaceutical products
commonly seen in the prescription and over the counter drug market place. This type of drug delivery
system is known to provide a prompt release of drug. There fore to achieve as well as to maintain the
drug concentration with in therapeutically effective range needed for treatment, it is often necessary to
take this type of drug delivery system several times day. This result in a significant fluctuation in drug
levels. In order to overcome these problems controlled drug delivery systems were employed.
Fig : Hypothetical drug concentration profiles in the systemic circulation resulting from the consecutive
administration of multiple doses of an immediate release drug delivery system compared to the ideal
drug concentration profile required for treatment.
1. ADVANTAGES
i] Patient Compliance: (patient acceptability)
Lack of compliance is generally observed with
1. Long term treatment of chronic disease.
2. Increase in number of doses.
3. Increase in side effects
The problem of lack of patient compliance can be resolved to some extent by
administering controlled release drug delivery system.
ii] Reduced 'see- saw' fluctuation:
A well designed controlled release drug delivery system can significantly reduce the frequency
of drug dosing and also maintain a more steady drug concentration in blood circulation and target tissue
cells.
iii] Reduced total dose
Controlled release drug delivery systems have repeatedly been shown to use less amount of total
drug to treat a diseased condition. By reducing the total amount of drug, decrease in systemic or local
side effects are observed. This would also lead to greater economy.
iv] Improved efficiency in treatment:
A controlled release dosage forms leads to better management of the acute or chronic disease
condition.
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OTHER ADVANTAGES
 Reduction in dosing frequency
 Reduced fluctuations in circulating drug levels
 Increased patient compliance and convenience
 Avoidance of night time dosing
 More uniform effect
 Reduction in GI irritation and dose related (local and systemic) side effects
4. DISADVANTAGES
i) Dose dumping:
Dose dumping is a phenomenon where by relatively large quantities of drug in a controlled
release formulation is rapidly released.
ii) Less flexibility in accurate dose adjustment
In conventional dosage forms, dose adjustments are much simpler e.g. tablet can be divided
into two fractions. In case of controlled release dosage forms, this appears to be much more
complicated. Controlled release property may get lost, if dosage form is fractured.
iii) Poor In Vitro – In Vivo correlation
In controlled release dosage form, the rate of drug release is deliberately reduced to achieve
drug release possibly over a large region of gastrointestinal tract. Here the so called ‘Absorption
window’ becomes important and may give rise to unsatisfactory drug absorption in vivo despite
excellent in-vitro release characteristics.
iv) Patient variation
The time period required for absorption of drug released from the dosage form may vary among
individuals. Co-administration of other drugs, presence or absence of food and residence time in
gastrointestinal tract is different among patients. This also gives rise to variation in clinical response
among the patient.
Other disadvantages
 High cost
 Unpredictable and often poor invitro invivo correlation
 Dose dumping
 Reduced potential for dosage adjustment
 Increased potential for first pass clearance and also of poor systemic availability.
 Need additional patient education.
5. RATIONALE FOR SUSTAINED/ CONTROLLED DRUG DELIVERY
The rationale for sustained/ controlled drug delivery is to alter the pharmacokinetic and
pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by
modifying the molecular structure and/ or physiological parameters inherent to a selected route of
administration. It is desirable that the duration of drug action become more a design properly of a rate
controlled dosage form, and less, or not at all, a property of drug molecule’s inherent kinetic properties.
As mentioned earlier, the primary objectives of sustained/controlled drug
delivery are to ensure safety and to improve efficacy of drugs as well as patient compliance. This is
achieved by better control of plasma drug levels and less frequent dosing. For conventional dosage
forms, only the dose (D) and dosing interval () can vary and, for each drug, their exist a therapeutic
window of plasma concentration, below which, therapeutic effect is insufficient and above which
undesirable or toxic side effects or elicited.as an index of this window, the therapeutic index TI can be
used.

Therapeutic index is defined as the ratio of median lethal dose (LD 50) to median
effective dose(ED50). It is also defined as the ratio of maximum drug concentration(c max) in blood that
can be tolerated to the minimum concentration (cmin) needed to produce therapeutic response.
Theeuwes and bayne given the following relationship for the drugs whose disposition
show pronounced linear,one compartment characteristics.it is given by
τ < t1/2 (In T I ) /In 2
where,
t1/2 = half life.
Since the therapeutic index for most drugs is 2,it will be necessary to dose the patients at
intervals shorter than the half life.such inconvenient regimens often result in reduced compliance and
inadequate treaetment.for drugs with multicompartmental characteristics a better estimate of the dosing
interval may be obtained by replacing t 1/2 with 0.693*(MRT),where MRT is the mean residence time.in
such cases the drug should be given even more frequently than suggested by above equation.
In general, the dosing interval may be increased either by modifying the drug molecule to
decrease the rate of elimination or by modifying the release rate of a dosage form. Both approaches
seek to decrease fluctuations in plasma levels during multiple dosing,allowing the dosing interval to
increase without either overdosing or underdosing.
6. FACTORS
A. FACTORS INFLUENCING THE DESIGN & PERFORMANCE OF
SUSTAINED/CONTROLLED RELEASE PRODUCTS
The following are factors influencing the design & performance of sustained/controlled release
products.
1. Drug properties:
The drug properties (physico chemical) such as stability,solubility,partitioning
characteristics,charge & protein binding play a dominant role in the design & performance of controlled
release products.
Route of drug delivery:
 Route of drug delivery plays important role in design of controlled release products.
 At times, in certain routes of administration the drug delivery system exerts negative influence
on drug efficacy,hence other routes of administration should be considered.
In this way route of drug delivery play a role in design of controlled release products.
2. Target sites:
In order to minimize the unwanted side effects the drug is allowed to reach the targeted site
directly.this can be achieved by the use of carriers.
3. Acute or chronic therapy:
Consideration of whether one expects to achieve cure or control of a condition and the expected
length of drug therapy are important factors in designing controlled release systems.
4. The disease:
Disease state plays a significant role in the design of a suitable drug delivery system.
Eg: To design an ocular controlled release product for an external inflammation,the time course of
changes in protein content in ocular fluids and in the integrity of the ocular barriers would have to
taken into consideration.
5. The patient:
Whether the patient is ambulatory or bedridden,young or old,obese or gaunt etc can influence the
design of a controlled release product. An implant or intramuscular injection of a drug to a

bedridden patient with little muscle movement may perform in a manner significantly different
from that of an ambulatory patient.
6. PHYSICO CHEMICAL PROPERTIES OF A DRUG INFLUENCING DRUG
PRODUCT DESIGN & PERFORMANCE
The following are the physico chemical properties of a drug influencing drug product
design & performance
1. Polymer solubility (CP)
2. Solution solubility (CS)
3. Partition Coefficient (K)
4. Polymer Diffusivity (DP)
5. Solution Diffusivity (DS)
6. Drug loading dose (A)
7. Surface area.
8. Protein binding
1. Polymer solubility (cp):
Until unless the drug particle dissociates from crystal, dissolve into
surrounding polymer, diffuse through it, the drug cannot be treated to be released from the controlled
release devices. This suggests that the solubility of drug in a rate controlling polymer matrix or
membrane plays a rate controlling role in its release from polymeric device. To release at an
appropriate rate, the drug requires adequate solubility. Hence polymer solubility (CP) can be
appropriately seen in all the release rate equations of all types of controlled drug delivery systems. The
relationship between the drug release rate (Q/t) & the magnitude of polymer solubility (CP) will be
linear. This relationship should be followed by membrane-permeation type as well as for
microreservoir type of drug delivery devices. .
The difference in solubilities among drugs is very striking.
Example 1: Solubility of steroids in silicone polymer can range from 1-2 g/ml to as high as
1152.8 g/ml. This dramatic difference is very much dependent on the differences in their chemical
structure, variation in functional groups & their stereochemical configurations.
Example 2: Addition of –OH group reduces the solubility of Progesterone in lipophillic
polymer. Estrification of –OH groups increases the solubility.
The presence of fillers (silicon earth) was reported to increase the polymer solubility of drugs as a result
of Langmuir adsorption of drugs on to the filler particles.
2. Solution solubility (CS)
Various studies stated that the release of drugs from controlled release devices is
truly influenced by its solution solubility (CS). In-vivo sink condition is effectively simulated in In-
vitro studies. This can be done by
 Concentration in bulk (Cb) should be zero.
 By maintaining solution concentration (CS) very high than bulk concentration (Cb). i.e., CS>>
Cb.
 By using cosolvent (Water miscible co-solvents)
Ex: Aqueous solubility of ethynodiolactate was increased 3.584 fold by using PEG 400.
Aqueous solubility of drug varies significantly similar to that of polymer solubility, which is
very much dependent upon the difference in their chemical structure, the type and physiochemical
nature of the functional groups and stereochemical configuration.
Ex: Esterification of Testosterone reduces aqueous solubility.

The drug having very low aqueous Solubility like steroids and Metronidazole, the solubility of
the drugs can be increased by various Pharmaceutical approach like Micelle formation, complexation,
cosolvency, without chemical modification of drug molecules.
Finally due to the solution solubility, variations are seen in release pattern of the controlled drug
delivery device (Invirto study).
Ex: Norgestomet & hydron implants.
3. Partition coefficient (k):
The Partition Coefficient (K) of a drug for its interfacial partitioning from the surface of a drug
delivery system towards an elution medium is defined as
K = Cs/Cp
Any variation in either Cs or Cp values results in a change in the magnitude of K values.Invitro studies
of Norgestomet from silicon capsules shows that, by changing the solubility of Norgestomet in elut ion,
the magnitude of partition coefficient thus varies, leading to a variation in drug release rate. The effect
of alkyl chain length on the magnitude of the partition coefficient is exponential as defined below.
Log Kn = log k0 - nCH2
Where Kn is the partition coefficient for the compound with an alkyl chain length of n CH2 groups. K0
is the Y intercept at zero carbon number,  CH2 is the slope of the log Kn versus n plot. The attainment
of negative slope results from the fact that as alkyl chain increases, polymer solubility (CP) of the drug
is enhanced with an expense of their solution solubility (CS) leading to reduction in partition
coefficient (Kn).
On the other hand, addition of hydrophilic functional groups, such as –OH groups to a drug
molecule tends to improve the solubility at the expense of the polymer solubility in a lipophilic
polymer.Ex: Progesterone in silicone Polymer & elution solution. This results in increase in partition
coefficient.
The linear relationship between membrane permeability Pm and the partition coefficient K is
Pm = DPK
Ex: Transdermal permeation of steroid
Variation in the cosolvency also have an effect on partition coefficient(K) – either increase or decrease,
has also been reported.
4. Polymer diffusivity (dp):
The diffusion at small molecules in a polymer structure is an energy activated process, in which
the diffusant molecule move to a successive series of equilibrium positions when a sufficient amount of
energy, called energy of activation for diffusion Ed, has been acquired by the diffusant & its
surrounding polymer matrix. The energy activated diffusion process is frequently described by the
following Arrhenius relationship.
DP = Do e -(Ed/RT)
Where,
Do is a temperature frequency factor,
Ed is the energy of activation of polymer for diffusion, distributed throughout many degree
of freedom in the system, R & T have their usual thermodynamic meaning.
The energy of activation for polymer diffusion Ed is thus the sum of the energy intramoleculer bending
Eb & the energy of intermolecular repulsion Er.
Ed = Eb + Er
The results of model calculation indicated that the magnitudee of Eb is very high for short segment
polymer chain, but decreases as polymer chain becomes longer. On the other hand, Er increases as
polymer chain becomes lnger, i.e., degree of freedom becomes larger.

5. Solution diffusivity (ds):

The diffusion of solute molecules in a solution medium may be considered as a
resuklt of random motion of molecules. The solution diffusion process can be discussed by void
occupation model & the theory of free volume.
DS= Do e -(En/RT)
Where,
DS = solution diffusivity
D0 = pre-exponential factor
En = energy of activation for solution diffusion.
For a solute whose molar volume is greater than or equal to the molar volume of water molecules,
the diffusivity of the solute molecules in the aqueous solution (at 250C) is inversely proportional to the
cube root of molar volume. The molar volume of a solute molecule is an additive property of its
constituent atoms and functional groups. When solution diffusivity of various chemical group was
compared on the basis of molecular volume.The relative rates found that
Alkane>Alcohols>Amides>Acids>Aminoacids>Dicarboxylic acids.
The diffusivity of solute molecules in an aqueous solutio usually decreases as its concentration
increase. This reduction is frequently related to the increase in viscosity that usually accompanies the
increase in solution concentration. The effect of viscosity (μ) is related to solution diffusivity (DS).
DS = w / μ
Where,
w is proportional constant.
6. Protein binding
Drug protein binding can serve as a depot for drug producing a prolonged release profile,
especially if a high degree of drug –binding occurs. Drugs bound to mucin may increase absorption, if
the bound drug acts as a depot.
Drugs are plasma protein bound and their distribution into extravascular space is governed by
equilibrium process of dissociation of drug from protein. The drug-protein complex acts as require
SRDF. In general charged compounds have a greater tendency to bind a protein.
Ex: 95% PPB drugs are Diazepam, Dicoumarol, Novobiocin.
7. Molecular size and diffusivity
A drug must diffuse through a variety of biological membranes in the body. The ability of a
drug to diffuse through membranes is so called diffusivity which is a function of molecular weight.
Log D = - Sv log v + Kv = - SM log M + Km
Where,
D=Diffusivity
V= Molecular volume
M= Molecular weight
Sv, SM, Kv, Km= Constant
The normal range of molecular weight is 150-400.High molecular weight drugs shows slow release.
8. Dose size
For oral dosage form a dose size of 0.5 to 1.0 gm is considered maximal. Higher doses have to
be given as liquids. Drugs with low therapeutic index needs to given additional core if dose size is high.

9. Surface area
 Both the in-vivo & in-vitro rates of drug release dependant on the surface area of the drug
delivery device.
 Greater the surface area greater will be the rate of drug release.
10. Drug loading dose
 In preparation of the device varying loading doses of drugs are incorporated, as required for
different length of treatment.
 Variation in the loading doses results only in the change in duration of action with constant drug
release profile.
7. BIOLOGICAL FACTORS INFLUENCING DESIGN & PERFORMANCE OF
SUSTAINED/CONTROLLED RELEASE PRODUCTS
Absorption:
To maintain constant blood or tissue level of drug, it must be uniformly released from the
sustained release system and then uniformly absorbed. Usually, the rate-limiting step in drug delivery
from a sustained release product is release, from the dosage form rather than absorption. The rate,
extent and uniformity of absorption is an important factor, as here Kr<<<Ka. The optimum absorption
rate must be 0.17 to 0.23 hr -1. The area of absorption in the GIT is also important.
A drug with slow absorption is a poor candidate for such dosage forms since continuous
release will result in a pool of unabsorbed drug e.g. iron.
Distribution:
The distribution of drugs into tissues can be an important factor in the overall drug elimination
kinetics since it not only lowers the concentration of circulating drug but it also can be rate limiting in
its equilibration with blood and extracellular fluid.
The Vd and the ratio of drug in tissue to that of plasma at steady state are important
parameters to be considered in determining the release rate.
Metabolism:
Metabolism to other active form can also be considered as sustained effect. Enzyme inhibition
or induction by drug results in fluctuating blood level with chronic use. Hepatic first pass metabolism
also has the same effect. The extent of metabolism should be identical and predictable when the drug is
administered by different routes.
If a drug, upon chronic administration, is capable of either inducing or inhibiting
enzyme synthesis, it will be poor candidate. If there is a variable blood level of drug through either
intestinal metabolism or through a first-pass effect, this also will make preparation of sustained release
product difficult.
Elimination half life:
The biological half-life and hence duration of action of a drug obviously play a major role in
the process of considering a drug for sustained
release. Factors influencing the biological half-life of a drug include its elimination, metabolism, and
distribution patterns.
Most drugs have half-life of elimination in the range of 1-20 hr. Smaller the t ½, larger the amount of
drug to be incorporated in the sustained release dosage form. For drugs with t ½ less than 2 hours, a
very large dose may be required to maintain the high release rate. Drug with the half life in the range of
2 to 4 hours make good candidate for such a system. e.g. Propranolol. Drugs with long half-life need
not be presented in such a formulation e.g. Amlodipine. A candidate drug must have t ½ can be
correlated with its pharmacologic response.

Side effects:
The incident of side effects can be minimized by controlling the concentration at which the drug
exists in plasma at any given time, hence sustained release formulation appear to offer a solution to this
problem.
Dosage form index (DI):
It is defined as the ratio of Css.max to Css.min. Since the goal of controlled release formulation
is to improve therapy by reducing the dosage form index while maintaining the plasma drug levels
within the therapeutic window, ideally its value should be as close to 1 as possible.
Margin of safety:
The most widely used measure of the margin of safety of a drug is its therapeutic index.
Ti = TD50 /Ed50
Where,
TD50 = Median toxic dose
ED50 = Median effective dose
The larger the value of Ti, the safer the drug. The release rate of a drug with very small value of Ti
usually is poor candidates for formulation into sustained release products
7. PHARMACOKINETIC BASIS
 The compartmental analysis approach was initially proposed to describe the multi-exponential line
course and plasma concentrations of drug is the body following drug administration.
 Physiological models were subsequently derived relating drug transfer on the basis of organ x tissue
blood flows x extraction ratios of the active moieties.
Conventional dosage forms are rapidly absorbed, with the pealex and valley (or) Saw –tooth
kinetic blood concentration profile (Ascending x descending).
 Dose response data define a quantitative term, frequently used in pharmacokinetic analysis of
controlled drug delivery is known as the Therapeutic Index DDTI
TI = -
Controlled drug delivery following aims were identified to study the pharmacokinetic behavior.
 The maintenance of Therapeutic concentrate with minimal fluctuations x *** over an extended period
of time throughout a during interval.
 To keep the drug concentrations with in a therapeutic range, at a steady state.
 To keep the release rate (limitations to which) to such an extent that the final product should have a bio
availability at least 80% relative to that of conventional delivery device.
 To minimize the role of formulation factors in the development of a dosing regimen, nor example
increasing the elimination T½ of the drug.
 Better compliance and lower oxcident of toxicity.
Compartmental Pharmacokinetic models used in sustained/controlled Drug Delivery
In classical cases, the rate of drug absorption generally exceeds the rate of elimination. Under such
conditions, a distribution phase can be run following a conventional drug delivery administration.
 However a sustained ion controlled release delivery system is a drug with a relatively short elimination
half life (T½ x 4 hrs) exhibits a situation in which the rate of absorption is so slow that it eventually
creates on indefinable distribution phase.
 Further if the rate constant of absorption not less than the rate constant of elimination a flip-flop model
results in this case, the terminal phase is a reflection on the rate constant for absorption.
 The ideal situations is one where the delivery system releases the drug at a constant rate, associated
with a constant rate of absorption and producing sustained ion controlled therapeutic concentrations
over a prolonged period time.
Several models have been proposed which will help in understanding the in-vino absorption and
elimination of the drug, the following 4- models, are useful.
1) Models of drug input and elimination
2) Loo - Reigelman a wagner – Nelson Pharmacokinetic methods.
3) Model independent pharmacokinetic analysis
4) Pharmacokinetics of multiple dosing.
1) Models of Drug input & Elimination: (Welling 1983)
These are based upon either Zero-order (or) 1st order rate constants for absorption and elimination.
Drug input Drug Input Elimination Rate limiting step Model selected
Stage I Stage II
Zero order - First order Rate of drug release IV Infasion
Slow 1st order - First order The rate of drug Conventional
elimination formula
Rapid first Zero order First order The rate of drug Sustaenous release
order absorption
Rapid first Slow first First order The rate of drug Sustained
order order absorption
These models are based on following assumptions.

 The elimination of drug follows first order process.
 The rate of drug distribution is governed by the rate of drug absorption and drug elimination.
 All the kinetic processes except for drug absorption are linear.
i. Zero order absorption followed by I – order elimination.
ii. Show I-order absorption followed by I-order elimination.
iii. Rapid I-order absorption of part of the dose, then release and absorption of the remainder
over an extended period of time by a O-order kinetic process followed by a I-order
elimination.
iv. Rapid F-order absorption of part of the dose, then release and absorption of the remainder
over an extended period of time by a slower I-order kinetic process followed by I-order
elimination.
Drugs after oral administration follow multicompartment pharmacokinetic models
and this is a function of the affinity of the administered drug (or) delivery system for various tissues.
Slow absorption of drugs from controlled release formulations impleads distribution phase, which
remains observed by absorption process. It leads to a drug profile that can be more satisfactory defined
by kinetic model based on one compartment modeling assumptions. In order to define the
pharmacokinetic modling of sustained release products following assumptions are made (Welling
1986).
 Drug absorption, metabolism and excretion are I-order rate processes.
 Drug absorptions elimination are irreversible.
 Drug that is released after oral administration is completely absorbed in the unionized form.

 Drug release from the modified release product is rate limiting in the absorption process.
These assumptions follows Kalonkr significantly smaller than Ka the absorption step has been deleted
from the original one compartment model in designing the model for modified release products.
a. Zero order absorption:
Drug profile from this type of delivery system is influenced by the rate at which drug is released
from the dosage form and also the elimination rate.
 The time course of accumulation following a single dose administration is independent of release rate
constant more over, the drug levels are directly proportional to controlled release rate constants.
 A drug with a short elimination half –life will approach steady state (sustained release) at a time faster
than a drug with a longer elimination half life.
Case Study: Drug with elimination half life – 1.5, 2 & 2.5 hrs
{Kq = 0.46, 0.34 & 0.27 respectively} approaches steady state at 8 hrs.
 Whereas drugs with longer elimination, half life of 7.5 hr (Kq = 0.09 th) could not achieve it in the same
time period.
This indicates that for longer elimination half life drugs it is not always possible to achieve a
plateau (or) steady state with a single dose of a Zero-order release formulation.
 This model presents a situation where the orally administered drug is absorbed by an apparent O-order
process/on process. In this case, the release of the drug out of the drug product is the rate limiting step.
Following a single dose the concentration at any time given by equation.
C=
Ko  Zero order absorption state.
f  time 9th drug administration
T constant corresponding to the absorption time
V  Volume of distribution
F Bioavailability factor
During absorption T =t. In the post absorption phase  t = T+t1. Where t1 time from the start of
the post absorption phase.
C=
 Theoretical plots have been provided that describe the concentration time course of a drug given at
various O- order rates of absorption & I – Order rate of elimination.
In general, the greater the value of Ke(shorter half life) greater the amount needed to maintain
concentrations close to a desired value. It a drug follows an apparent Zero-order absorption process &
first order elimination process following multiple doing at steady state.
Css =
Css  Drug concentration at steady state.
KeV  Product total clearance.
When F = 1,  Complete absorption, then
Css =
b. First-order absorption
 The amount and concentration of drug after single dose administration from a sustained release product
following a I-order release kinetics can be given by equation.

 This is the most frequently selected model describing drug pharmacokinetics following conventional
oral dose formulations following a single dose, the concentration vs. line curve for a drug at any time
described by.
C= C=
D Dose
For conventional formulations where relationship can be approximated by
C=
However this might not be the case for a sustained release formulation since the absorption process will
be slower, Ka will be smaller and the tissues may approach in bewne smaller than that of K e.
c. Rapid 1-order – Zero order – I – order elimination
Basic principle of this type relies on the fact that a controlled release component should be
prescribed by an immediate release component, which will establish the desired blood level in the
body.
 The amount of drug after single dose administration from a sustained release product equipped with a
fast release component which then follows a Zero-order release loinetly.
 To achieve therapeutic level promptly and sustain the level for a given period of time, the total dose,
thus required with delivery system can be presented.
Ex: Dose = Di+Dm.
Several methods have been adopted to calculate the proportions of D i and Dm that are required to
achieve therapeutic blood levels.
 The most recent method is based on the assumption that the fast release component should provide the
quantity of drug that would yield the desired therapeutic response at steady state . Ass. For Zero-Order
release kinetics and for the total duration of drug release of the equation.
Dose = Ass + Ko Td
Dose = + Ko Td
There is no correction factor is needed of the delivery system is constructed such a way that the
maintenance dose not begins to release drug until time.
Ex: Theophylline
Reported dose adjustment.
Thophylline hex elimination half life – approx to 4 hrs.
Distribution volume is 32 bits. A steady state level 0.5 mg/ml is thus equivalent to A ss+Di = 160 mg.
This results in a controlled rate Ko – 160x0.17 = 27.2 mg/h. In this the required level will reach in 2 hrs
and maintain through 12 hrs. This leads to a total dose of 500 mg (160 mg ax Di = 340 mg o x Dm)
This model presents a case where the release of the drug from the dosage form occurs in two ways
first a fraction of the total dose and released for immediate availability (Burst effect) and remaining
fraction is absorbed at constant rate i.e., a slow Zero-Order process which results in Zero-order for
prolonged period of time.
C= +
Ko  Slow, O – Order rate
T  Duration of the Zero-Order input
Ka  Fast, first order

Limitations: The limitations of these models which operate following various rates of absorption and
elimination is the difficulty of selection for fitting and analyzing experimental rate after administration
of sustained delivery systems.
 Model dependent equation cannot analyzed the PK parameters of a sustained release product.
 In the case of oral administration the leonetic order of absorption possess may be a time ion size
independent phenomena before it absorbs, reverse through the GIT to reach the site of absorption.
d. First -order, slow first-order & first– order elimination
 The amount of drug after single dose administration from a sustained release product equipped with a
fast release (I – order) followed by a first order.
Where Ko is the rate constant governing absorption and Kr <<Ka
Similar to previous model, satisfactory approximately of a control drug level can be obtained by
suitable combinations of Di and Dm that release its drug by first order process.
Dose = Di+(Ke cd/Ka) vd
 Oscillations may occur with in a narrow and therapeutically acceptable range.
C=
Kr  fast
Ua  slow
A and B  Hybrid rate cost.
2. Loo – Riegelman and Wagner – Nelson Model:
It is well established that the plasma content ration course after IV administration can be expressed
in terms of an apparent biexponential equation and that of oral administration by an apparent
multiexponential equation of the processes like absorption is not required in the former case.
 The process of slow release from a sustained (or) controlled release delivery system may obscure the
distribution phase, thus vanishing the exponential term which usually defines the distribution phase.
 The Loo-Reigelman model assesses drug absorption in general and specifically absorption from
sustained release delivery systems.
The model states that the amount of drug absorbed at any given time equals the sum of the
amount of drug present in the Central & peripheral compartment and of the amount eliminated by the
all routes.
Thus the model does not predict any particular kinetic order of absorption and obviously it can
be O-order, I-order (or) a combination or both.
The only assumption with this model is that the drug pharmacokinetics can be described by at
least or two compartment model.
However, this is not a limiting presumption as this is the preferred category after IV
administration of the majority of the drugs.
 This method can be applied to any multicompartment model.
 The implementation of this model requires the administration of the drug through the intravenous route
as a reference. The model can be used for the following features.
 To measure the rate of extent of absorption.
 To determine the pharmacokinetic order of the absorption process.
The Kinetic equation using Loo-Riegelman model can written as.
=
Where ( )T x ( ) + Amount absorbed drug at time Tx fraction of dose absorbed at time ‘t’.
CTx(Xp)T – Drug plasma concentrations
Amount in peripheral compartment at time ‘t’.

Vc  Volume of distribution of the central Compartment.
K10  I – order elimination relt
2 approximations can be made from Kinetic equation.
 If a plot is percent unabsorbed (l10-lXA4/lXA) Vs time on semi log plot yields straight line. It is
suggestive of an apparent I-order absorption kinetics.
 If a plot of % unabsorbed [100(1-lxA4/XA)] Vs time on a rectilinear plot yields a straight line it is
suggestive on apparent O-order absorption kinetics.
Wagnes – Nelson Model on the other hand, is restricted to drugs, which follow one-
compartment open-model characteristics and in way demonstrate the actual disposition of some potent
drugs after IV administration however a reference Iv drug administration is not required in this model.
 The kinetic order of the absorption process of the values of K0 and Ke can be determined using the
following kinetic equations.
=
Where Ke – Overall elimination constant.
Limitations: This model is usually not recommended for the analysis of data of the oral administration
of controlled drug delivery devices which follow multicompartmental disposition characteristics.
 Rapid Iv objections soluble – Pk atleast 2-compartment model.
3. Independent pharmacokinetic analysis
 This is suitable when the drug is eliminated following linear pharmacokinetics.
 This is based upon the statistical moment analysis and states that for any theoretical relationship b/w.
plasma concentration of time.
 Calculation of Area Under Curve (AOC) and area under the moment curve (AUMC) respectively for
Zero x I – order.
 These values useful for calculating the MRT (Mean Resident Time) and Mean Absorption Team
(MAT) of the drug of the administration standard and sustained release depot formulations.
MRT can be defined as “The mean time for the intact drug molecule to transit through the body and
involved a composite of all Kinetic processes including release from the delivery devices MRT
expressed as
MRT = =
AUC  Area under curve
AUC round the curve.
Area under the curve of Product of concentrate first moment versus time
The MRT- can be used in a competitive sense to evaluate the in vivo performance of a sustained
release dosage form.
 The longer the MRT, the more sustained (or) prolonged is the absorption of the drug assuming a
constant elimination rate constant.
 Another model independent parameter that has been utilized in assessing the pharmacokinetics of
absorption process in sustained drug delivery is mean absorption time [MAT].
However this can be assessed when an IV reference is available, subtraction of the MRT from
iv administration from the MRT of oral administration yields mean absorption time.
MAT = MRT Oral – MRT I.V.
MAT is more relevant in assessing the absorption process than MRT oral is longer the MAT, the
more sustained(or) prolonged in the absorption of the drug.

 This parameter can be further used in calculation of apparent absorption rate constant, denoted as K a in
the case of a I-order absorption process of absorption time (P) in the case of a Zero-order absorption
process.
MAT = 1/Ka
MAT = T/2
However these parameters especially MAT are not compartment model dependent but applied with the
absorption Kinetic order which should be properly defined and must be consistent throughout the
duration of absorption.
 If the kinetic order for absorption is complex (or) time dependent the MRT (or) MAT can be used as an
estimate to perform a model –independent pharmacokinetic evaluation or a sustained release delivery
system.
When the drug is absorbed following I (or) O-order kinetic input process, a term known as
MRT is defined that equal.
MRT = MRTiv +
MRT = MRTiv +
It is interesting to note that through the terms Ko and Ka do not figure A the Calculation of AUC,
but they change the value of AUMC and thus ultimately affect the value of MRT and MAT.
 Equations provide a linear relationship between MRT ni x in the cases when the absorption process
follows the I-order kinetics and between MRTni x  Zero-order rate.

 Way of calculation of AUC and AUMC depends upon experimental setup and condition.
 Relationship between MRT and (or) are model indepnednent.
Further, the disposition through these model - independent parameters holds as long as the drug is
eliminated following linear pharmacokinetics.
Multiple Dosing: Minimizing the fluctuations in plasma Dry concentration.
 Total dosage required will be reduced.
% fluctuation = 100
Fluctuation index [FI] =

Av. Drug plasma conc is calculated from the quotient of the area under the drug plasma conc Vs time
curve (AUC) during a steady state doing interval and the dosage interval [AUC sc/T]
8. PHARMACODYNAMICS
Pk not only in the facilitating predictions of the time course of drug concentration in the body,
but also in the developing a better understanding of the time course of drug action on the body.
 P kinetics describe what the body does to the drug. P. dynamics can relate drug effects on the body.
 P.D. can be defined as a Quantitive assessment of the time course of drug effects on the body after
administration by any route.
 The measured response to a drug may be all (or) none (or) it may be graded.
There are 2 fundamental ways that Pharmacodynamic principles can be applied to the drug
development process.
(i) The pharmacokinetics of a drug will be known and a pharmacokinetic model can be established for
the drug in humans (or) in some animal species. This pharmacokinetic model can then be worked to

available pharmacodynamic data resulting in a unified concept relating the kinetics of the drug to the
time course of the drug effect.
(ii) Where the pharmacokinetic characteristics of the drug cannot be adequately defined (or) where
drug effect is apparently unrelated to concentration, alternative approaches can be utilized.
(iii) Implicit to many pharmacodnyanmic models is that measured drug (or) active metabolite
concentrations in a sampled bio phase age in equilibrium with concentrations at the receptor (or) the
site of drug action.
Concentration data obtained at Steady state may be particularly useful in defining a
Pharmacodynamic model since single dose data alone may not be adequate to describe the effect of
drug (or) active metabolite accumulation on the drugs pharmacological action upon multiple dosing.
 These models not only help to explain empirical data, but also provide a rationale for elucidating
fundamental mechanisms thereby facilitating a prediction (or) drug activity in different subject (or)
under altered physiological/disease state conditions.
Useful pharmacodynamci models are based on concentration Vs time data that are obtained at an
“effect” site these models are based on the assumption that the actual blood sampling site is in
equilibrium with drug at its effect site.
Pharmacodynamic model
Oldest model – fixed –effect model, where drug concentration can be related to a pharmacological
effect which is either observed (or) not observed.
Limitation on this model, however is that at a given drug concentration, the effect may (or) may not be
obtained in a given individual.
 The most fundamental model directly linking drug concentration and effect is the linear model, which
can be described mathematically.
E = P.C.
E contified effect
CDrug concentration
P Linear parameter best linking E and C.
Depending on the drug and the effect being evicted a base line effect may be measured in the
absence of drug i.e., when C = O at t = O) and in thus core the relationship can be rewritten.
Ex: E = P.C. + E0. E0  effect at time t = 0, C = 0.
The parameter P will then be estimated from a plot of E = E 0 and C., Estimating E0 may not be a trivial
matter necessarily and a variety of problems and methods for their solution have been Logarithmic
model.
E = P.Logc+E0.
Of a dosage form is given chronically, and concentrations at steady state are measured, this equation
can be rewritten as
Ess = P.Log Css + E0ss.
Maximum drug effect Emax model, however incorporating concepts from enzymology and equilibrium
theory and allows for a prediction of C max.
E=
Emax  Theoretical maximas attainable effect attributable to the long and E 50 is the concentration of
drug elicting 50 of this maximal effect.
As written the Emax model predicts  to equal o when C = 0, Ev  non – drug related baseline
measurements.
E = E0+

Where the Drug effect is to reduce an effect measurable in the absence of drug. Such as a drug given to
reduce blood pressure ion heart rate this even will transformed to
E = E0-
Where I50  Drug concentration producing 50% reduction with Baseline measured Biological
parameter.
9. SYNTHETIC AND BIOCOMPATIBLE POLYMERS USED IN CONTROLLED
RELEASE DOSAGE FORMS
Polymers are the macromolecules having large chains containing variety of functional groups can be
blended with other low & high molecular weight materials.
 Polymers control the drug release rate from the formulations
 These polymers shows increased effectiveness in novel drug delivery
 Advances in polymer science shows the more development in novel drug delivery. This new
technologies which has been developed improved the
1. Drug modification by chemical mucous
2. Carrier based drug delivery
3. Drug entrapment in polymer matrices
 Newer technologies improve the efficacy of drug therapy their by improves human health
 Newer technological development in polymer based encapsulation and control drug release
systems offer possibilities for optimizing the administration of drugs. These improvements
contribute to make medical treatment more efficient and to minimize side effects and other
types of inconviences for patients.
Polymers used as
 Taste masking agent
 Film coating agent
 Control release agent
 To enhance stability
 To enhance bio availability
By use of monolithic delivery devices in which drug is dispersed in polymer matrix, the rate of drug
release from matrices depends on initial concentration and relaxation of polymer chains. In case of
biomedical area polymers are expected to perform long term studies.
WATER SOLUBLE SYNTHETIC POLYMERS
Poly acrylic acid:
It is used as
 Cosmetic agent
 Immobilization of cationic drugs
Poly ethylene oxide:
It is used as
 Coagulant
 Flocculating agent
 Swelling agent
Poly ethylene glycol
Mol.wt of PEG uses

< 1000 Acts as liquid
> 1000 Acts as wax
poly vinyl pyrrolidone:

 It is used to make betadine with less toxicity than iodine
 It is used in tablet granulation
Poly vinyl alcohol:
 It acts as tablet binder
 Used in tablet coating
CELLULOSE BASED POLYMERS
Ethyl cellulose:
 It is insoluble but dispersible in water
 Acts as a aqueous coating system for sustained release preparations
Carboxy methyl cellulose
 Acts as super disintegrant
 Acts as emulsion stabiliser
Hydroxy ethyl cellulose & hydroxy propyl cellulose:
 soluble in water & alcohol
 used in tablet coating
Hydroxy propyl methyl cellulose:
 acts as binder for tablet matrix
 used in tablet coating
Cellulose acetate phthalate(CAP)
It is used in enteric coating technology
Hydrocolloids
 Acts as thickening agent
 Suspending agent in case of pastes, creams & gels
 Stabilizing agent for oil in water emulsions
 Acts as binder
 Acts as disintegrating agent
Chitosan
 Used in control drug delivery
 Muco adhesive dosage forms
 Rapid release dosage forms
STARCH BASED POLYMERS
Starch acts as
 Binder
 Diluents
 Glidant
 Disintegrant
Sodium starch glycolate
It act as super disintegrating agent
PLASTICS AND RUBBERS
Poly urethane
It is used in transdermal patches
Silicones
 Used in therapeutic devices
 Used in implants

 Used as medical grade adhesive for transdermal drug delivery

Poly iso butalene
It is used as pressure sensitive adhesive
Poly cyano acrylline:
It is Very important bio degradable polymer which acts as carrier for micro particles
Poly vinyl acetate
It is used as binder for chewing gum
Poly methyl methacrylate:
It is used in hard contact lenses
Poly hydroxy ethyl methyl acrylate
It is used in soft contact lenses
NATURAL ORIGIN POLYMERS USED AS PHARMACEUTICAL EXCIPIENTS:
Polysaccharides
This polysaccharides is a class of biopolymers constituted by either one or two alternating
monosaccharides which differ in their monosaccharide unit in the length of the chain , types of linking
units and in the degree of branching.
Alginate
It is derived from marine polysaccharides. It consist of β.D. mannuronic acid and
α.L.guluronic acid
Haluronic acid
Used as lubricant, shock absorbers
Bovine serum albumin(BSA)
These are biodegradable,non toxic and suitable for controlled drug delivery systems.these are
prepared under mild conditions by coacervation method and desolvation process.in this cross linking
was done by gluteraldehyde.
Collagen
It is a major protein component.27 types of collagen has been identified.type1 collagen is used
as a polymer because of high strength and more bio compatability.
10. ORAL CONTROLLED DELIVERY DOSAGE FORMS
Two basic types of controlled-delivery dosage forms have been designed in which diffusion
is the rate-limiting step to generate temporal input profiles for drug delivery: matrix- and reservoir-
type systems.
A matrix type system consists of a rate-controlling ingredient such as a polymer with drug uniformly
dissolved or dispersed in it, and typically, a half-order drug release corresponds to desorption from the
preloaded matrix.
A reservoir-type system separates a drug compartment from a polymer membrane that presents a
diffusional barrier to yield drug flux of either zero order (with infinite dose) or first order (by dose
depletion).
Diffusion Theory
Diffusion can be defined as a process by which molecules transfer spontaneously from
one region to another in such a way as to equalize chemical potential or thermodynamic activity.
Although diffusion is a result of random molecular motion, with a wide spectrum of physicochemical
properties occurring in various conditions and situations, the diffusion process can be abstracted to a
simple system involving molecules of interest, a diffusional barrier, and a concentration gradient. The
migrating molecules are termed diffusants (also called permeants or penetrants). The membrane or
matrix in which the diffusant migrates is called the diffusional barrier. The external phase is called the

medium. The concentration gradient or profile of the diffusant within the diffusional barrier is the
driving force for diffusion. The mathematics of diffusion are discussed briefly in this section, with
emphasis on both diffusion across a barrier membrane and diffusional release from a preloaded matrix
the basic equations were put forth by Fick in 1855 as an analogy to the heat-conduction equation
developed by Fourier in 1822. The theory of diffusion in isotropic substances therefore is based on the
hypothesis that the flux J or rate of diffusion (amount Qt in time t) through a unit area of a barrier
section is proportional to the concentration gradient within and normal to the section; that is,
This is Fick’s first law, with the proportionality constant D termed diffusivity or diffusion coefficient.
The negative sign arises because the direction of molecular movement is opposite to the increase in the
concentration.
11. ORAL DIFFUSION-CONTROLLED SYSTEMS
Matrix systems
A matrix system consists of active and inactive ingredients that are homogeneously mixed in the
dosage form. It is by far the most commonly used oral CR technology, and the popularity of matrix
systems can be attributed to several factors. matrix system is capable of accommodating both low and
high drug load and active ingredients with a wide range of physical and chemical properties
. The drug molecules elute out of the matrix only by dissolution followed by diffusion through
the polymer structure in to the surrounding environment.It has been suggested that firstly the drug
particles present in the layer closer to the surface of the device elute and after complete depletion of
this layer the drug particles present in next layer starts depleting.
With the passage of time and continuous drug release,the delivery rate normally decreases in
these type of systems since the bioactive agent has to traverse a long distance progressively and
thereby requires a longer diffusion time for ultimate delivery of drug
Mechanism;
In the matrix or monolithic system, drug is distributed through a polymer that serves as the diffusion
barrier . The polymer matrix can either be nonporous/homogeneous or porous/granular. In the former,
the matrix can be considered to consist of one phase through which the drug diffuses. In the latter,
diffusion is restricted to pores in an otherwise impermeable material. The drug can be dissolved in the
matrix or be dispersed in solid form. Whereas diffusion is the major rate-controlling mechanism
matrix swelling and erosion can have significant impacts on the release rate for other matrix materials
* To further this discussion, we divide matrix systems into two categories, hydrophobic and
hydrophilic systems, based on rate-controlling materials
Hydrophobic matrix systems. This is the only system where use of a polymer is not essential to
provide controlled drug release, although insoluble polymers have been used. As the term suggests, the
primary rate-controlling components of a hydrophobic matrix are water insoluble in nature. These
ingredients include waxes, glycerides, fatty acids, and polymeric materials such as ethylcellulose and
methacrylate copolymers. To modulate drug release, it may be necessary to incorporate soluble
ingredients such as lactose into the formulation. The presence of insoluble ingredients in the

formulations helps to maintain the physical dimension of a hydrophobic matrix during drug release.
Very often, pores form within a hydrophobic matrix as a result of the release of the active ingredient.
For a porous monolithic system
where t and r are the tortuosity of the matrix and density of drug particles, respectively. Tortuosity is
introduced to account for an increase in diffusion path length owing to branching and bending of the
pores.
Hydrophilic matrix systems.

The primary rate-controlling ingredients of a hydrophilic matrix are polymers that would swell on
contact with the aqueous solution and form a gel layer on the surface of the system. Hydroxypropyl
methylcellulose (HPMC) is the most commonly used hydrophilic polymer. Other polymers include
high-molecular-weight polyethylene oxide (Polyox™), hydroxypropyl cellulose (HPC), hydroxyethyl
cellulose (HEC), xantham gum, sodium alginate, and polyacrylic acid (Carbopol™). polymer
dissolution (erosion) and diffusion of drug molecules across the gel layer have been identified as the
rate-controlling mechanisms.
Advantages:
1. Very easy to fabricate in a wide range of sizes and shapes.
2. Suitable for both non-degradable and degradable systems.
3. No danger of ’dose dumping’ in case of rupture.
Disadvantages:
1. Acheivement of ‘zero order’ release is difficult.
2. Not all drugs can be blended with a given polymeric matrix.
3. Water soluble drugs have a tendency to ‘burst’ from the system.
Reservoir systems
A typical reservoir system consists of a core (the reservoir) and a coating membrane (the
diffusion barrier). The core contains the active ingredients and excipients, whereas the membrane is
made primarily of rate-controlling polymer(s). The governing release mechanism is diffusion from the
reservoir across the membrane to the bulk solution, It is a membrane controlled reservoir system in
which the therapeutic agent is contained in a core surrounded by a thin polymer membrane and the

active agent is released to the surrounding environment by diffusion process through the rate-limiting
membrane. For the reservoir type of systems the drug delivery rate remains fairly constant .These
systems consist of a reservoir of either solid drug dilute solution or highly concentrated drug solution
within a polymer matrix, which in turn is surrounded by a film or membrane of a rate controlling
material.
The drug molecules in the outer most layer of particles firstly have to dissociate from the
crystal lattice before dissolving into and subsequently diffusing through the polymer structure and
eventually leading to partitioning into the elution medium.
The rug release limiting structure is the polymer layer surrounding the reservoir.Since the polymer
coating is essentially uniform the diffusion rate of the active agent can be kept fairly stable throughout
the lifetime of the delivery systems.
Mechanism;
Reservoir systems are similar in design to osmotic pumping systems, where the dissolved
drug and constituent materials induce an osmotic pressure within the core. This pressure results in
outward convection of dissolved drug, through holes in the coating Although diffusion is generally
considered to be the dominating release mechanism in reservoir systems, osmotic pumping can also
influence the release rate .
The most commonly used materials for constructing the membrane are ethylcellulose
(Surelease™ or Aquacoat™) and acrylic copolymers (Eudragit™ RL30D, RS 30D, and NE 30D).
Water-soluble polymers such as HPMC and polyethylene glycol (PEG) are employed as pore formers.
Typically, special coating equipment such as the Wuster coater is required to apply the coating
material uniformly
Advantages:
1.Acheivement of ‘zero order’ release is easy.
2. Very easy to fabricate in a wide range of sizes and shapes.
3. Drug inactivation by contact with the polymeric matrix can be avoided.
Disadvantages:
1.Rupture can result in dangerous’dose dumping’
2. Degradable reservoir systems may be difficult to design.
ION-EXCHANGE RESIN OR ION-EXCHANGE POLYMER
 Ion exchange resins are polymers that are capable of exchanging particular ions with in the
polymer with ions in a solution that is passed through them.
This ability is also seen in various natural systems such as soils and living cells. The synthetic
resins are used primarily for purifying water, but also for various other applications including
separating out some elements.
 Ion exchange materials are insoluble substances containing loosely held ions which are able to be
exchanged with other ions in solutions which come in contact with them.
 These exchanges take place without any physical alteration to the ion exchange material.
Ionexchangers are insoluble acids or bases which have salts which are also insoluble, and this

enables them to exchange either positively charged ions (cation exchangers) or negatively
charged ions (anion exchangers).
 Many natural substances such as proteins, cellulose, living cells and soil particles exhibit ion
exchange properties which play an important role in the way the function in nature.
 Synthetic ion exchange materials based on coal and phenolic resins were first introduced for
industrial use during the 1930.s. A few years later resins consisting of polystyrene with
sulphonate groups to form cation exchangers or amine groups to form anion exchangers were
developed. These two kinds of resin are still the most commonly used resins today.
 The principle of ion exchange has been used for a long time in analytical and protein chemistry. It
is an attractive method for sustained drug delivery because, in theory, drug release characteristics
largely depends only on the ionic environment of the resin containing drug and should therefore
be less susceptible to environmental conditions. Such as
 Enzyme contents and
 PH, at the site absorption.
 Because this approach of sustained release requires the presence of ions in solution, it would not
be applicable to the skin, the external ear canal, or other areas with limited quantities of eluting
ions.
 In contrast the SC and IM routes,where the pool of available ions is more controlled, would
appear better suited for this approach. However the resin may undergo biodegradation with an
attendent alternation in the “pre-programmed” release rate.
 While the GIT appears to possess a rather constant ionic content, the variability in diet, water
intake, and GI content composition make this constant ionic content unlikely.
The Resins are water insoluble materials containing anionic or cationic groups in repeating
position on the resin chain.
 The drug charged resin is prepared by mixing the resin with drug solution either by repeated
exposure of the resin to drug in chromatographic column or by keeping the resin in contact with
the drug solution for extended period of time.
 When a high concentration of drug charged ions is in contact with the ion exchange group, the
drug molecules is exchange and diffuse out of the resin to bulk solution according following
scheme.
Resin [N (CH3)] + X¯ + Z - Resin [N (CH3)] + Z + X-
(Drug-charged resin)
 The release rate can be controlled by coating the drug resin complex using the one of the
microencapsulating process.
TYPES:
1. Cation exchange resins
2. Anion exchange resins
1. CATION EXCHANGE RESINS:
These are synthesised by copolymerization of divinyl benzene and styrene. Polymerization
reaction involves initially the formation of linear chains of polystyrene,which are subsequently
attached to each other at intermittent points by divinylbenzene cross links results in the formation
of three dimensional insoluble hydrocarbon network.when this is treated with sulphuric acid,
sulphonic acid groups(-SO3-H+) are introduced into most of the benzene rings of the copolymer
ultimately producing a cation exchange resin.

2. ANION EXCHANGE RESINS:

These are synthesised by chioromethylation of benzene rings of 3 dimensional styrene-
divinyl benzenecopolymer network leading to the insertion of -CH2CL groups allowing these to
react with a tertiary amine viz,trimethyl amine resulting in formation of strong anion exchange
resin.
MECHANISM OF DRUG RELEASE:
Cation exchange resins contain acidic functional groups,generally they contain polystyrene
polymer with either phenolic, carboxylic or sulphonic groups.on the other hand anion exchange
resins involve basic functional groups capable of extracting anions from acidic solutions.
Ion exchange resins are used to sustain the effects of drugs based on the concept that negatively
or positively charged drug moities combine with appropriate resins producing insoluble polysalt
resinates.
Where R-SO3-H+ and R-NH3+OH- represents cationic and anionic
resins,respectively,where as H2N-A and HOOC-B depicts basic and acidic drug
respectively.where admistered orally resins come in contact with acidic fluid that contains HCL
with a following reaction takes place
R-SO3-H+ + H2N-A → R-SO3- + H3N+ -A
R-N H3 OH- + HOOC-B→ R-N+H3- OOC-B + H2O
+
Drugs that are suitable for the preparation of controlled release resinates should have
 Acidic or basic nature.
 Biological half life between 2-6 hrs.
 Absorption window in all regions of the GI tract.
 Sufficiently stable in gastric juices.
Most commonly available resins are
Resin type chemical constituent
Strong acidic cation exchanger Sulfonic acid groups attached to a styrene and
divinyl benzene copolymer
weak acidic cation exchanger Carboxylic acid groups linked to an acrylic acid 9I9I divinyl benzene copolymer
Strong basic anion exchanger Quarternary ammonium groups attached to a
styrene and divinyl benzene copolymer
Weak basic anion exchanger Polyalkyl amine groups linked to a styrene and DJIJ divinyl benzene copolymer

Controlled Drug Delivery

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CONTROLLED DRUG DELIVERY

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5. Solution diffusivity (ds):

Log D = - Sv log v + Kv = - SM log M + Km

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These models are based on following assumptions.

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Amount in peripheral compartment at time ‘t’.

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follows the I-order kinetics and between MRTni x  Zero-order rate.

Fluctuation index [FI] =

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Mol.wt of PEG uses

poly vinyl pyrrolidone:

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 Used as medical grade adhesive for transdermal drug delivery

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Hydrophilic matrix systems.

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2. ANION EXCHANGE RESINS:

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