EFFECT OF SYSTEM PARAMETERS ON

CONTROLLED RELEASE

SINDHOOR S M
1ST M.PHARM
DEPARTMENT OF PHARMACEUTICS

1
 INTRODUCTION

 The term “Controlled release” has become associated with

those systems from which therapeutic agents may be
automatically delivered at predefined rates over a long period
of time.This has a meaning that goes beyond the scope of
sustained drug action.
 It also implies a predictability & reproducibility in the drug
release kinetics, which means that the release of drug ingredient
from a controlled delivery system proceeds at a rate profile that
is not only predictable kinetically, but also reproducible from
one unit to another.
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SYSTEM PARAMETERS

1. Polymer solubility (Cp)

2. Solution solubility (Cs)
3. Partition coefficient (K)
4. Polymer diffusivity (Dp)
5. Solution diffusivity (Ds)
6. Thickness of polymer diffusional path(hp)
7. Thickness of hydrodynamic diffusion layer (hd)
8. Drug loading dose (A)
9. Surface area
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 1.POLYMER SOLUBILITY(CP)

 In CDDS drug particles are not released until

they dissociate from their crystal lattice
structure, dissolve or partition into
surrounding polymer
 This suggest that Solubility of drug in
polymer membrane or matrix plays important
role in it’s release from a polymeric device.

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 Equation for Polymer membrane permeation type

Q CPKD dDm

T KDfor dh m  D mh d
 Equation membrane matrix type

dQ AC pD p
 2
dt  
 1 1 

 D pK m    4 AC pD Pt
1/ 2


 Pm P
  d 

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 Equation for microreservoir partition controlled
drug delivery systems
dQ D p D d mK p  D l S l 1  n   1 1 
  nC p     
dt D p h d  D d h p mK p  ht  Kl Km 
 Equation for polymer matrix diffusion type

Q
  2 AC p D p 
1/ 2
1/ 2
t

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 There is a wide variation in the polymer
solubility of different drugs
 Eg; polymer solubility of progesterone in the
silicon elastomer is significantly reduced in
presence of OH groups
 The polymer solubility can be increased by
esterification of the OH groups

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 2.SOLUTION SOLUBILITY(Cs)

 Solution solubility refers to the aqueous

solubility of the drug
 Invivo sink conditions are maintained by active
haemoperfusion
 Hence invitro studies must be done under sink
condition for better data co-relation
 Also to ensure that release of drug is controlled
by design of system itself &not complicated by
solution solubility of drug
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 HOW TO MAINTAIN SINK CONDITIONS?
1. Maintaining drug concentration in bulk as small
as possible
2. By making solution solubility much greater than
the bulk solution concentration i.e Cs >>>>Cb

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 How to improve the aqueous solubility
1. Micelle formation
2. Complex formation
3. Use of co- solvents
 Influence of solution solubility from matrix
diffusion controlled device is biphasic in case of
lipophilic polymer
 In case of hydrophilic polymer drug release will
follow Q/t1/2 profile from beginning itself.
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 Aqueous solubility varies from one drug to another
 Difference in aqueous solubility is depend on the difference
in their chemical structure, types & physicochemical nature
of functional groups & the variations in their stereo
chemical configurations
 for eg; esterification of testosterone reduces the aqueous
solubility
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 3.PARTITION COEFFICIENT(K)

 Partition co-efficient K of a drug refers to interfacial

partitioning from the surface of a drug delivery
device towards an elution medium as given :
K = Cs/Cp
Where,
Cs = conc. Of drug at the solution/polymer
interface
Cp = solubility of drug in the polymer phase.
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 Any changes in the Cs or Cp value results in an
increase or decrease in the magnitude of K value
 The magnitude of Q/t values is a linear function
of K incase of
1. Polymer membrane permeation type
2. Membrane matrix hybrid type
3. Micro reservoir partition type

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 The effect of K on the controlled release of drugs
from matrix type drug delivery device was
reported to be biphasic
 Eg- controlled release of ethynodiol diacetate
from matrix type silicon devices

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4000 Partition Transition Matrix control
control phase

2000

1000
800
600

400

200

100

Q/T
60 .6 4 6
.02 .04 .06 .1 .2 .4 1 2
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K
 When magnitude of K is small the drug release will show Q/t
profile
 This region is governed by partition controlled process

 When the partition coefficient is increased beyond a critical

point(k=0.5), the matrix controlled mechanism become
predominant & a Q / t1/2 release profile is then observed

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 Between the partition control & matrix controlled
process there exist a transition phase.
 The time at which the drug release profile
undergoes transition from a partition controlled
process to matrix controlled process is inversely
proportional to the partition coefficient

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 Eg: controlled release of a homologous series of
alkyl- p- amino benzoates from matrix type
silicone devices.
 As the alkyl chain length of the ester increases &
the time for the transition from partition- controlled
process to the matrix controlled process become
longer & the K of p- amino benzoates from the
silicone devices toward the elution solution
decreases
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 4.POLYMER DIFFUSIVITY(Dp)

 The diffusion of small molecules through polymer

structure is a energy activated process
 Described by Arrhenius relationship

DP = D0-(Ed/RT)
D0 = temperature independent frequency
factor
Ed = energy of activation for polymer
diffusion

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 It can be better understood by activated state
model of Brandt
 it involves 2 neighboring polymer chains that
have move apart to permit the passage of
diffusant molecule

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POLYMER CHAINS

DIFFUSANT MOLECULE

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POLYMER CHAINS
1. The bending of polymer chains to make room for the diffusing
molecule
2. The intermolecular repulsion from their neighboring polymer chains &
simultaneously, the intra molecular resistance due to rigid bond
distances & bond angles
3. A partial rotation of chain units out of their equilibrium positions
against a hindering potential of internal rotation
4. The no. of degree of freedom found in a segment of the polymer chain
is proportional to the length of the segment
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 The energy of activation for polymer diffusion

Ed = Eb + Er

Eb = Energy for inter molecular bending

Er = Energy for inter molecular repulsion

 the magnitude of the Eb is very high for short segments of
polymer chain but decreases as the polymer chains becomes longer
 Er increases as the polymer chains becomes larger

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 Polymer diffusion depends on….

 Molecular diameter of diffusant molecule

 Composition of polymer
 Type of functional group
 Stereo chemical position of the diffusant
molecule

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FACTORS AFFECTING POLYMER
DIFFUSIVITY

 Effect of cross-linking
 Effect of crystallinity
 Effect of fillers

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 Effect of cross-linking

 The reduction in the polymer diffusivity DP is a

linear function of the reciprocal of the extend of
cross-linkage.
 The combination of decreased porosity & increased
tortuosity resulted in a reduction in polymer
diffusivity as expected from the relationship

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 The relationship between porosity and tortuosity
of polymer as a result of cross linking is given by
the equation

Dp  D *


 D = intrinsic diffusivity
 ε = porosity
 θ = tortuosity
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 The effect of cross-linking agent & copolymer
composition on the polymer diffusivity of drugs in
hydrophilic polymer is related to the water content of
the polymer
 The diffusivity is exponentially dependent upon the
reciprocal of the degree of hydration of the
hydrophobic copolymer.
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 Effect of crystallinity
 LDPE has a higher degree of side-chain
branching than HDPE.
 Therefore LDPE has lower degree of crystallinity
than HDPE
 The crystallites acts similar to the cross-linking
agent.
 Crystallinity introduces regions of very low
diffusion compared to the rest of the polymer,
this leads to gross reduction in Dp
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 Effect of fillers
 Fillers are often incorporated into a polymer to
enhance its mechanical strength
 Eg: silica or diatomaceous earth are added as
fillers to increase the mechanical strength of
silicon elastomers
 Effect of fillers on polymer diffusivity of similar
to that of crosslinking and crystallinity but still
more complicated

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 The polymer diffusivity DP.f in a filler containing polymer can be related
to the effective polymer diffusivity DP in a filler less polymer by the
relationship

1/DP.f = 1/DP + Kf /Dp .vf

 Kf = adsorption capacity of filler

 Vf= volume fraction of filler in polymer

 Dp.f.= polymer diffusivity in filler containing polymer

 Dp =polymer diffusivity in filler less polymer

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 5.SOLUTION DIFFUSIVITY(Ds)

 The diffusion of solute molecules in a solution

medium is a result of random motion of the
molecules
 Solute molecules will move from higher to lower
concentration until distribution of solute
molecules is uniform through the system

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 On a microscopic level solution diffusivity can be
studied based on void occupation model
proposed by Bueche

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 The magnitude of Ds is a function of jump frequency
& jump distance and can be represented by the
following relationship
1
D S  V 2
6
 Ds= solution diffusivity
 V = jump frequency
 λ = jump distance

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 When solution diffusivity are compared on bases of molecular
volume, alkanes are most rapidly diffusing chemicals.
 The relative rates of diffusion of various chemical classes are
as follows :
alkane > alcohol > amides > acids > amino acids >
dicarboxylic acid
 Diffusivity of solute molecule in aqueous solution usually
decreases as its concentration increases.

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 The effect of viscosity on solution diffusivity is given by;
 
DS 

ω = propotionality constant
µ = viscosity coefficient
 Viscosity coefficient is determined by poiseuille equation

pd 4
 *t
128vl
 ‘t’is the time required for V ml of a solution to flow
through a capillary tube of length ‘l’ and diameter
‘d’under applied pressure∆p and π is constant
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6. THICKNESS OF POLYMER DIFFUSIONAL
PATH(hp)

 Control release of drug species from both

polymer membrane & polymer matrix controlled
drug delivery system is governed by
1) The diffusion coefficient of solute in the
membrane lipid.
2) The thickness of the membrane.

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 hp value for polymer membrane controlled reservoir devices,
which are fabricated from non biodegradable and non
swollen polymer, the value is defined by polymer wall with
constant thickness that is invariable with time span.
 In polymer matrix controlled reservoir devices, which are
fabricated from non biodegradable polymers, the thickness
of diffusional path is defined as drug depletion zone
progressively in proportion to the square root of time.

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 The rate of change in the hp value can be defined mathematically
by :

1/ 2
hp  2CpDp 
  
 A  Cp / 2 
1/ 2
t

Cp = solubility of drug in the polymer phase

Dp = diffusivity of drug in the polymer matrix
A = loading dose of a drug

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7. THICKNESS OF HYDRODYNAMIC
DIFFUSION LAYER(HD)

 The hydrodynamic diffusion layer has a rate limiting

role on controlled release dosage form.
 Effect of hd on drug release can be understood by
considering the device immersed in a stationary
position in solution
 As a result a stagnant layer is established on the
immediate surface of the device

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 The effective thickness of stagnant layer is
related to Ds as follows

( h d ) nr  ( D s ) 1/ 2 1/ 2
t
 π = propotionality constant
 nr = stationary state
 DS = solution diffusivity
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 If the device is rotated at constant speed convection
occurs
 This convective diffusion will be faster than the
natural diffusion due to concentration gradient
 Hd can be related to Ds by levich equation as
follows
 (hd)r = 1.62 Ds1/3V1/6 W-1/2

V= kinematic viscosity of elution medium

W=angular rotation speed of device
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 In invitro experiments for evaluating drug release
from a drug delivery device the hd should be
controlled at a small but constant value
 This is done by controlling the angular rotation
speed

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 8.DRUG LOADING DOSE(A)

 In preparation of the drug delivery device

varying loading doses of drugs are
incorporated, as required for different length
of treatment
 Incase of matrix diffusion controlled system
variation in drug loading dose affects the
magnitude of release rate Q/t1/2

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 Rate of drug release from polymer membrane
permeation type is independent of the drug
loading dose
 In matrix systems changes in loading dose can
also affect t-trans from partition controlled
process to matrix diffusion controlled process as
a mechanism of action

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 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.

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 CONCLUSION
 A thorough understanding of the system
parameters gives flexibility to design systems so
as to achieve a ‘defined’ drug release profile

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 REFERENCE
 Chien Y. W., Novel Drug Delivery Systems, Edn
2, Informa Healthcare, New York. 2009;p: 56-
110.
 Robinson Joseph R., Lee Vincent H, Edn 2,
Informa Healthcare, New york.2009;p:9-15.
 Overview on controlled release dosage forms,
Ummadi Sathish, Shravani B, Reddy srikanth M,
nayak Sanjeev;IJPS:3:239-256

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THANK YOU

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