EFFECT OF PARTITION COEFFICIENT & POLYMER DIFFUSIVITY ON

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EFFECT OF PARTITION COEFFICIENT & POLYMER DIFFUSIVITY ON CDDS: 

EFFECT OF PARTITION COEFFICIENT & POLYMER DIFFUSIVITY ON CDDS by ARYA SOMAN 1 ST YEAR M.PHARM

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CONTROLLED RELEASE SYSTEM 2

CDDS: 

CDDS Controlled release refers to the use of a delivery device with the objective of releasing the drug into the patient body at a predetermined rate or at specific profile. 3

ADVANTAGES: 

ADVANTAGES Total dose is decreased Decreased GIT side effect Better patient compliance Less fluctuation of plasma levels Improved efficacy 4

DISADVANTAGES: 

DISADVANTAGES Chances of dose dumping is increased by the collapse of system Additional patient education problems Stability concerns are increased 5

Classification : 

Classification Based on their technical sophistication : Rate preprogrammed drug delivery system Activation-modulated drug delivery system Feedback-regulated drug delivery system Site targeting drug delivery system 6

1. RATE PREPROGRAMMED DDS: 

1. RATE PREPROGRAMMED DDS In this group , the release of drug molecule from the system has been preprogrammed at specific rate profile. They can be classified as Polymer membrane permeation-controlled drug delivery system Polymer matrix diffusion-controlled drug delivery system Membrane- Matrix hybrid-controlled drug delivery system Micro reservoir partition-controlled drug delivery system 7

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POLYMER MEMBRANE PERMEATION –CONTROLLED DRUG DELIVERY SYSTEMS : 

POLYMER MEMBRANE PERMEATION –CONTROLLED DRUG DELIVERY SYSTEMS A drug formulation is totally or partially encapsulated within a drug reservoir compartment. Its drug release surface is covered by a rate controlling polymeric membrane having a specific permeability. The drug reservoir may exist in solid, suspension or solution form. 9

The release of drug molecule from this type of rate controlled DDS is controlled at a preprogrammed rate by controlling : Partition coefficient Diffusivity of drug molecule Thickness of the rate controlled membrane 10

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POLYMER MATRIX DIFFUSION CONTROLLED DRUG DELIVERY SYSTEM The drug reservoir is prepared by homogeneously dispersing drug particles in a rate controlling polymer matrix fabricated from either a lipophilic or hydrophilic polymer 11

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The drug dispersion is accomplished by: Blending a therapeutic dose of finely ground drug particle with a liquid polymer or a highly viscous base polymer, followed by cross linking of the polymer chains Mixing drug solid with a rubbery polymer at an elevated temperature. It is then molded or extruded to form DDD. By dissolving the drug & polymer in a common solvent followed by solvent evaporation at an elevated temperature & under vacuum condition. 12

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The release of drug molecules is controlled at a pre programmed rate by controlling the loading dose, polymer solubility of the drug its diffusivity in the polymer matrix . Eg: transdermal drug delivery systems 13

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Micro reservoir partition controlled DDS: 

Micro reservoir partition controlled DDS The drug reservoir is fabricated by micro dispersion of an aqueous suspension of drug using a high energy dispersion technique in a biocompatible polymer Depending on the physicochemical properties of the drug & the desired rate of drug release, the device can be further coated with a layer of biocompatible polymer to modify the mechanism & the rate of drug release 15

2. ACTIVATED- MODULATED DDS: 

2. ACTIVATED- MODULATED DDS In this type of systems the release of drug molecules from the delivery system is activated by some physical, chemical or biochemical processes or facilitated by the energy applied externally 16

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3. Feed-back regulated drug delivery systems: 

3 . Feed-back regulated drug delivery systems Here the release of drug molecule from the delivery system is activated by a triggering agent such as a biochemical substance in the body and also regulated by its concentration via some feed-back mechanism. The rate of release is controlled by the concentration of triggering agent detected by the sensor in the feed-back regulated mechanism. 18

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4 Site targeting drug delivery systems: 

4 Site targeting drug delivery systems Site targeting drug delivery system is constructed from a non immunogenic and biodegradable polymer backbone having three types of attached functional groups A site specific targeting moiety A solubiliser A drug moiety 20

FACTORS AFFECTING CONTROLLED RELEASE DRUG DELIVERY: 

FACTORS AFFECTING CONTROLLED RELEASE DRUG DELIVERY Partition co - efficient Polymer Diffusivity Polymer Solubility Solution Solubility Thickness of Polymer Diffusional Path Thickness of Hydrodynamic diffusion layer Drug Loading Dose Surface Area 21

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Polymer Diffusivity 22

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It is an energy activated diffusion process Described by Arrhenius relationship D P = D 0 -(Ed\RT) It is best described by activated state model of Brandt it involves 2 neighboring polymer chains that have move apart to permit the passage of diffusant molecule 23

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The bending of polymer chains to make room for the diffusing molecule The intermolecular repulsion from their neighboring polymer chains & simultaneously, the intermolecular resistance from the rigid bond distances & bond angles A partial rotation of chain units out of their equilibrium positions against a hindering potential of internal rotation 24

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The no. of degree of freedom found in a segment of the polymer chain is proportional to the length of the segment 25

factors affecting polymer diffusivity: 

factors affecting polymer diffusivity Energy of activation Molecular diameter of diffusant molecule Composition of polymer Type of functional group Stereo chemical position of the diffusant molecule 26

ENERGY OF ACTIVATION: 

ENERGY OF ACTIVATION The energy of activation for polymer diffusion E d = E b + E r the magnitude of the E b is very high for short segments of polymer chain but decreases as the polymer chains becomes longer E r increases as the polymer chains becomes larger 27

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The molecular diameter of the diffusant affects very strongly the magnitude of E d But certain features of molecular structure has only small effect such as: Shape of the potential barrier for hindered rotation No. of degree of freedom per monomer unit 28

molecular diameter of diffusant molecule: 

molecular diameter of diffusant molecule The magnitude of the self diffusing co-efficient of the silicone polymer decreases as the length of the linear polydimethyl siloxane chain is increased. By comparing the diffusivities of simple gas molecules in a silicone polymer with its self diffusion co-efficient of the linear silicone polymer chain 29

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In such cases the polymer diffusivity of a diffusant molecule must be inversely proportional to the cube root of a molecular weight 30

COMPOSITION OF POLYMER: 

COMPOSITION OF POLYMER Eg: diffusion of antitumor drugs across the hydroxyethyl methacrylate polymer membrane As the fraction of HEMA is replaced by butyl methacrylate, dependence on D P is still followed, but the magnitude is decreased 31

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The diffusion process in the polymer structure is governed by the segmental motion of the polymer chain 32

TYPE OF FUNCTIONAL GROUP: 

TYPE OF FUNCTIONAL GROUP The bulkier the functional group attached to the polymer chain the more difficult the segmented motion is & the lower the polymer diffusivity Eg; the effect of phenyl replacement in a silicone polymer on the polymer diffusivities of small gas molecule 33

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The polymer diffusivities of gas molecule was considerably decreased : as the methyl groups attached to the silicone atom was replaced by the bulkier phenyl group It is proportional to the % of phenyl replacement Type & molecular diameter of the diffusant 34

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The magnitude of polymer diffusivity D p is also dependent upon the type of functional group & their stereo chemical positions in the diffusant molecule 35

EFFECT OF CROSS LINKING: 

EFFECT OF CROSS LINKING The reduction in the polymer diffusivity D P 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 36

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D P = D ε ϴ Increase in the extend of cross-linkage will lead to: Reduction in the polymer diffusivity Increase in energy of activation for polymer diffusion Increase in the frequency factor D o 37

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As a result of the reduction in the polymer diffusivity the release profile of drug from hydro gel based drug delivery system was observed to decrease as the degree of cross linking increased. Eg; controlled release of norgestromet, Invitro & in vivo from hydro gel- based sub dermal implants 38

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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. 40

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The addition of a cross linking agent results in the decrease in the porosity & an increase in tortuosity of these pore channels, leading to a reduction in polymer diffusivity 41

EFFECT OF CRYSTALLINITY: 

EFFECT OF CRYSTALLINITY LDPE has a higher degree of side-chain branching than HDPE. The crystallinity acts similarly to the cross-linking agent. Greater the degree of side-chain branching in LDPE, which requires a high energy of activation for the motion of polymer chain & also a greater frequency factor in response to the increase in the entropy of activation Δ S d 42

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Log D 0 = constant + Δ S d \2.303R Thermodynamically the energy of activation for diffusion E d & the entropy of activation Δ S d are linearly related 43

EFFECT OF FILLERS: 

EFFECT OF FILLERS Fillers are often incorporated into a polymer to enhance its mechanical strength The polymer diffusivity D P.f in a filler containing polymer can be related to the effective polymer diffusivity D P in a filler less polymer by the relationship 1\D P.f = 1\D P + K f \D p .v f 44

DETERMINATION OF POLYMER DIFFUSIVITY: 

DETERMINATION OF POLYMER DIFFUSIVITY The diffusivity of a drug molecule through the rate – controlling membrane of a polymer membrane permeation controlled drug delivery system can be determined from the relationship; Dp = hp 2 \6t 1 45

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Elastomeric polymer often contain very pure & finely ground filler particles to enforce their mechanical strength. In such cases polymer diffusivity can be determined by the following relationship: 47

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If the filler is inert & its presence adds only a tortuosity factor to the process If the filler is active & has a constant adsorption capacity K f Dp.f = h 2 .p . 1 + K f . V f t 1 4 2K P. C a. D P 48

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If the filler is active & its adsorption capacity K f is in direct proportion with the local conc. Of diffusant molecule D d .f = h 2 .p (V p + K f .V f ) 6t 1 49

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PARTITION CO-EFFICIENT 50

PARTITION COEFFICIENT: 

PARTITION COEFFICIENT Partition coefficient K, is a parameter that characterizes the relative affinity of a compound in its un-ionized form, for water and an immiscible model lipid solvent. P = Co/Cw . 51

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A balance in the partition coefficient is needed to give an optimum flux for permeation through the biological & rate controlling membrane Partition co-efficient is the measure of the lipophilic character. 52

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Partition co-efficient not only influence the permeation of drug across the biological membrane, but also diffusion across or through a rate controlling membrane /matrix. Drugs with high partition co-efficient readily penetrate the membrane. The ability of drugs to diffuse through the membrane is called diffusivity & is related to its molecular size. 53

Effects of structure on Partition coefficient : 

Effects of structure on Partition coefficient Substituent that increase K -aryl -halogens Substituent that decrease K ALKYL -OH -COOH -NH2 -CO 54

Application of Partition Coefficient K, in drug delivery. : 

Application of Partition Coefficient K, in drug delivery. Preservation of oral liquid pharmaceutical dosage forms Passage of drugs across cell membranes-Drug absorption 55

Effect of partition coefficient on CDDS: 

Effect of partition coefficient on CDDS Partition coefficient K of a drug for its interfacial partitioning from the surface of a drug delivery device towards an elution medium is defined as K= C S ̸ Cp 56

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Any variation in either C s or C p value result in the change in the magnitude of K value. Eg: Invitro release of norgestromet from silicone capsule into the elution media with varying solution solubility's 57

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Q\t = KD d C p \hd or K C p = C s Q\t = C s D d \hd 58

DIFFUSION CONTROLLED RELEASE: 

DIFFUSION CONTROLLED RELEASE There are basically 2 types of diffusion controlled release, they are Matrix type Reservoir type 59

MATRIX DEVICES: 

MATRIX DEVICES A solid drug is dispersed in an insoluble matrix. The rate of drug release is dependent on the rate of drug diffusion but not on the rate of solid dissolution 60

Effect of K on matrix type devices: 

Effect of K on matrix type devices The effect of K on matrix type drug delivery device was reported to be biphasic Eg: controlled release of ethynodiol diacetate from matrix – type silicone devices 61

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4000 2000 1000 800 600 400 200 100 60 .02 .04 .06 .1 .2 .4 .6 1 2 4 6 Partition control Transition phase Matrix control 62 Q/T K

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In partition controlled process ; Q = K - D d K C p . h d When the partition coefficient is increased beyond a critical point(k=0.5), the matrix controlled mechanism become predominant & a Q v/s t 1\2 release profile is then observed 63

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Between the partition control & matrix controlled 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 64

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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 65

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The effect of alkyl chain length on the magnitude of the partition co -efficient is exponential , as defined by the eq. log k n = log k 0 – n π CH 2 66

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Partitioning is the process involving molecular equlibrium at the interface there fore an equlibrium constant directly related to standard gibb’s free energy Δ F d = -RTln K 67

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When 2 structurally closely related molecule are partitioning in the same system ,the diff. in the free energy of interfacial transfer for this mol. is directly related to a specific structural modification. Δ F fg = 2.303RT [ log K derivative - log K parent ] 68

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log K derivative = log K parent + Ƹ π fg π fg = Δ F fg 2.303RT 69

MICRORESERVOIR TYPE: 

MICRORESERVOIR TYPE A water insoluble polymeric material encases a core of drug. Drug as micro particles will partition into the membrane & exchange with the fluid surrounding the particle or tablet. 70

Effect of K on micro reservoir type: 

Effect of K on micro reservoir type A co solvent system has been used in micro reservoir dissolution controlled drug delivery system to form a homogenous dispersion of microscopic drug saturated liquid compartment in a solid polymer matrix 71

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Variation in the composition of this co-solvent system results in a change in the controlled release rate profile of drug Eg : the steady state permeability of p- amino acetophenone across, silicone membrane from a binary co- solvent system of propylene glycol &H 2 O 72

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Membrane permeability P m is defined as: P m = D P K l log K l = log C p – log C s addition of a co solvent system into the drug solution also affect the membrane permeability of drug molecule as a result of its effect on interfacial partitioning of drug molecules from drug solution to a polymer membrane 74

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The addition of co solvent in drug formulations was also reported to affect the absorption & pharmacological responses of drugs An increase in the volume fraction of co-solvent in a formulation with a constant drug dose results in the saturation solubility of the drug in the vehicle & hence an increase in the drug concentration on the skin surface at eqlbm which yields an increase in percutaneous absorption. 75

REFERENCE: 

REFERENCE Novel drug delivery system by Yie.W.Chien Controlled drug delivery system Concept & advances by S.P. Vyas www.google.com 76

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Thank you… 78