A SEMINAR PRESENTATION ON

DIFFUSION AND ITS IMPORTANCE IN PHARMACEUTICAL PROCESSES

AISSMS COLLEGE OF PHARMACY

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CONTENT

INTRODUCTION

DIFFUSION

STEADY STATE DIFFUSION

DIFFUSION THROUGH MEMBRANE

PROCEDURE AND METHOD FOR ASSESSING DRUG

DIFFUSION

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PHARMACEUTICAL IMPORTANCE OF DIFFUSION

Drug absorption and eliminationDrug release from various dosage forms.OsmosisDiffusion as mixing mechanism.Ultra filtration and dialysisBioadhesion mechanism Diffusion batteries Filtration and integrity testing of filters.Evaluation of antimicrobial.

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OBJECTIVE

Define diffusion and describe relevant example in the pharmaceuticals science and the practice of pharmacy.

Understand the process of dialysis, osmosis, and ultra filtration as they apply to the pharmaceutical sciences and practice of pharmacy.

Describe the mechanism of transport in the pharmaceuticals system and identify which one of are diffusion based.

Define and understand the fick’s law of diffusion and there application.

To understand diffusion coefficient, permeability.Describe various driving forced in diffusion.

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Study the different pharmaceutical process which

based on the diffusion mechanism.

To study different method used for study of diffusion.

Study different process such as evaluation of

aerosol ,

Mechanisms which involve diffusion such as

bioadhesion, drug release, diffusion batteries .

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INTRODUCTION

Diffusion is also defined as a process of the mass transfer of the individual molecule of a substance brought about by the random molecular motion associated with a driving force such as concentration gradients.

Free diffusion of the substance through liquids, solids, and the membranes are process of considerable interest in the pharmaceutical sciences. Mass transfer phenomenon applying in the pharmaceuticals sciences include the release and dissolution of the drug from the tablet, powder, and the granules; lyophilysation, ultatrafiltration, and other mechanical processes; release form the ointment, pastes suppository bases. The dosage forms additives through coating, packaging, films, plastic containers, seals, and caps; and permeation and the distribution of drug molecules in the living systems.

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DIFFUSIONBasic principle of diffusion is based on the thermodynamic

consideration.

Diffusion of a dissolved substance from a region of the higher

concentration to region of the lower concentration following

random molecular motion and result in the decrease in the free

energy of the system.

We many conveniently illustrate that by the simple experiment

of the diffusion of the dye from a solution in to the pure water

solvent.

The” random walk “nature .

Net result in the formation of homogeneous solution.

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STEADY-STATE DIFFUSION

Thermodynamic basis –

Mass transfer is the movement of molecules in an applied driving

force. Convective and diffusion mass transfer are important to

many pharmaceuticals processes. mass transfer is a kinetic process, occur in the system that

are not in equilibrium.

Chemical potential A.1 > A .2

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FICK’S LAWS OF DIFFUSION

The amount of material, M of material flowing through a unit cross sections, S, of a barrier in a unit time, t, Is known as a flux , j;

The flux, in unit turn, is proportional to the concentration gradient, dC/dx ;

Where D is a diffusion coefficient in cm2/sec. C is the concentration in g/cm3

D is affected by the concentration ,temp., pressure, solvent property, and chemical nature of diffusant.

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FICK’S SECOND LAW

Fick’s second law of diffusion forms the basis for most

mathematical models of diffusion processes. One often wants to examine the rate of change of mass transport that emphasizes the change in concentration with time at a definite location rather than the mass diffusing across a unit area of barrier in unit time is known as fick’s second law.

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APPLICATION

Equations based on Fick's law have been commonly used to model transport processes in foods, neurons and biological membranes , biopolymers , pharmaceuticals ,dosage forms etc.

Theory of all diffusion based methods is based on solutions of Fick's equation.

A large amount of experimental research in polymer science and food science have been going on where diffusion plays important role. 

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STEADY STATE

A system is said to be at steady state ,if the condition of the system do

not change with time.An important condition in diffusion is that of steady state.

Ficks' first law gives the flux in the state of steady state of flow.

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DIFFUSION DRIVING FORCES

There are many diffusional driving forces in the pharmaceutical system.

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Driving force example

concentration Passive diffusion, drug dissolution.

pressure osmotic drug release.

Temperature Lyophilization

Electrical potential electrophoresis , iontophoresis.

PROCEDURE AND APPARATUS FOR ASSESSING DRUG DIFFUSION

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Diffusion cell for permeation

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This cell is used to study the diffusion through the stratum corneum (forearm) of various permeates e.g. gases, liquids and gels.

Kept at constant temperature.

DIFFUSION THROUGH MEMBRANE

There are several ways that a solute or a solvent can

traverse a physical or biologic membrane. The first e.g. is

diffusion through the polymeric membrane. The matter

through a solid barrier can occur by simple molecular

permeation or by the movement through pores and

channels.

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Steady diffusion across a thin film and diffusional resistance

Yu and Amidon are two scientist developed an analysis for steady

state diffusion across a thin film as it relate to diffusional

resistance. as shown in figure, steady diffusion across a thin film of

thickness h. In this case the diffusion coefficient is considered

constant because the solution on the both side of the thin film are

dilute. The concentration on the both side of the film , Cd and the

Cr, are kept constant and both side mix well. now diffusion occur

through the region of high conc. To the lower conc. i.e. from Cd to

Cr. after sufficient time steady state is achieve and the conc. are

const. at all points in the film.

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At steady state

dC/dt= 0 , so fick’s second law become

D. d2e/dz2 =0

Now integrating this by twice using the conditioned that at

z=0, C=Cd and z=h, C=Cr, yield

J=D/h ( C1-C2)

THE TERM H/d IS THE DIFFUSIONAL RESISTANCE

And is dinoted by R.

Permeability and diffusional resistance are opposite to each other.

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PHARMACEUTICAL IMPORTANCE OF DIFFUSION

Osmosis - Osmosis is the diffusion of water down its concentration

gradient.

If two solutions of different concentration are separated by a semi-

permeable membrane which is permeable to the smaller solvent molecules

but not to the larger solute molecules, then the solvent will tend to diffuse

across the membrane from the less concentrated to the more concentrated

solution. This process is called osmosis.

Osmosis is of great importance in biological processes where the solvent is

water. The transport of water and other molecules across biological

membranes is essential to many processes in living organisms.

Osmotic drug release system .

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The process of osmosis

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Osmotic Controlled Drug Delivery System

A number of design options are available to control or modulate the drug release from a dosage form

Osmotic systems utilize the principle of osmotic pressure for the delivery of drugs. Drug release from these systems is independent of pH and other physiological parameter to a large extent .

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Different types of osmotic systems-Design, mechanism and uses.

1) Osmotic Pump - The water penetrates inside the dosage form at the rate determined by the fluid permeability of the membrane and osmotic pressure of core formulation. This will result in formation of saturated solution of drug within the core, which is dispensed at a controlled rate from the delivery orifice in the membrane.

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2) Controlled-porosity osmotic pump - Water-soluble additives

dissolve after coming in contact with water, resulting in an in situ formation of a

micro porous membrane. The resulting membrane is substantially permeable to

both water and dissolved solutes and the mechanism of drug release was found

to be osmoticaly control diffusion.

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Micro porous membrane

3) Sandwiched Osmotic tablets-

The middle push layer swells and drug is released from delivery orifices

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Ultra filtration and dialysis

Dialysis is primarily used to provide an artificial replacement for lost kidney function (renal replacement therapy)due to renal failure.

Dialysis works on the principles Diffusion of solutes, Ultrafiltration of fluid across a semi permeable

membrane Actual process. The counter-current flow of the blood and dialysate

maximizes the concentration gradient of solutes between the blood and dialysate, which helps to remove more urea and creatinine from the blood.

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Types –There are two primary types

Hemodaylasis and Peritoneal dialysis

In hemodialysis, the patient's blood is pumped through the blood compartment

of a dialyzer, exposing it to a semipermeable membrane. The cleansed blood is

then returned via the circuit back to the body. Ultra filtration occurs by

increasing the hydrostatic pressure across the dialyzer membrane. This usually

is done by applying a negative pressure to the dialysate compartment of the

dialyzer. This pressure gradient causes water and dissolved solutes to move

from blood to dialysate, and allows the removal of several liters of excess fluid

during a typical 3 to 5 hour treatment

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Peritoneal dialysis

A sterile solution containing minerals and glucose is run through a tube into the

peritoneal cavity, where the peritoneal membrane acts as a semipermeable

membrane. The dialysate is left there for a period of time to absorb waste products, and

then it is drained out through the tube and discarded. This cycle or "exchange" is

normally repeated 4-5 times during the day.

Ultrafiltration

The process of water removal from the blood stream is called ulrtafiltration; the fluid

removed is the ultrafiltrate .  The UF during dialysis is performed for the purpose of

removing water accumulated by ingestion of fluid or by metabolism of food during the

interdialytic period. It is essential to prescribe and control the fluid removal rate so that

total fluid removed during dialysis will be equal to the total fluid gained .

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DRUG RELEASE

Considering the sink condition the factor affecting the apparent

rate of the release of the core molecule

The diffusion path length

Molecular collision radius of the diffusing substance

Microscopic viscosity of the diffusion environment

Surface area of the dosage form in contact with the sink

conditions medium

And concentration difference between the start of the molecular

diffusion and sink condition.

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DRUG RELEASE

DIFFUSION IN HYDROGEL- Hydrogel is water swollen network polymer

familiar hydrogel includes gelatin desserts soft contact lenses. All hydrogel

regardless of there actual origin, may be thought of an being composed of

hydrophilic monomer unit linked to form the water soluble polymer and then

cross linked to form the insoluble polymer network and it is manly use in

controlled drug delivery.

DIFFUSION IN HYDROGELS-

Hydrogels can be designed to release drug by various mechanism,

erosion of the gel

hydrolysis of the drug from the polymer backbone

most common mechanism is the passive diffusion .

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The swollen hydrogel (diffusion in swollen hydrogel )

The most important parameter governing the diffusion coefficient in the swollen gel is the water content. In general the diffusion coefficient increase with the increasing in water content , it have very low value in dry gel.

hydrogels are studied for the development of self-regulated insulin delivery system, which releases the insulin in response to changing glucose concentration

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Rate-controlled delivery system

Rate-controlled delivery system deliver a drug at a predetermined rate for a

specific time period.

Delivery either can systemically or locally .

There are commonly used method are

1) diffusion systems

2) dissolution systems

3) osmotic system

4) swelling systems

5) erosion-controlled systems

6) controlled release by stimulation

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Diffusion system In these systems, the release rate of a drug is determined by its diffusion through an inert

membrane barrier, usually an insoluble polymer.There are two type 1) reservoir devices 2) matrix devices

reservoir devices – the release of drug here governed by the first law of diffusion ( fick’s).

Diffusion reservoir devices has been some of the widely used and most successful oral system. Common methods used to developed such type is microencapsulation and film coating tablets. e.g. of microencapsulation both diffusion and dissolution.Diffusion controlled reservoir devices also used in parental ( e.g. levonorgesterol implants), ocular, transdermal route.

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Diffusion controlled implants – Implants are most commonly used for parental administration over the

significantly prolong time of period of time. (e.g.).

In that the drug release governed by diffusion .

Two type of devices that we have seen that is reservoir and matrix type

Transdermal patches –

Have several advantages.

Provide large area for diffusion,

noninvasive, easy to apply and remove,

long term drug release.

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Disintegration,deaggrigation,dissolution.Diffusion also plays important role.The rate at which solid dissolves in the

solvent was given by Noyes and WhitneyAqueous diffusion layer or stagnant liquid

film.

solid layer

Drug release from tablet

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DIFFUSION AND BIOADHESION

Natural and synthetic bioadhesive polymers that can adhare to hard or

soft tissue have been used for many years in dentistry, orthopedics,

ophthalmology and surgical procedures.

mucoadhesive.

There are various mechanism by which the adhesion is take place. Electronic theory Fracture theory Adsorption Wetting theory Diffusion theory

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The mean diffusional pathway can be calculated by

S= (2tD) 1/2

T= contact time , the rate of penetration is directly

proportional to the d.c of mucosal glycoprotein’s structure

into the polymer matrix and polymer strand into the

mucosal matrix.

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DIFFUSION AS A MIXING MECHANISM

There are various mechanism of mixing that is for both fluid as well as for the

solid.

In case of the liquid the mechanism are,

Bull transport

Turbulent mixing

Laminar mixing

molecular diffusion

molecular mixing - the primary mechanism for fluid mixing at molecular level

is diffusion resulting from the thermal motion of the molecules. When it occur

with conjunction with the laminar flow result in complete mixing. The

mechanism is given by the fick’s law of diffusion.

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DRUG ABSORPTION AND ELIMINATION

Passive Transport

Passive transport requires no energy from the cell. Examples include

the diffusion of oxygen and carbon dioxide, osmosis of water, and

facilitated diffusion.

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facilitated diffusion

Facilitated diffusion of the drug takes place through proteins, or

assemblies of proteins, embedded in the plasma membrane.

These transmembrane proteins form a water-filled channel

through which the ion can pass down its concentration gradient.

Many ion channels open or close in response to binding a small

signaling molecule or "ligand". Some ion channels are gated by

extracellular ligands; some by intracellular ligands. In both

cases, the ligand is not the substance that is transported when

the channel opens

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Absorption via BBB

Lipophilic drug.

Lipophobic drug.

Lipophilicity can be increase by chemical means

by conjugation with lipophilic drug carrier .

Use of dihydropyridine system.

DIHYDROPYRIDINE SYSTEM

Diffusion as the mechanism.

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DIFFUSION TESTING

Diffusion test used to evaluate the filter which are use to filter the large volume.

This test measure the amount of the air flows through the wet membrane.

The mechanism is based on the fick's first law of diffusion.

Actual process.If at low pressure the large amount of air is

displace then filter is damaged more.

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DIFFUSION BATTERIES

Diffusion batteries have been used to evaluate the aerosol in concern with the partials size.

Consist of series of the cylindrical tube containing series of the screen.

Diffusion coefficient , d is given by D = K T Cc 3 Dp pay u

Amount of particles retain , the concentration is determined.

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AGAR DIFFUSION TEST

The agar diffusion test, or the Kirby-Bauer disk-diffusion method, is a means of measuring the effect of an antimicrobial agent against bacteria grown in culture.

Zone of inhibition . MIC

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RESEARCH AND WORK. Gastro-intestinal diffusion tablet: Influence of polyoxyethyleneglycol 400.

international journal of pharnaceutics volume 129 isseu 1-2, 8 March 1996, Pages 279-282

Controlled Release Formulation of Tramadol Hydrochloride Using Hydrophilic and Hydrophobic Matrix System.

Osmotic Flow Through Asymmetric Membrane: A Means for Controlled Delivery of Drugs With Varying Solubility Anil K. Philip and Kamla Pathak Department of Pharmaceutics, Rajiv Academy for Pharmacy,Mathura-286001,UttarPradesh,India.

Osmotic Drug Delivery: An Update a review article by M.C.Goyel Parikh R.K, Shah R. Y. Pharma info.net.

Transdermal Patch and Method For Delivery Of Vitamin B12 Inventors: Jon D zeltman, patents doc.

Hydrogels as controlled drug delivery systems: Synthesis, crosslinking, water and drug transport mechanism CS Satish, KP Satish, HG Shivakumar Year : 2006  |  Volume : 68  |  Issue : 2  |  Page : 133-140

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Brian W. Barry , drug and pharmaceutical science dermatological formulation , perceutanous absorption, volume 18 Dekker series , 1983, 49,50,57.

Peter J . Tarcha , polymer for controlled drug delivery , 1990 cps press., 2, 22,3.

Leon Lachman , Herbert A. Lieberman ,Joseph L. Kanig , the theory and practice of industrial pharmacy, third edition , Varghese publication house mumbai 14, 3-6,15,158-159.

Remington the science and practice of pharmacy , 21th edition, volume 1 , Indian edition, Lippincott William's & Wilkins ,

www. Aaps pharmascience .comP. Arnaud, I. Guillard, D. Brossard and J. C. Chaumeil, Gastro-intestinal

diffusion tablet: Influence of polyoxyethyleneglycol 400 , international journal of pharmaceutics volume 129,issue 1-2 , 8 March 1996, Pages 279-282 .

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http;//en.wikipedia.org/wiki/dialysisKoichi linoyo, Keishi Gotohko,Higasitani. Powder

technology hand book, dekker series, New york 1990 . 33,34

Robinson and lee . Controlled drug delivery , fundamentals and application , 2nd edition revised and expanded, volume 19 , Marcel Dekker series, 180,182.

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THANK YOU

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