CHAPTER 11: DIFFUSION

DIFFUSION
-spreading
-process of mass transfer of individual molecules of a substance brought about by random molecular
motion and associated with a driving force such as a concentration of a gradient
-solute moves from higher to lower concentration

WAYS THAT A SOLUTE OR A SOLVENT CAN TRANSVERSE A PHYSICAL OR BIOLOGIC MEMBRANE :

a) Simple molecular penetration

-involves dissolution of a drug in the matrix
-diffusion through homogenous film
-depends on the solubility of the permeating molecules in bulk membrane

b) Diffusion through a solvent-filled pores

-passage of substance influenced by the relative size of the penetrating molecules and the diameter and
the shape of the pores
-nucleopore
-drug and solvent transport across the skin
-passage of steroidal molecules through the human skin (hair follicles, sebum ducts and sweat pores)

c) movement through and /or between the fibrous membrane strands

-dependent on the size and shape of the diffusing molecules
-if too large, the diffusant dissolve on the polymer matrix and pass through the film by simple diffusion
-cellulose materials used in the filtration process, showing the intertwining nature of the fiber and
tortuous channel

Pharmaceutically important diffusion based processes

I. Drug absorption and elimination

a. Transcellular diffusion
-through lipoidal bilayer of the cells
-transverse
b. Paracellular diffusion
-through the spaces between adjacent cells
>Membrane transporters are specialized proteins that facilitate drug transport across biologic
membranes
>The interaction between drugs and membrane transporter can be
-energy dependent (active transport)
-energy independent (facilitated diffusion)

II. Drug release

-a multistep process; diffusion, disintegration, deaggregation and dissolution
-drug release must occur before the drug can be pharmaceutically active
-topical, oral such as creams, ointments, transdermal patches, tablets, capsules and liquid suspension
III. Osmosis
-to dilute and attained equilibrium
-originally was defined as the passage of both solute and solvent across a membrane but now refers to an
action in which only the solvent is transferred.
-the passage of solute together with the solvent is called DIFFUSION or DIALYSIS
Osmotic pump delivery system

IV. Ultrafiltration and Dialysis

-used to separate colloidal particles and macromolecules by the use of a membrane
-Hydraulic pressure is used to force the solvent through the membrane, where the microporous
membrane prevents the passage of large solute molecules
-similar to process called reverse osmosis

Reverse osmosis
-uses as much higher osmotic pressure
-used in desalination of brackish water
Ultrafiltration
-used in the pulp and paper industry
- in research, to purify albumin and enzymes
Microfiltration
-employs membranes of slightly large pore size
-100 nm to several micrometers
-removes bacteria from intravenous injections, foods and drinking water

Dialysis
-separation process based on unequal rates of passage of solutes and solvent through microporous
membranes, carried out in a batch or continuous mode
Hemodialysis -used in treating kidney malfunction to rid the blood of metabolic waste products
(small molecules) while preserving the high molecular weight components of the blood

Osmosis and Dialysis

-does not involved the high applied pressures of ultrafiltration and reverse osmosis
TYPES OF DIFFUSION AND MEASUREMENT RATES

1. Steady state diffusion

 Diffusion takes place at a constant rate
 guided by Fick’s first law which states that the amount or concentration of a substance is constant with respect to
time
 EXAMPLE: Leaking gas from a cylinder
 can be described in terms of Fick's 2nd Law

Fick's First Law

𝑑𝑀
J=𝑆.𝑑𝑡

Where:
J = flux; proportional to the concentration gradient dC/dx
M= amount of material (unit is g or mole)
S= area in 𝑐𝑚²
T= sec

(Fig 11-3)

*Solutions constantly removed and replaced by fresh solvent to keep the concentration at a low level ("sink condition")

2. Non steady state diffusion

 diffusion is a time dependent process
 guided by Fick's Second Law
 EXAMPLE: When a material diffuse deeper into the substrate as it increases

Fick's Second Law

- "states that the change in concentration with time in a particular region is proportional to the change in the
concentration gradient at that point in the system"

3. Convective diffusion
 Convective, the transfer of heat (energy) in the presence of agitation accompanying the movement of
fluid, may be combined with diffusion to provide a convective diffusion model for the study of
dissolution
 Intestinal absorption of drugs is fluid flow down the intestine (radial diffusion and axial convection)

4. Multilayer Diffusion
• Diffusion across biologic barriers
• involve a number of layers, cell membrane, cell contents and fluids of distribution
• Passage of gaseous liquid or liquid solutes through the walls of the container and plastic packaging
materials
• Passage of topically applied drugs for its vehicle through the lipoidal and lower hydrous layers of the skin
Driving forces in Pharmaceutical System
 Table 11-1

Driving Force Example Description Ref

Concentration Passive diffusion Passive diffusion is a process of mass transfer of individual molecules of a substrate brought about by 3
random molecular motion and associated with a concentration gradient
Pressure Osmotic drug Osmotic drug release systems utilize osmotic pressure as the driving force for controlled delivery of 11
release drugs; a simple osmotic pump consists of an osmotic core (containing drug with or without an osmotic
agent) coated with a semipermeable membrane; the semipermeable membrane has an orifice for drug
release from the pump; the dosage form, after contacting with the aqueous fluids, imbibes water at a
rate determined by the fluid permeability of the membrane and osmotic pressure of core formulation;
this osmotic inhibition of water results in high hydrostatic pressure inside the pump, which causes the
flow of the drug solution through the delivery orifice
Pressure-driven jets Pressure-driven jets are used for drug delivery; a jet injector produces a high-velocity jet (>100 m/sec) 12
for drug delivery that penetrates the skin and delivers drugs subcutaneously, intradermally, or intramuscularly without
the use of a needle; the mechanism for the generation of high velocity jets includes either a
compression spring or compressed air
Temperature Lyophilization Lyophilization (freeze-drying) of a frozen aqueous solution containing a drug and a inner-matrix 13
building substance involves the simultaneous change in receding boundary with time, phase transition
at the ice–vapor interface governed by the Clausius–Clapeyron pressure–temperature relationship, and
water vapor diffusion across the pore path length of the dry matrix under low temperature and vacuum
conditions
Microwave - Microwave -assisted extraction (MAE) is a process of using microwave energy to heat solvents in 14
assisted extraction contact with a sample in order to partition analytes from the sample matrix into the solvent; the ability
to rapidly heat the sample solvent mixture is inherent to MAE and is the main advantage of this
technique; by using closed vessels, the extraction can be performed at elevated temperatures,
accelerating the mass transfer of target compounds from the sample matrix
Electrical Iontophoretic Iontophoresis is used to enhance transdermal delivery of drugs by applying a small current through a 15,
potential dermal drug reservoir that contains ionized drugs; one electrode (positive electrode to deliver positively charged 16
delivery ions and negative electrode to deliver negatively charged ions) is placed between the drug reservoir
and the skin; the other electrode with opposite charge is placed a short distance away to complete the
circuit, and the electrodes are connected to a power supply; when the current flows, charged ions are
transported across the skin through a pore
Electrophoresis Electrophoresis involves the movement of charged particles through a liquid under the influence of an 17
applied potential difference; an electrophoresis cell fitted with two electrodes contains dispersion;
when a potential is applied across the electrodes, the particles migrate to the oppositely charged
electrode; capillary electrophoresis is widely used as an analytical tool in the pharmaceutical sciences

 Driving forces
o Concertation- passive and active diffusion
o Pressure - osmotic drug release and pressure driven jets
o Temperature- lyophilization and microwave-assisted extraction
o Electrical potential- Iontophoretic dermal delivery and electrophoresis

DIFFUSION PRINCIPLES IN BIOLOGIC SYSTEM

1. Gastrointestinal absorption of drugs

 Drug absorption by means of diffusion through intestinal cells and or in between those cell is governed by;
 State of ionization of the drug
 Solubility and concentration in the intestine
 Membrane permeability
 EXAMPLE: Taxol
 drug pass through living membranes according to two main classes of transport systems;

A. Passive diffusion
⁃ The passage of the drug molecules from a region of high in the GIT to a region of low concentration
in the systemic circulation through a membrane which behaves inertly in that it does not actively
participate in the process.
 ⁃ Lipid drug molecules are transported via this mechanism
⁃ Described by Fick's First Law

B. Carrier-mediated transport
 Active transport
⁃ A specialized transport system which requires energy source such as enzyme or
biochemical carrier to ferry the drug across the membrane
⁃ Transport can proceed from regions of low concentration to high concentrations through
the "pumping action" of the biologic transport system
⁃ Body nutrients such as sugars and amino acids, thiamine, niacin, riboflavin and Vit.B6,
methyldopa and
5-flourouracil are examples of drug molecules transported via this mechanism
⁃ Fick's First Law- "the rate of diffusion through a unit area (flux) is proportional to the
concentration gradient"

 Facilitated diffusion ⁃ a carrier mediated transport system that does not require an energy
source such as ATP

Absorption of drugs is favorable for the unionized or salt form of a drug.

• For a weak molecular acid,
100
% ionized= 1+𝑎𝑛𝑡𝑖𝑙𝑜𝑔 (𝑝𝐾𝑎−𝑝𝐻)
Similarly, for a weak molecular base,
100
% ionized= 1+𝑎𝑛𝑡𝑖𝑙𝑜𝑔 (𝑝𝐻−𝑝𝐾𝑎)

2. pH Partition Hypothesis
⁃ Drugs absorbed from the GIT by passive diffusion depend on the fraction of the undissociated drug at the pH of the
intestine

STOMACH
• pH is Low, acidic
• Acidic drugs are in their undissociated form (lipophilic) so can across barrier
• Basic drugs are greatly ionized so cannot cross the barrier

SMALL INTESTINE
• pH is High, basic
• Basic drugs are undissociated, so can cross the barrier
• Acidic drugs are ionized, thus cannot cross the barrier

3. Transcorneal permeation
• Corneal penetration
• Pilocarpine

4. Percutaneous absorption
Passage through the skin involves:
• Dissolution of a drug in its vehicle
• Diffusion of solubilized drug from the vehicle to the surface of the skin
• Penetration of the drug through the layers of the skin, principally the stratum corneum. Figure 11-18
• Diflorasome diacetate
 5. Buccal Absoption
 The absorption is based on the pH partition hypothesis such as pKa of the compound and lipid-water partition
coefficient
 Buccal membrane does not posses significant aqueous pore pathways and surface pH is the same with buffered
drugs
 First order reaction

6. Uterine Absorption
 Progesterone in diffusion- controlled form (IUD)
 First- order rxn

CALCULATION:
1 𝑥 100
% Ionization =
1+1 𝑎𝑛𝑡𝑖𝑙𝑜𝑔 (𝑝𝐾𝑎−𝑝𝐻)

100
%I for weak acid= 1+ 𝑎𝑛𝑡𝑖𝑙𝑜𝑔 (𝑝𝐾𝑎−𝑝𝐻)

1 𝑥 100
%I foe weak base= 1+1 𝑎𝑛𝑡𝑖𝑙𝑜𝑔 (𝑝𝐻−𝑝𝐾𝑎)

Sample Problem: Calculate the % ionization of papaverine at pH= 3.9; pKa 5.9
100
Solution: % Ionization =
1+ 𝑎𝑛𝑡𝑖𝑙𝑜𝑔 (3.9−5.9)

100
= 1+0.01

%I = 99
%U= 1 at 3.9

When boric acid is distributed between water and amyl alcohol at 25º, the Cw= 0.0510 M and the Co= 0.0155 M. What is
the Kd?

Kd= Co/ Cw
0.0155𝑀
Kd= 0.0510𝑀
= 0.304

Therefore boric acid is more hydrophilic