PROCESS OF TRANSDERMAL

PERMEATION
 Skin
Skin:
 Skin is a large multilayered organ. It is far more than just the
outer covering of human beings. It is an organ just like heart,
lung or liver.

 Why skin is considered as an organ?

Skin is considered as an organ because it consists of two
tissues: 1) epithelial and 2) connective

 The skin and its appendages (hair, nails) form the

integumentary system. The term integumentary is derived
from Latin word “integumentum” integere i.e. to cover. The
integumentary system is the largest organ system accounting
for about 16% of the total body weight and covers 1.5-2 m2 of
the surface area.
Anatomy of Skin
Anatomically skin may be described as a stratified organ
with 3 distinct tissue layers:

 Epidermis
 Dermis
 Hypodermis (subcutaneous fatty layer or superfacial fascia)
Anatomy of Skin
 Epidermis: Epidermis is the outermost skin layer an comprises
of stratified squamous epithelial cells. The main function of
epidermis is

 Protection
 Absorption
 Homeostasis

 Stratum corneum is the outermost layer of epidermis;

structurally it consists of keratinized stratified squamous
epithelial cells. The major cells of epidermis are keratinocytes
which produce keratin. Keratin is a fibrous protein that helps in
protection. The majority of the skin on the body is keratinized
i.e. water proofed. The only non keratinized skin on the body is
the skin lining inside the mouth.
 Anatomy of Skin
 Protein keratin stiffens the epidermal tissue to form finger nails.

 The stratum corneum or horny layer consists of dead keratinized cells in stratified layers
with a density of about 1.4 -1.55 g/cm3. Hence it is also referred as stratum compactum. Because
of this dense nature, it acts as a barrier for inward or outward movement of chemical substance
making it impenetrable.

 Stratum corneum exhibits regional differences in thickness. It several hundred micrometers

on the friction surfaces of the body (palms & soles). However most of the body it is about 10
microns thick. It is constantly subjected to wear and tear and new cells are constantly replaced.

 The keratinized squamous cells of stratum corneum are linked by intercellular bridges.
The lipid rich intercellular space in the stratum corneum contains lamellar matrices of
alternate hydrophilic and lipophilic bilayers formed during keratinization. Hence this
region is tough as well as flexible and coherent.

 The stratum corneum is hygroscopic and its thickness is hygroscopic and its thickness increases to
40 -50 micron when hydrated. Chemically stratum corneum is 75-80% protein, 15-20% lipid and
15% water. Stratum corneum is covered by an acidic film of pH 4 – 6.5, made up of emulsified lipids.
Anatomy of Skin
 Viable Epidermis: beneath the stratum corneum are the metabolically active layers of
the epidermis. These germinal layers just above the dermis start their mitotic activity
upward to the surface. They flatten and shrink and slowly die because of lack of
nutrition and oxygen.

 Cells at the basement of the stratum corneum contain high water activity where as at the
surface there is low water activity. As a result water diffuses out through the skin leading
to water loss called as insensible perspiration.

 Viable cells of epidermis are classified into 4 layers viz:

Stratum lucidum
Stratum granulosum
Stratum spinosum
Stratum basale

 Apart from keratinocytes, epidermis also consists of other cells Langerhan cells, Merkel
cells and melanocytes. These melanocytes secrete pigment granules that give the
human race their unique coloration.
Anatomy of Skin
 Dermis: dermis is a gel structure situated between epidermis and
subcutaneous fat. It is complex structure comprising of fibers, collagen,
reticulum and elastin protein in mucopolysaccharide gel called as
ground substance.

 The dermis ranges from about 1mm to about 5 mm in thickness. Dermis

comprises of 2 layers viz. the outer papillary layer which nurtures
epidermis. The inner layer is reticular layer which is the main structural
element of skin.

 The dermis is penetrated by sensory nerve endings (pressure,

temperature and pain) and lymphatic network and blood vessels.
Dermis consists of fibroblasts and mast cells. Mast cells synthesize
ground substance and histamine. Histamine is released in response to
allergic and immunologic reactions. The dermis supports epidermis and
conforms it to muscles and bones.
Anatomy of Skin
 Hypodermis / Subcutaneous layer: this layer of tissue is directly underneath the
dermis. It is composed of connective and adipose tissue. The function of this layer is
insulation, storage of energy. This is the thickest layer of skin.

 Skin appendages:
 Hair follicles and their associated sebaceous glands (pilosebaceous glands), sweat glands
(eccrine and apocrine) and nails are considered as skin appendages. Hair follicles are
distributed over the entire skin surface with exception of sole, palms and lips. The
density varies from 250 follicles / sq cm for scalp and 50 / sq cm for other areas.

 Human hair consists of compacted keratinized cells formed by follicle. Sebaceous glands
empty into follicle to form pilosebaceous units. The human hair, follicles are surrounded
by sensory nerves.

 Sebaceous glands population in the scalp face and anogenital area can vary from 400 –
900 / sq cm and less than 100 / sq cm in other areas. Sebaceous glands are supplied with
blood vessels. Sebaceous glands secrete sebum. Sebum is comprising of lipids (squalene,
triglycerides, wax esters, cholesterol) which is secreted out through pilosebaceous canal
via duct. Blockage to the surface causes bacteria Propionibacterium acne to multiply
thereby causing acne.
Anatomy of Skin
 Sweat glands: are of 2 types eccrine and apocrine. Apocrine
glands are secretory but not responsive to thermal stimulation.
Apocrine glands are located in the axillae and anogenital
regions. Eccrine glands (salty sweat glands) equipped with blood
supply and found over entire body. They are coiled secretory
glands extending from dermis to epidermis.

 Sweat glands regulate body temperature. Distribution of eccrine

glands varies from 100 to 400 glands / sq cm. sweat is hypotonic,
slightly acidic (pH = 5 due to traces of lactic acid) aqueous
solution of salt.
Functions of skin
 The skin has an important job of protecting the body and it acts as the body’s
first line of defense against infection, temperature change and other challenges
to homeostasis.

 The functions of skin are:

 Containment: Protect the body’s internal living tissues and organs and holding
them. The containment function relates specifically to ability of skin to confine
underlying tissues and movements. This function is contributed from tough and
fibrous dermis. The skin is taut at resting position but when in motion it is
extensible.

 Microbial barrier (Protection against invasion by infectious organisms): stratum

corneum is impenetrable and acts as an absolute barrier to microbes
preventing it form reaching the viable tissue. Apart from physical barrier,
the secretions of sebum and sweat are acidic and bacteriostatic. Sebum
contains short chain fatty acids like propanoic, butanoic, hexanoic and
heptanoic acid which are fungi and bacteriostatic.
Functions of skin
 Chemical barrier: intact stratum corneum is a barrier to
chemicals. It offers resistance to diffusion.

 Radiation barrier: it protects the body against sunburns by

secreting melanin. UV wavelengths in the range 290-310 nm of
UV – B band of radiation are not fully atmospherically filtered.
These rays cause tissue damage principally. On exposure to UV
rays, melanin is secreted from melanocytes. The melanin is
dispersed throughout the epidermis and it diffracts harmful UV
rays.

 Electrical barrier: dry skin offers resistance to a flow of an

electric current. It acts as a prime electric insulator.
Functions of skin
 Thermal barrier and body temperature regulation: it protects the body against
abrupt changes in temperature. The body is finely tuned at 37°C. When body is exposed
to chilling temperatures, that remove heat faster than body’s metabolic output, changes
take place in skin so that blood supply is slowed and heat is conserved. Conversely when
body is overheated, physiological changes occur leading to cooling. These changes are
brought about by variations in blood circulation in skins periphery. The eccrine glands
cause sweating leading to heat removal.

 Protects the body from dehydration.

 Helps in excreting waste material through perspiration.

 Acts as receptor for touch, pressure, pain heat, cold.

 Generates Vitamin D on exposure to UV light.

 Storage of fat, water and vitamin D.

 Formation of new cells from stratum germinatum to repair minor injuries.

STRUCTURE OF HUMAN SKIN
 STRUCTURE OF HUMAN SKIN
 Human skin
 The stratified avascular cellular
epidermis
 An underlying dermis of
connective tissue
 Stratum corneum or horny
layer
 Rate-limiting or slowest step in
the penetration process
 Transport mechanism
 Transepidermal pathway across
the horny layer either intra- or
intercellularly
 Via hair folicles and sweat glands
(the appendageal route)
 Mechanisms of drug penetration
 The skin structure has an outer layer (stratum corneum) that is made of dead
keratinized cutaneous epithelial cells. This layer is a barrier to water-soluble diffusion.
Next to it is a layer of keratohyaline granules and water-soluble substances. This layer is a
barrier to lipid-soluble substances. This follows the innermost layer of viable epithelial
cells .

 While designing transdermal dosage form, one must take into account the permeability
nature of the skin membrane and desired effect (local or absorption) of the dosage form
in question.

 The drug may diffuse freely in an uncombined form with a kinetic energy appropriate to
its thermal environment, or alternatively, it may travel in combination with extracellular
or cellular constituents. These processes sometime allow the complexes or molecules to
overcome the barrier to simple diffusion.

 Five different types of transport processes and their characteristics are summarized
further on
 Passive Transport
 Ionic or Electrochemical Diffusion
 Facilitated Diffusion
 Active Transport
 Pinocytosis.
 Passive Transport
In this type of transport process, molecules in solution move in random
fashion, provided they are not charged and moving in an electrical
ingredient. Such random movement is called diffusion. If the molecule is
uncharged, it is called nonionic diffusion. In this type of movement, the net
movement is from higher to lower concentration and is proportional to the
concentration gradient.

 Ionic or Electrochemical Diffusion

In the case of ionized drugs, the transport properties are modified in such a
way that movement is also a function of a potential difference or electrical
gradient across the membrane. Accordingly, a cationic drug molecule will be
repelled from the positive charge on the outside of the membrane, and only
those molecules with high kinetic energy will pass through the ion barrier.
Once inside the membrane, a cation will be attracted to the negative charge
on the intracellular surface of the membrane and repelled by the outer
surface.
 Facilitated Diffusion
This type of accelerated movement is due to a presence of special molecules within the
membranes called carriers. The carrier-drug complex has greater permeability than the
pure drug and therefore, movement rate is enhanced. Once across the membrane, the
carrier-complex either dissociates and returns to outside of the membrane to restart the
complex formation or is constantly generated for further transfer of the drug molecules.

 Active Transport
This transport process is defined as energy-dependent movement of drugs against an
electro-chemical gradient. The process is characterized by transportation from lower to
higher electro-chemical activity. This type of movement approaches an asymptote
(saturable) as concentration increases. This system is required for transport of
anticancer drugs across cell membranes. Some drugs are also secreted from renal tubules
into urine, liver cells into bile, and cerebrospinal fluid into blood by this process.

 Pinocytosis
In this process, the cell membrane invaginates into a saccular structure containing
extracellular material and then pinch off the saccule at the membrane. In this way, the
saccule remains as a vesicle or vacuole inside the cell. This process is normally slow and
inefficient except in GI absorption of macromolecules and larger particles.
Percutaneous absorption
 Penetration of drugs through skin or percutaneous absorption is defined as the
penetration of substances into various layers of skin and permeation across the
skin into systemic circulation.
 The percutaneous absorption is a stepwise process and can be divided basically
into three steps:
 Penetration: - This is the entry of a substance into a particular layer.
 Permeation: - This is the permeation from one layer into another, which is
different both functionally and structurally from the first layer.
 Absorption: - This is the uptake of a substance into the systemic circulation.

• Diffusion through the stratum corneum is purely a passive process.

Epidermal diffusion is the first phase and clearance from the dermis is the
second, the later being dependent on the effective blood flow.
• Intestinal fluid movement, lymphatics and other factors such as
combination with dermal constituents assume significance after this step.
Mechanisms of drug penetration
Absorption through skin
 Principal absorption route are identified:
 Transepidermal absorption
 Transfollicular (shunt pathway) absorption
 Transappendagel pathway
 Routes of skin permeation
 The structure of skin shows number of diffusional pores like hair follicles,
sweat glands, intercellular spaces, etc., which help in the absorption of the
drug substance.
 The various routes of skin permeation are
Transcellular Pathway - (Across lipid rich region).
 The transcellular pathway in which drug travels through cells & across them. This is
the most shortest & also the most likely route, given the relative area presented to a
diffusion molecule. Transcellular route provides the main pathway during
percutaneous absorption.
Intercellular pathway – (Between the cells)
 Intercellular pathway avoids diffusion through cell content but is substantially more
tortuous. Structural data on the appendages of the skin, relevant to diffusion
indicate that the fractional area of the skin covered by appendages over most of body
is quite small (0.1%) & that the appendages do not constitute a completely open-pore
area but filled with hair keratin or sebum or in case of sweat ducts, water.
Transappendagel pathway –
 Transappendagel route usually cannot contribute appreciably to the steady state flux
& fractional area available for absorption is small. This route may be important for
ions & larger polar molecules, which cross-intact stratum corneum with difficulty.
 Kinetics of permeation
 Permeation of a drug involves the following steps,
 Sorption by stratum corneum,
 Penetration of drug though viable epidermis,
 Uptake of the drug by the capillary network in the dermal papillary layer.

 This permeation can be possible only if the drug possesses certain

physicochemical properties. The rate of permeation across the skin (dQ/dt)
is given by:

 Permeability coefficient is given by the relationship:

 a constant rate of drug permeation can be obtain when Cd >> Cr i.e., the drug concentration at
the surface of the stratum corneam (Cd) is consistently and substantially greater than the drug
concentration in the body (Cr).
 And the rate of skin permeation (dQ/dt) is constant provide the magnitude of Cd remains
fairly constant throughout the course of skin permeation. For keeping Cd constant, the drug
should be released from the device at a rate (Rr) that is either constant or greater than the rate
of skin uptake (Ra) i.e., Rr >> Ra
 Dissolution of drug in
vehicle

Diffusion of drug through vehicle to skin

Transepidermal surface Tranfollicular
Route Route

Partitioning into Stratum Partitioning into sebum

Corneum

Diffusion through Protein-Lipid Matrix of Stratum

Diffusion through lipids in sebaceous pore
corneum

Partitioning into viable epidermis

Diffusion through cellular mass of

epidermis

Diffusion through cellular mass of upper

epidermis

Capillary uptake & Systemic dilution

Fig: Schemes of events for percutaneous absorption

 Percutaneous Absorption &
Penetration
 Drugs can take either one or both the routes. Molecular penetration through various regions
of skin is limited by diffusional resistance of skin depicted by following equation:

 Rskin = Rsc + Re + R pd

 R is diffusional resistance, sc= stratum corneum, e=epidermis, pd= papillary dermis

 Greater resistance to diffusion of drug is met in stratum corneum and this becomes rate
limiting step for Percutaneous absorption. The resistance of a layer to permeation is
proportional to thickness and inversely proportional to diffusion coefficient, partition
coefficient (capacity of layer to solubilize the substance) and area of membrane through
which diffusion is taken place.

 Ri = Hi
------------------
Fi x Di x Ki

H= thickness D= diffusion coefficient

K= partition coefficient F = fractional area
Percutaneous Absorption &
Penetration
 The role of skin appendages like hair follicles and sweat glands in
absorption is minimal because or relatively small fractional area.

 Conventionally lipophilic compounds transfer preferentially through

intercellular and hydrophilic compounds transfer through intracellular
route of stratum corneum.

 Permeability experiments have shown had hydrated stratum corneum

has affinity for both lipophilic and hydrophilic compounds. This
bifunctional / biphasic solubility is due to the hydrophilic corneocytes
and lipid rich lamellar structure of intercellular spaces.
Percutaneous Absorption &
Penetration
The stratum corneum is not an inert system but a passive diffusion membrane where adsorption
is linear with concentration. The flux of solute can be depicted as:
Js = Km x D x Cs
--------------------------
§
Kp = Km x D
--------------------------
§
Js = Kp x Cs
Js = steady state flux of solute
Cs = concentration difference of solute across membrane
§ = membrane thickness
Km = correlation between external and surface concentrations is given in terms of solvent
membrane distribution coefficient.

Km = solute sorbed / cubic cm of tissue

--------------------------------------------------------
Solute in solution / cubic cm of solvent
 Factors influencing penetration
 Factors associated with the Skin.
 Hydration of the horny layer
 Thickness of the Horny layer
 Skin Conditions
 Factors associated with the API.
 Solubility
 Dissociation constant
 Particle Size
 Crystal Structure / Polymorphism
 Factors Associated with the Vehicle.
 Contact with Body Surface
 Hydration Stratum Corneum
 Penetration of the Epidermis
 Alteration of Skin Permeability
 KEY ASPECTS OF
ABSORPTION
The stratum corneum permeability
is the limiting resistance

Thermodynamic activity of the drug in the formulation

is the driving force for absorption

Formulation additives can alter barrier properties of the

skin (permeability)
THE THEORY FOR PENETRATION-
ENHANCER ACTIVITY
 Activity of penetration enhancers
 Interaction with the polar head groups of lipid via
hydrogen and ionic bonding
 Change in hydration sphere of lipids and affect the packing at
the head region
 Increase volume of the aqueous layer : swelling and
hydration
 Alter the packing of the lipid tails  disorder and
traverse by a lipid-like penetrant
 Solvents
 DMSO, propylene glycol, ethanol
 Partition coefficient elevate drug concentration in the skin
 Cosolvent
 Azone (1-dodecylazacycloheptane-2-one)
 Cis-unsaturated oleic acid
 Additive : PG  increase solubilizing ability for lipid-like
materials
 Flip over to insert between the hydrophobic groups of the
membrane lipids  increasing fluidity of lipid
 Interaction mechanism of solvents and surfactants
with proteins
 Interaction with polar groups
 Relaxation of binding forces and alterations in helix
conformations
 Pore route formation
 Pressure Sensitive Adhesives
 The peripheral adhesive system is less elegant and
contains several layers.
 It is larger and difficult to manufacture than the face
adhesive system.
 In case of peripheral adhesive systems, there is no need
to further pack the drug reservoir layer.
 However in case of face adhesive systems. They cannot
be hermetically sealed, therefore they are required to be
packed in aluminium foil pouch.

 E.g. polyisobutylenes, acrylics, silicones.

•In this system, drug reservoir is sandwiched between drug impermeable backing laminate
and rate controlling polymeric membrane
•Drug release through rate controlling polymeric membrane.
•In the drug reservoir, drug is dispersed uniformly in solid polymer matrix
(polyisobutylene) suspended in unleachable viscous liquid medium (silicone fluid) to form
paste like suspension or dissolved in a solvent (alcohol) along with gelling agent like HPC /
HEC to form clear solution.
•Rate controlling membrane can be microporous or nonporous membrane made of
ethylene vinyl acetate copolymer.
•On the external surface of the polymeric membrane a thin layer of drug compatible
hypoallergenic pressure sensitive adhesive polymer i.e. silicone adhesive may be applied to
provide intimate contact of the TDD with skin surface.
•Drug release can be varied by changing the composition of drug reservoir formulation,
permeability coefficient &/or thickness of rate controlling membrane
•Drug reservoir is formed by homogenously dispersing the drug solid in hydrophilic or
lipophilic polymer matrix.

•This medicated polymer matrix is then molded into disc with definite surface area &
thickness.

•Drug polymer reservoir disc is then mounted on occlusive base plate then into
compartment made of impermeable plastic backing.

•Unlike the first system, where the adhesive is applied directly on the surface of disc. Here
in this system adhesive polymer is applied along the circumference of the patch to form a
strip or rim of adhesive surrounding the medicated disc.
•The rate of drug release from this polymer matrix drug dispersion type TDD is given by
•dQ Ld Cp Dp 1/2
------- = ------------------ Ld = drug loading dose, Cp & Dp solubility & diffusivity of
dt 2t drug in the polymer matrix

•At steady state Q vs t ½ is given by

•Q [(2Ld –Cp) Cp Dp] 1/2

------- =
t 1/2
In another TDD of this type drug is dispersed directly in pressure sensitive adhesive
polymer viz. polyacrylate / polyisobutylene and coating this drug dispersed adhesive
polymer by solvent casting or hot melt on to a flat sheet of a drug impermeable backing
laminate to form single layer of drug reservoir. This kind of TDD patch is thin and small
and release profile follow linear Q vs. t1/2 pattern as seen in matrix diffusion process.
 •To improve the Q versus t1⁄2 drug release
profile , the polymer matrix diffusion-
controlled rate-controlled DDSs can be
modified to have the drug loading level varied,
in an incremental manner, to form a gradient
of drug along the diffusional path in the
polymer matrix.
•A constant drug release profile is thus
achieved. The rate of drug release from this
reservoir gradient-controlled drug delivery
system is given by the equation mentioned
R1>R2>R3>….>Rn •In this system thickness of the diffusional path through which drug
molecules, diffuse increases with time [ha(t)] . To compensate for
this time dependent increase in diffusional path occurring because
of drug depletion due to release, the drug loading concentration in
the multilaminate adhesive layer is made to increase proportionally
[Cp(ha)]. Hence, a constant drug release profile results.
•e.g. Nitroglycerin-releasing Deponit® system. This TDDS is also a
polymer matrix diffusion-controlled , but its drug reservoir is a
multilayered laminated adhesive polymer matrix containing
nitroglycerin as the active ingredient for the prevention of anginal
attacks.
• Each of the polymer laminates contains a loading dose, in gradient,
of nitroglycerin, which increases as the laminate moves away from
the surface in contact with the skin. The system is specifically
designed to provide a 12–14-hour rate-controlled delivery.
Microreservoir Partition- Dissolution Controlled
Systems •In this type, drug reservoir is a suspension. Drug
solids are suspended in an aqueous solution of a
water-miscible polymer, such as PEG.

•This suspension is then homogenously dispersed in a

lipophilic polymer by higher shear mechanical force.
This forms a homogeneous dispersion of many
discrete, unleachable, microscopic drug reservoirs in a
biocompatible polymer, such as silicone elastomers .

•This thermodynamically unstable dispersion is

quickly stabilized by immediately crosslinking the
polymer chains in situ to form medicated polymer disc
of constant surface area & fixed thickness.

•Medicated disc is then mounted at the centre of an

adhesive pad.

•Depending upon the physicochemical properties of

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.
Microreservoir Partition- Dissolution Controlled
Systems
Microreservoir Partition- Dissolution Controlled
The rate of drug release (dQ/dt) is given by the equation
Systems where m = a/b
•a = ratio of drug conc. in the bulk of elution solution to
drug solubility in the same medium.

•b = ratio of drug conc. at the outer edge of the polymer

coating membrane to drug solubility in the same polymer)

•n = ratio of drug conc. at the inner edge of the interfacial

barrier to drug solubility in the polymer matrix.

• Kl, Km & Kp = partition coefficients for the interfacial

partitioning of drug from the liquid compartment to the
•Release of drug from the polymer matrix, from the polymer matrix to the polymer
microreservoir-type rate-controlled coating membrane, and from the polymer coating
DDSs can follow either a dissolution or a membrane to the elution solution, respectively.
matrix diffusion-controlled process,
depending upon the relative magnitude • Dl, Dp & Dd = diffusivities of the drug in the liquid layer
of Sl and Sp. surrounding the drug particles, in the polymer coating
•e.g. Nitrodisc, Transdermal membrane enveloping the polymer matrix and in the
Contraceptive device hydrodynamic diffusion layer surrounding the polymer
coating membrane (elution layer) with thicknesses of hl,
hp and hd, respectively .

•Sl & Sp are the solubilities of the drug in the liquid

compartment and in the polymer matrix, respectively.
Polymer (Membrane / Matrix) hybrid Systems
Polymer (Membrane / Matrix) hybrid Systems
% Moisture uptake = Final weight – Initial weight x 100
Initial weight
•1. Human tissue ex vivo:
It may be difficult to obtain sufficient quantities of normal, healthy human tissue to
perform permeability experiments with large enough sample sizes for statistical analysis.
Many laboratories use human cadaver skin obtained from accredited human tissue banks.
There might be ethical and legal considerations in obtaining human tissue biopsies and
surgical specimens.

•2. Small animals:

Models such as rats, mice, and rabbits have traditionally been used in research for human
tissue permeability as they are usually inexpensive to purchase and maintain. Drawbacks are
the tissue areas are usually thinner than human skin and have a different morphology
resulting in higher compound permeabilities.

•3. Large animals:

Monkeys, dogs, pigs, and other large animals have also been used extensively but may be
expensive to purchase, especially in the cases of monkeys and dogs. Pig and monkey soft
tissue is very similar to human soft tissue in terms of morphology and function, therefore is
widely used as a surrogate for human skin.

•4.Polymeric membranes:
These kinds of membranes are usually used for in vitro release testing (IVRT). According to
the FDA SUPAC-SS (May 1997), any “appropriate inert and commercially available synthetic
membranes such as polysulfone, cellulose acetate/nitrate mixed ester,” ... “of appropriate size
to fit the diffusion cell diameter” . can be used. Usually hydrophilic polymeric membranes
with a pore size of 0.45 μm are used.