The document discusses various mechanisms of drug release and diffusion processes. It describes: 1) Different types of drug release including immediate, modified, delayed, extended, and controlled release. Diffusion, dissolution, disintegration, and degradation play roles in drug release. 2) The process of diffusion, including Fick's laws of diffusion. Diffusion describes the spread of particles down a concentration gradient. 3) Factors that influence diffusion and drug release from formulations, such as physicochemical drug properties, formulation components, and release mechanisms like diffusion, degradation, and swelling. 4) Equations that describe processes like diffusion (Fick's laws), dissolution (Noyes-Whitney), and drug release

1. Ana Marie L. Rubenicia, RPh

2. Diffusion
 Diffusion
describes the
spread of particles
through random
motion from
regions of higher
concentration to
regions of lower
concentration

3. Diffusion
 Mass transport phenomena includes:
1. Release and dissolution of drugs from
tablets, powders and granules.
2. Lyophilization, ultrafiltration, and other
mechanical processes
3. Release from ointments and suppository
bases
4. Passage of water vapor, gases, drugs and
dosage form additives through
coatings, packaging,films, plastic container
walls, seals and caps
5. Permeation and distribution of drug
molecules in living tissues.

4. Diffusion
Ways that a solute or a solvent can traverse a
physical or biologic membrane
 Simple molecular diffusion or permeation (fig.
11-1a)- homogenous membrane w/o pores
 Diffusion through a solvent-filled pores (fig.
11-1b)- membrane with straight through pores
 Movement through and/or between the fibrous
membrane strands (fig. 11-1c)- cellulose
membrane(filtration process);with interwining nature of
the fibers and the tortuous channels.

5. Passive Diffusion
 Diffusion is the net
movement of material
from an area of high
concentration to an area
with lower
concentration. The
difference of concentration
between the two areas is
often termed as the
concentration gradient,
and diffusion will continue
until this gradient has
been eliminated.

6. Passive Diffusion
 Facilitated
diffusion
also called carrier-
mediated diffusion, is
the movement of
molecules across the cell
membrane via special
transport proteins that
are embedded within the
cellular membrane. Not
energy-dependent.

7. Passive Diffusion
 Filtration
is movement of water and
solute molecules across
the cell membrane
.Influenced by hydraulic
pressure.
Depending on the size of
the membrane
pores, only solutes of a
certain size may pass
through it.

8. Passive Diffusion
 Osmosis
the diffusion of water
molecules across a
selectively permeable
membrane. The net
movement of water
molecules through a
partially permeable
membrane from a solution
of high water potential to
an area of low water
potential.

9. Drug Absorption and Elimination
LIPID BILAYER

10. Drug Absorption and Elimination
 Transcellular
permeation
pathway for chemicals to
be absorbed into and
through the skin is
transcellular, or cell-to-
cell. Diffusion
occuring through the
lipoidal bilayer of
cells.

11. Drug Absorption and Elimination
 Paracellular
Diffusion
occurs through spaces
between adjacent cells.

12. Drug Absorption and Elimination

13. Drug Absorption and Elimination

14. Drug Release
STEPS IN DRUG
RELEASE
INCLUDES
DIFFUSION,
DISSINTEGRATION,
DEAGGREGATION
AND
DISSOLUTION.

15. Drug Release

16. Drug Release
OSMOTIC DRUG RELEASE SYSTEM

17. Diffusion
 Ultrafiltration is used
to separate colloidal
particles and
macromolecules by
the use of a
membrane.
Hydraulic pressure is
used to force the
solvent through the
membrane.
Used to purify albumin
and enzymes.

18. Diffusion
 Microfiltration –
employs
membranes of
slightly larger pore
size, 100 nm to
several
um, removes
bacteria from IV
injections, foods
and drinking water.

19. Diffusion
 Dialysis is the separation
process based on unequal
rates of passage of solutes
and solvent through
microporous membranes.
 Hemodialysis is used to
rid of the blood of
metabolic waste
products(small molecules)
while preserving the high-
molecular weight
components of the blood.

20. Fick’s Law of Diffusion

21. Fick’s Law of Diffusion
 Diffusion is described
by Fick’s laws. Fick’s
first law relates the
diffusion flux, J , to the
steepness of the
concentration gradient
 where D is the
diffusion coefficient, C
is the
concentration, and x is
distance.
 the units of J are
moles cm−2 s−1

22. Fick’s Laws of Diffusion

23. Fick’s Law of Diffusion
 Fick’s Second Law
Change in the conc
with time at a
definite loction.
 where
∆C/∆t, concentration
of diffusant in the
volume element
changes with time
and ∆J/∆x, the flux or
amount diffusing
changes with
distance

24. Fick’s Law of Diffusion
 Fick’s second law
states that the
change in
comcentration with
time in a particular
region is
proportional to the
change in the
concentration
gradient at that
point in the system.

25. Biological Diffusion
 GI absorption of
drugs- major pathway
for drugs absorption
the body.
Governed by state of
ionization of the
drug, its solubility and
concentration in the
intestines, and its
membrane
permeability.

26. Biological Diffusion
 Percutaneous
absorption
Involves:
a. Dissolution of the drug in its
vehicle.
b. Diffusion of the solubilized
drug from the vehicle to the
surface of the skin.
c. Penetration of the drug
through the layers of the
skin, principally the stratum
corneum (most impermeable
biological membrane). Stratum Corneum

27. Biological Diffusion
Percutaneous absorption
Factors Influencing the Penetration of a Drug Into the Skin:
a. Concentration of dissolved drug.
b. Partition coefficient
c. Diffusion coefficient
Rate limiting step: either release from vehicle or passage
through the skin.
Guidelines for effective topical dosage forms:
a. All the drug should be in a solution in the vehicle.
b. The solvent mixtures must maintain a favorable partition
coefficient so that the drug is soluble in the vehicle and yet
have the great affinity for the skin barrier into which it
penetrates
c. Components of the vehicle should influence the
permeability of the stratum corneum.

28. Biological Diffusion
 Buccal Absorption –
buccal membrane does not
have significant aqueous
pore pathways.
Utilizing an aqueous-in a
lipid phase model, the
weak acid specie are
transported across the aq
diffusion layer and only
the nonionized species
pass across the lipid
membrane. ORAL MUCOSAE

29. Pressure in Pharmaceutical
Systems
 Jet injectors
A jet injector is a type of
syringe that uses
pressure instead of a
needle to penetrate the
epidermis. Pressure
driven jets that produce
a high velocity
jet(>100m/sec) that
pebetrates the skin.
INSULIN JET INJECTOR

30. Temperature in Pharmaceutical
Systems
Lyophilization
 The process of freeze
drying can achieve
product stability, and
improved shelf-life
Frozen aqueous solution
containing the drug and
an inner matrix building
substance.

31. Electrical potential in
Pharmaceutical Systems
 Fentanyl iontophoretic
transdermal system
 Used to enhance
transdermal delivery of
drugs by applying a small
current through a
reservoir that contains
ionozed drugs.

32. Electrical potential in
Pharmaceutical Systems
 electrophoresis
apparatus – involves
the movemen of
charged particles
through a liquid under
the influence of an
applied potential
difference. Used as an
analytical tool in
pharmaceutical
science.

33. Temperature potential in
Pharmaceutical Systems
 Microwave-assisted
extraction - elevated
temperature
accelerates the mass
transfer of target
compounds from the
matrix.

34. Ana Marie L. Rubenicia, RPh

35. Drug Release
The process by which a
drug leaves a drug
product and is subjected
to
absorption, distribution
, metabolism, and
excretion (ADME)
Described in several ways;
 Immediate-release
 Modified-release
 Delayed-release
 Extended-release
 Controlled-release
 Pulsatile release

36. Dissolution
DISSOLUTION
 Is the process by which a solid solute with relatively low solubility
enters into solution in the presence of a solvent.
 Importance of dissolution
 A predictor of the in vivo behavior of a drug formulation
 Important tool to evaluate batch-to-batch uniformity of formulation
DISSOLUTION
 It is the rate-limiting step in the bioabsorption of drugs possessing
low solubility.
 Slowest of the various stages involved in the release of drug from its
dosage form and passage into systemic circulation
DISSOLUTION RATE
 The rate at which solid (tablet, capsule, and granule) dissolves in a
solvent is described by the NOYES AND WHITNEY EQUATION
 ―The HIXSON-CROWELL CUBE ROOT LAW‖ describes the dissolution
rate of drug powder consisting of uniformly sized particles.

37. Dissolution
The dissolution rate is the time required for a drug substance to
dissolve in the fluids at the absorption site. It is often the rate-
limiting step in the absorption process .
 Dissolution is important for the bioavailability of solid dosage
forms including oral capsules, tablets and suspensions and
intramuscular suspensions.
Methods for increasing dissolution rates:
 Decrease particle size. This increases the available surface area
to the dissolving fluid. [Note: In rare cases, agglomeration of the
particles may occur leading to decreased dissolution rates.]
 Increase solubility in the diffusion layer. The ionized form of the
drug (salt of the weak acid or salt of the weak base) will have
greater solubility in the diffusion layer than the unionized weak
acid or weak base. (e.g. penicillin V potassium will dissolve
faster than penicillin V itself).
 Alter pH of dissolution medium (e.g. buffered aspirin).
 Increase agitation of dissolution medium (e.g. effervescent,
buffered aspirin)

38. Dissolution

39. Dissolution
Noyes-Whitney Equation
 where,δC/δt = dissolution
rate
- D = Diffusion coefficient
- S = Surface area of the
dissolving particle
- h = Thickness of the
diffusion layer
- V = Volume of the
dissolution medium
- Cs = Saturation Solubility
of the drug in the medium
- Ct = Conc. of drug in the
medium at time, t

40. Dissolution
Noyes-Whitney Equation
 Problem 1. Calculate the rate of dissolution
(dM/dt) of relatively hydrophobic drug particles
with a surface area of 2.5 x 103 cm2 and a saturated
solubility of 0.35mg/mL at 25°C in water. The
diffusion coefficient is 1.75 x 10-7 cm2/s, and the
thickness of the diffusion layer is 1.25 m. The
concentration of drug in bulk solution is 2.1 x 10-4
mg/mL

41. Dissolution
FACTORS AFFECTING DRUG DISSOLUTION
1. PHYSICOCHEMICAL PROPERTIES OF THE
ACTIVE INGREDIENT
 Ionized VS Unionized Forms – dissolution rate
increases with ionization, absorption of drug is
more efficient when the drug is in the unionized
state
 Particle size
 Crystalline state
 Drug complexes

42. Dissolution
2. FORMULATION FACTORS
a. Solid dosage forms
 For tablets, dissolution depends on disintegration and deaggregation,
which are affected by tablet excipients and compression force.
 Effect of excipients to dissolution rate
 Binders – increase rate of dissolution of hydrophobic drug particles
probably through an enhanced wetting on the surface
 Diluents – increase dissolution rate
 Lubricants – decrease dissolution rate
b. Suspensions and emulsions
 Dissolution of suspensions are affected by settling, aggregation and
change in the crystalline structure upon aging
 Viscosity affects the dissolution rate of suspensions and emulsions
c. Semisolid dosage forms
 Dissolution depends on the base used

43. Drug Release
Physico-Chemical Factors In Designing a
Controlled or Sustained-Release
Formulation
a. Drug concentration
b. Aqueous solubility
c. Molecular size
d. Crystal form
e. Protein binding
f. pKa

44. Drug Release
CONTROLLED-RELEASE MECHANISMS
There are three primary mechanisms by which active
agents can be released from a delivery system:
 diffusion,
 degradation, and
 swelling followed by diffusion.
Any or all of these mechanisms may occur in a given
release system. Diffusion occurs when a drug or other
active agent passes through the polymer that forms the
controlled-release device.

45. Drug Release
 A polymer and active agent
have been mixed to form a
homogeneous system, also
referred to as a matrix
system.
 Diffusion occurs when the
drug passes from the
polymer matrix into the
external environment. As
the release continues, its
rate normally decreases
with this type of
system, since the active
agent has a progressively
longer distance to travel and
therefore requires a longer Drug delivery from a typical
diffusion time to release. matrix drug delivery system.

46. Drug Release
 Solid drug, dilute
solution, or highly
concentrated drug solution
within a polymer matrix—is
surrounded by a film or
membrane of a rate-
controlling material. The
only structure effectively
limiting the release of the
drug is the polymer layer
surrounding the reservoir.
Since this polymer coating
is essentially uniform and
of a nonchanging
thickness, the diffusion Drug delivery from typical
rate of the active agent reservoir devices: (a)
can be kept fairly stable implantable or oral
throughout the lifetime of systems, and (b) transdermal
the delivery system. systems.

47. Drug Release
 Higuchi (Equation) Model
Calculate Q, the amount in milligrams, of micronized
benzocaine released per cm sq of surface area from an
aqueous gel after 9000 sec (2.5 hr) in a diffusion cell.
Assume that the total concentration,A, is 10.9
mg/mL;the solublity, Cs, is 1.31 ng/mL; Cv = 1.05
mg/mL; the diffusional resistance, R, of a silicone
rubber barrier separating the gel from the donor
compartment is 8.10 x 103 sec/cm; and the diffusivity ,
D, of the drug in the gel is 9.14 x 10-6 cm2 / sec.

48. Polymer-based drug
release mechanisms.
Scheme showing
several mechanisms for
temporally controlled
polymer-based drug
release systems.
(a) Delayed dissolution
mediated by a polymer
which dissolves or
degrades slowly,
(b) Diffusion-controlled
release through voids in
polymeric devices, and
(c) Controlled flow of the
drug solution utilising
an osmotic potential
gradient across a semi-
permeable membrane