Biopharmaceutics

1. Diffusional and interfacial
Resistance
Ph.D. students: OMAR SAEB SALIH
Supervisor
Assist.Prof.Dr.Entidhar J. Al-Akkam
2021
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2. Diffusional Resistance
The resistance, R, to diffusion in each layer is equal to the reciprocal of the
permeability coefficient, P, of that
particular layer. R = 1/ P
Permeability, P, was defined earlier as the diffusion coefficient, D,
multiplied by the partition coefficient, K,
and divided by the membrane thickness, h.
P = D K / h
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3. The total resistance, Rt, is the reciprocal of the total
permeability, Pt, and is additive for a series of layers. It is
written in general as
Rt = R1 + R2 + ……Rn
R = 1/P = h / DK
Rt = h1/D1K1 + h2/D2 K2 +…….hn/Dn Kn
The total permeability for the two layers of the skin is obtained by taking the reciprocal of Rt equation;-
Pt = (D1K1D2 K2)/( h1D2K2+h2 D1 K1 )
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4. The fluid mosaic model, allows the protein – lipid complexes to form either hydrophilic or
hydrophobic ‘gates’ to allow transport of materials with different characteristics.
Biological membranes are more complex and more dynamic than synthetic membranes and
there are many confounding factors.
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5. Poor diffusion is more likely when the drug molecule:
● Has more than five hydrogen-bond donors (OH groups or NH groups)
● Has a molecular weight more than 500Da
● Has a log P more than 5
● Has more than 10 H-bond acceptors
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6. P-glycoproteins (Pgp):
One of the most barrier for diffusion of drug, is the existence of efflux mechanisms centered
on P-glycoproteins (Pgp).Drugs are ejected from cells by the efflux pump, so that these
drugs have a lower apparent absorption than predicted on physicochemical grounds. Like in
blood brain barrier and in cancer cells.
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7. Unstirred water layers:
A layer of relatively unstirred water lies adjacent to all biological membranes. The boundary between
the bulk water and this unstirred layer is indistinct but, it has a real thickness. During absorption,
drug molecules must diffuse across this layer and then on through the lipid layer. The overall rate of
transfer is the result of the resistance in both water layer and lipid layer. The flux J, for a substance
across the unstirred layer is given by the expression
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8. where C1 and C2 are the concentrations of the substance in the bulk water phase and in the
unstirred water layer respectively, D is the diffusion coefficient and δ is the effective
thickness of the unstirred layer.
The flux of molecules which pass by passive diffusion through the lipid membrane can be
written as
where Pc is the permeability coefficient. The rate of absorption must equal the rate of
transport across the unstirred layer so,
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9. The rate of movement across the unstirred layer, as can be seen from the equations the rate
of absorption is proportional to Pc . Compounds with a large permeability coefficient may
be able to penetrate across cell membranes much faster than they can be transported through
the unstirred layer. Under these circumstances diffusion through the water layer becomes
the rate-limiting step in the absorption process. Neglect of the unstirred layer causes errors
in the interpretation of experimental flux data.
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10. The total drug permeation resistance is the sum of resistance within the unstirred
water layer (RAq) and the lipophilic membrane (RM), and their relative importance
depends on the physicochemical properties of both the drug and the membrane.
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11. Since the permeability constants are the reciprocals of the resistance the following
equations are obtained:
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12. If the value of the permeability constant through the lipophilic membrane (PM) is much greater than the value of
the permeability constant through the diffusion layer (PAq) then:
and the unstirred water layer becomes the main barrier, i.e. the permeation is
diffusion controlled. On the other hand, if PAq is much greater than PM then:
and the permeation will be membrane controlled.
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13. The diffusion constant within the unstirred water layer (DAq) will decrease with
increasing viscosity of the layer as well as with increasing molecular weight of the
drug. For example, small lipophilic drug molecules frequently possess a large
permeability coefficient (i.e. large PM value) and, thus, under such conditions
diffusion through the water layer becomes the rate-limiting step in the absorption
process.
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14. When the membrane resistance to diffusion is much greater than the
resistances of the aqueous diffusion layers, that is, Rm is greater than Ra by
a factor of at least 10, Pm is much less than Pa, the rate-determining step
(slowest step) is diffusion across the membrane.
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15. In case of topical skin diffusion, the hydration of the stratum corneum is one
determinant of the extent of absorption: increased hydration decreases the resistance
of the layer, presumably by causing a swelling of the compact structures in the
stratum corneum layer.
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16. Occlusive dressings increase the hydration of the stratum corneum by
preventing water loss by perspiration; certain ointment bases are
designed to be self-occluding. The diffusion coefficient and the skin
barrier thickness can be replaced by a resistance, Rs, to diffusion in the
skin.
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17. drug release from homogeneous solid or semisolid vehicles using a quadratic expression
Q is the amount of drug released per unit area of the dosage form, D is an effective diffusivity of the drug in the
vehicle, A is the total concentration of drug, Cs is the solubility of drug in the vehicle, Cv is the concentration of
drug at the vehicle–barrier interface, and R is the diffusional resistance afforded by the barrier between the donor
vehicle and the receptor phase. A∗ is an effective A and is used when A is only about three or four times greater
than Cs.
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18. when,
Under these conditions, resistance to diffusion, R, is no longer significant at the interface between vehicle and
receptor phase. When Cs is not negligible in relation to A, the vehicle-controlled model of Higuchi becomes:
The diffusional resistance, R, is determined from steady-state permeation, and Cv is then obtained from the
expression
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19. Conventional penetration enhancers, such as fatty acids, fatty amines and fatty alcohols, enhance drug delivery
through biological membranes by permeating into the membrane and disrupting its barrier without affecting the
unstirred aqueous layer.
They decrease the diffusional resistance R of the membrane so enhance the permeation of the drug through the
stratum corneum.
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20. Interfacial Resistance
Most practical mass transfer operations involve the transport of molecules between phases (liquid-solid, liquid-
liquid, or liquid-gas). Usually the fluids are in convective flow, and the following assumptions are made. A
laminar film exists at the boundary of each liquid phase. In this laminar film the transport is entirely the result of
molecular diffusion. This transport in this film is slow compared with turbulent transport in the main body.
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21. The role of the interface between two phases on mass transfer is a problem of both basic and practical
importance. Many efforts have been made to clarify the role of the interface or interfacial resistance, using
either dynamic methods such as the laminar jet or static methods with no bulk motion. However, as the
rate process associated with interface may be comparatively rapid, there exists no generally accepted
explanation about the role of the interface.
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22. Interfacial resistance should be affected by the chemical properties of both the solute and the solvent.
Hydrogen bond might be closely related to the interfacial energy barrier for solute transfer.
The dynamic interfacial tension during mass transfer is considered to be determined by the excess
quantities of solute interface. Therefore, we can estimate whether the process between the aqueous phase
and the interface or that between the organic phase and the interface is the rate-determining step, by
observing the change of interfacial tension.
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23. The interfacial resistance increased remarkably with the number of CH2-groups by reaching equilibrium and decrease in the
desorption. It may be important that the resistance is closely connected with the properties of the transferring molecule.
• where γ SL is the interfacial tension between the liquid medium and the solid particles
• A is the surface area exposed
• ∆G is the free energy which negative sign means spontaneous process
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24. the effects of surfactants and bile salts on the gastrointestinal absorption is by their effect on the interfacial
resistance either decrease the interfacial tension and improve absorption or in some time like in case of
polyoxyethylene lauryl ether reduced the absorption of antibiotic in the stomach and increased it in the small
intestine. Some of these effects may result from alteration of the membrane by the surfactant.
Quaternary ammonium compounds are examples of surface-active agents that in themselves possess
antibacterial activity. The agents are adsorbed on the cell surface and supposedly bring about destruction by
increasing the permeability or “leakiness” of the lipid cell membrane.
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25. When the concentration of surface-active agent present exceeds that required to form micelles, however, the rate
of penetration of the anthelmintic decreases nearly to zero. This is because the drug is now partitioned between
the micelles and the aqueous phase, resulting in a reduction in the effective concentration.
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26. • Rferences
1-Martin physical pharmacy 6th edition chapter 11,chapter 13
2-Loftsson T, Konradsdottir F, Masson M. Influence of aqueous diffusion
layer on passive drug diffusion from aqueous cyclodextrin solutions
through biological membranes. Die Pharmazie-An International Journal
of Pharmaceutical Sciences. 2006 Feb 1;61(2):83-9.
3-Blank M. Monolayer and interfacial permeation. The Journal of
general physiology. 1968 Jul 1;52(1):191-208.
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27. THANKS
For listening!
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