1.3.1 Introduction
A number of mathematical models have been used to describe percutaneous absorption kinetics. In general, most of these models use either diffusion-based or compartmental equations which suffer from being too complex to be practically useful (98) however sound knowledge of the underlying mathematical principles of membrane transport is essential if we are to expand our understanding of how membrane barriers fulfil their function and how we can alter their properties to our advantage. Much of the early mathematics relating to transmembrane diffusion had its origin in the theoretical description of heat transfer and conductance. Indeed, the most basic of the diffusion equations, Fick’s first law, has its roots here (99).
1.3.2 Fickian model 1.3.2.1 Fick’s first law of diffusion
In transport, the flow (or flux, Ji in mol cm-2 s-1) is related to the velocity of molecular movement (υ in cm s-1) and the concentration (Ci in mol cm-3) of the molecules in motion in equation 1.1.
υ
i
i C
J = (1.1)
A fundamental principle of irreversible thermodynamics is that the flow, at any point in the system, at any instant, is proportional to the appropriate potential gradient. It can be expressed mathematically for a species i as shown in equation 1.2 where ∂μi ∂xi is the gradient and Li is the proportionality constant.
⎟⎠
⎜ ⎞
⎝
⎛
∂
− ∂
= L x Ji i μi
(1.2)
⎟⎠
⎜ ⎞
⎝
⎛
∂
− ∂
= x
D C
Ji i i (1.3)
1.3.2.2 Fick’s second law of diffusion
Fick’s second law relates the rate of change in concentration with time at a given point in a system to the rate of change in concentration gradient at that point. It is expressed in
equation 1.4 where x is the diffusion distance in the direction of the concentration gradient.
²
² x D C t C
∂
= ∂
∂
∂ (1.4)
Fick’s laws are more applicable if certain parameters or boundaries are specified. In this laboratory, the mathematical boundary conditions imposed are those of a well-designed diffusion experiment when the permeant is at a high, fixed activity on one side of an inert homogenous membrane through which it diffuses into a sink on the other side and before the start of the experiment the membrane is entirely devoid of permeant (99).
This implies that the diffusive flow begins at the high-concentration side (the donor side) of the membrane where C=C0 and x=h at all time intervals, t. There is no diffusant material within the membrane before ingress of the permeant being modelled, implying that at t=0 we have C =0for all values of x. Diffusion occurs in the direction of decreasing x toward the opposite side of the membrane where x=0 and C =0 (sink receptor phase) for all time intervals, t. The cumulative mass Q, of permeant that passes through a unit area of a membrane in a time t is shown in equation 1.5 where C0 is the concentration of diffusant in the membrane lamina juxtaposed to the donor vehicle, and h is the thickness of the membrane (99).
( )
⎥⎦
⎢ ⎤
⎣
⎡ ⎟
⎠
⎜ ⎞
⎝
− ⎛ −
−
−
=
∑
∞= ²
² exp ²
² 1
² 2 6 1
² 1 h
t Dn n
h h Dt C Q
n
n
o π
π (1.5)
Ast→∞, the exponential term tends to zero and Fick’s second law has been expanded to become equation 1.6.
⎥⎦⎤
⎢⎣⎡ −
= D
t h h Q DCo
6
² (1.6)
This equation is applicable to typical cumulative mass versus time diffusion plots that have an initial non-linear lag time followed by a linear steady state plot (100). From equation 1.6, we can solve for t and this yields the lag time (tlag) as described by equation 1.7 which relates inversely to the diffusion co-efficient and directly to the diffusional pathlength.
D tlag h
6
= ² (1.7)
When equation 1.6 is differentiated relative to time we obtain equation 1.8, possibly the most well-known form of Fick’s law of diffusion that describes the flux J, at steady state.
h J DC dt
dQ o
=
= (1.8)
It is often impractical to use the forms of equations 1.6 and 1.8 as shown because they include a term Co (the concentration of permeant in the outer layer of the membrane), that is extremely difficult to measure. The value Co is replaced with a term that links it to the concentration in the vehicle Cv through the partition co-efficient K, which rearranges to give equation 1.9.
h J DKC dt
dQ v
=
= (1.9)
The product of the partition co-efficient and the donor vehicle concentration will yield the diffusant concentration in the membrane lamina. Therefore the main variables influencing the rate of diffusion are D, K, Cvand h (100). Frequently, particularly in biological membranes, there is a practical difficulty in measuring the diffusional pathlength and that the information concerning the individual effects of changes in K and D is often not required, a
PCv
J = (1.10)
Equation 1.10 is perhaps the most basic and frequently used expression in the routine assessment of membrane permeability. However the principles upon which this equation is based stipulate that the donor concentration is constant and that the diffusion has reached steady state (99).
1.3.3 Higuchi model
Higuchi (101) describes drug release as a diffusion process based on Fick’s law, square root time dependant. This relation can be used to describe the drug dissolution from several types of modified release pharmaceutical dosage forms, as in the case of some transdermal systems and matrix tablets with water soluble drugs (102). For drug release from an ointment in which the drug is initially uniformly dissolved is governed by equation 1.11 and 1.12 where
Q is the amount of drug released per unit area of application, h is the thickness of layer, Co
is the initial concentration of the drug in the ointment, D is the diffusion co-efficient of drug in the ointment, t is the time after application and Ris the percent of drug released (101, 104).
2 1
2 ⎟
⎠
⎜ ⎞
⎝
= ⎛
π C Dt
Q o (1.11)
2 1
200 2 ⎟
⎠
⎜ ⎞
⎝
= ⎛
h R Dt
π (1.12)
If the rate of drug release obeys this law, the amount of drug released is a linear function of t½, and D can be calculated from the slope. The assumptions in this treatment are that the drug is the only component diffusing out of the vehicle, that sink conditions are maintained in the receptor phase and that D is constant with respect to time and position in the vehicle (101, 103). Permeation of this nature has a characteristic curved profile, exhibiting relatively high flux at early contact times which decreases as the diffusant front regresses into the bulk vehicle, away from the membrane. The path is progressively more tortuous and it takes
longer for drug molecules to diffuse from the region of high concentration in the vehicle to replenish the drug molecules at the membrane interface that have partitioned into the membrane, therefore the flux rate decreases with time (100).
Equations 1.1 - 1.12 describe drug diffusion through a homogenous membrane with a constant activity difference and a constant diffusion co-efficient and these mathematical functions have been employed in the analysis of data in this laboratory.
It is evident that from sections 1.2 - 1.3 that the transport of drugs though the skin depends on a number of factors such as the characteristics of the permeant, condition and type of skin, other chemicals present in the topical formulation (e.g., enhancers) and external conditions (e.g., temperature). The factor with perhaps the greatest influence is the physicochemical character of the permeant. According to Fick’s first law (section 2.3.2.1), the permeation of a drug through the SC depends on the permeability co-efficient and the concentration gradient of the permeant across the SC. The permeability co-efficient is the product of the partition and the diffusion co-efficient, divided by the length of the pathway through the SC. These factors, in turn, depend on variables such as molecular weight, size and structure and degree of ionization of the permeant (95).