Vol. 2 - 198o Pharmaceutisch Weekblad Scientific Edition I49

S H O R T C O M M U N I C A T I O N S

Diffusion of drugs through multibarrier

M . F R I E D M A N 1 ' 2 A N D M . D O N B R O W 1

ABSTRACT

Diffusional mass transfer acros s a ser ia l 2 or 3 unit lami- nate barrier of ethyl cellulose and polyethylene glycol membranes was studied using caffeine and salicylic acid as mo~el drugs. The overall membrane diffusional resistance was found to be the sum of the intrinsic membrane resist- ances. When the resistance of one layer was much higher than that of the others, the permeability was then con- trolled by the single layer in the laminate. (Pharm. Weekblad Sci. Ed. 2, i49-i52)

Coating is one of the accepted methods of prolongation of the activity of a drug prep- aration (BALLARD and NELSON I965). The present study deals with the use of non-erod- ible polymers such as those used in film-coat- ing, for this purpose.

When the kinetics of release from a coated spherical product is controlled by the film and when in addition the film thickness is much less than the core radius, the system may be treated as planar and the factors which determine the release rate are: the membrane permeabili ty properties, the membrane thickness and the effective contact area between the coated prod- uct and the extraction fluid. Change in any one of these factors will lead to a corresponding alteration in the release rate of the active sub- stance.

Ref inement in control of the release rate might be obtained by application of a number of coats each having a different permeabili ty with respect to the drug.

Previous work from this laboratory demon- strated the value of ethyl cellulose (EC) as a coating and matrix material for manufactur ing control led release drug products (OOrOROW and FRIEDMAN I975a, b; FRIEDMAN and DON- BROW 1978 , 1979). It was also shown that ad- dition of hydrophilic polymers such as poly-

ethylene glycol (PEG) furnished a me thod o f

raising the permeability of ethyl cellulose films (DOrOROW and ~mOMAN 1974).

In the present study, control of drug. trans- port through EC films with or without added PE~ was investigated using a technique in which films of different structure were built up in a laminate barrier as resistors to flux. The per- meat ion model through such barriers was de- te rmined using caffeine and salicylic acid.

Ethyl cellulose, N-type (Hercules Incorporated, Delaware, USA) had an ethoxyl content of 47.5 to 49.0% and the viscosity of a 50 g per kg solution in toluene--ethanol 80 x 20 (w/w) was IO -x Pa.s. Polyethylene glycol 4000, caf- feine and salicylic acid were from Merck, Darmstadt , Germany, and all were of BP grade.

Details of the methods of preparation of the films and measurement of the penetrat ion rates of the drugs through the films were described previously (DON'BROW and FRIEDMAN I975a ). EC and EC-PEG films were formed by spreading the polymers on Teflon plates in chloroform sol- ution, the solvent being allowed to evaporate at room temperature. The films were arranged in series and mounted between the flanges of the membrane holder of a diffusion cell having compar tments of equal volume. The standard conditions used throughout this work were as follows: free membrane area exposed for dif- fusion, 12.56 cm2; drug solution and absorption solution volumes, 5o ml; drug concentrations in the permeat ion measurements , 4.2 x io -2 M in caffeine and 4.2 • IO - 3 M in salicylic acid. Single film thicknesses were measured using a micrometer and summated to obtain the thick- ness of multiple films. The thickness of each

1 Department of Pharmacy, School of Pharmacy, Hebrew University - Hadassah Medical School, Jerusalem, Israel 2 Reprints.

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TABLE I. Permeation rates as a function o f barrier compo- sition

Drug Exper - PEG in Film Rate of iment dry film thickness permeat ion 1

% w/w (cm) (mol/s) x lO 4 • io a

Salicylic 1 20 19.6 3.00 acid 40 21.3

2 20 i9.6 1.64 30 24. I 40 21.3

3 30 24. I 3.28 40 21.3

4 o 22.1 0.95 40 21.3

Caffeine I 20 I9.8 o.2i 30 20.4

2 io 22.4 o. 15 40 21.2

3 30 20.4 0.32 40 21.2

1See equat ion 4.

single film was measured in ten different places and had an accuracy of + o.5%. Solutions were stirred by means of a peristaltic pump and the drugs were determined spectrophotometrically in the sink solution as previously (DONBROW and FRIEDMAN 1974). The compositions and thicknesses of the films used in each of the lami- nates studies are summarised in Table I.

For a composite planar laminar barrier, the steady-state flux of solute, F, is given by the Fick's law relation (JOST 1960):

F = dQ/Adt = D (C2 - C 1 ) / h eq. I.

where Q is the number of moles of drug pen- etrating in time t (s) through a surface of area A (cm2), C2 and Ca are the drug concentrations (mol/cm 3) in the permeating and sink solutions respectively, h is the total thickness of the membranes (cm) and D is the overall diffusion coefficient within the barrier (cm2/s).

The EC and EC-PEG membranes are not necessarily inert structural materials but may have affinity for the drugs. In such cases, the concentrations at the surfaces of the mem- branes are not usually equal to the concen- trations in the external solutions but are related to them in accordance with the membrane-drug solution sorption isotherm. The isotherm has been shown to be linear for the materials and sys- tems studied here (DONBROW and FRIEDMAN I975a ) and the correlation between external and surface concentration is expressed by the solvent-membrane partition coefficient of the drug, Kin. Under the experimental conditions used C2 >> C1 hence by integration of eq. I:

ADKmC2t Q - h eq. 2

The permeability coefficient, P, is defined by:

p _ DKm h eq. 3

For a plot of concentration of drug transferred against time, the permeation rate is given by the slope dC/dt in accordance with:

dC APC2 dt - V eq. 4

where V is the volume of the sink solution; it follows that

p = (dC/dt) V A C2 eq. 5

Slopes were calculated by the least squares method from the results of the permeability experiments and, as the other parameters of the equation were known, the permeability coefficients through laminated membranes could be calculated.

From permeability data for individual iso- lated EC or EC-PEG films, their contributions to the permeability of the laminar barrier as a whole can be obtained. The separate dif- fusional resistances of the individual layers of the composite sheet are additive and related to the overall permeability constant Pt (ZWOLINSKI et al. I949; CRANK I957; SCHEUPLEIN I968) by the equation:

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TABLE I I . Fractional resistances

Drug Exper- PEO Diffusion Fractional iment %w/w coefficient resistance

(cm2/s) X I01~

Salicylic i 20 6.26 o.641 acid 40 I 1.62 0.358

20 6. 26 o. 404 3 ~ 8.66 0.359 40 11.62 0.236

3 3 ~ 8.66 0.603 40 11.62 0.397

4 o o. 19 0.985 40 11.62 o.oi 5

Caffeine i 20 3.45 0.633 30 6.I3 0.376

1o 1.95 0.78I 40 7-37 o.218

3 30 6.I3 0.536 40 7.37 0.463

Rt - I _ Ra + R2 + . . . + R , eq. 6 Pt

or

_ I hi h2 + h .

Rt Pt - D1K1 I- D2K2 "" "+ D,K-----~ eq. 7

where hi, h2, . . . hn are the layer thicknesses, D1, D2, . . . Dn the layer diffusivities of the drug, and K~, K2, . . .Kn the solvent- f i lm par- tition coefficients of each layer. With knowl- edge of the individual thicknesses, diffusivities

and parti t ion coefficients, the total per- meabil i ty of the composi te barrier may be pre- dicted using equat ion 7. The D values used (DONBROW and FRIEDMAN I975a ) are presented in Table u.

Wate r - f i lm parti t ion coefficients for caffeine and salicylic acid were respectively I. 9 and I42 (DONBROW and FRIEDMAN I975a). Since the vel- ocity of stirring did not affect the pe rmea t ion rate it could be assumed that the unstirred layer effects were insignificant. Hence Pt for the two-ply laminate will be given by:

D1D2K1K2 P t - h l D 2 K 2 + h2D1K1 eq. 8

For the exper imental condit ions used, K1 = K2 (DONBROW and FRIEDMAN I975a ), hence

D1D2K Pt = hiD2 + h2D1 eq. 9

Similarly, for three-ply laminate

D1D2D3K Pt =h l D2D3 + h2D1D3 + h3D1D2 eq. Io

Table In summarises the P values calculated for the exper imental systems using equat ions 9 and I0 and those de te rmined experimental ly .by permeat ion studies for the caffeine and salicylic acid systems. The theoretical and exper imental values are in excellent agreement.

The fractional resistance of each componen t of the laminate may be predicted from the total resistance of the films in the barrier.

f R 1 - R1 f R 2 _ R2 Rn eq. II R t ' R t ' f R n ' - Rt

TABLE In. Experimental and theoretical permeability coefficients of laminated fihns

Experiment Salicylic acid Caffeine

Ptheor. Pexp. Ptheor/Pexp. Ptheor. Pexp.

(cm/s) x Io s (cm/s) x Ios Ptheor./Pexp.

l 2.86 2.84 I.Ol o.2I o.19 2 1.69 1.56 I.O8 o.i 3 o. 14 3 3.08 3.12 0.99 0.3 t 0.3 i 4 0.084 0.09 0.93

I . I 0 0.93 1.00

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where fRx, fR2 and fR, are the fractional re- sistances of the first, second and nth layer.

From the fractional resistances calculated for the systems studied, presented in Table II, in which the thicknesses of the individual films constituting the laminate ranged from I9.6 to 24.1 • lO -4 cm, it may be seen that: - when the laminate barrier is composed of

films having diffusion coefficients of the same order, each of the fractional resistances is involved in transport rate-determination, i.e. all the component membranes are effec- tively influencing the transfer rate of solute through the laminate (see caffeine, exp. 3);

- if one of the films in the laminate has a very much lower diffusion constant than the others, the resistance of the laminate as a whole will be controlled by the films with the lowest diffusivity (see salicylic acid, exp. 4).

The present work shows that the rate of trans- fer of drugs through a laminated barrier film may be regulated by preparation of individual

layers of suitable permeabilities and thick- nesses. Pharmaceutically, this research ap- proach may be utilised for the development of multiple layered film-coated products, intended for sustained and/or controlled release of the active substance.

R E F E R E N C E S

BALLARD, S. E., and E. NELSON (I965) In: Remington's Pharmaceutical Sciences, I3th ed., 612-64o.

CRANK, J. (I957) The mathematics of diffusion. Oxford Univ. Press, 42-55.

OONBROW, M., and M. FRIEDMAN (1974)J. Pharm. Pharma- col. 26, I48-15o; Ibidem 0975a) 27, 633-646; Ibidem 0975 b) J. Pharm. Sci. 64, 76-80.

FRmDMAN, M., and M. I~ONBROW (I978) Drug Dev. Ind. Pharmacy 4, 319-333; Ibidem (x979)J. Pharm. Phar- macol. 3 z, 396-399-

JOST, W. (I960) Diffusion in solids, liquids, gases. Aca- demic Press, New York, 8-12.

SCnEUPLEIN, R. J. (1968) J. Theoret. Biol. z8, 72-89. ZWOLINSKI, B.Y., H. EYRING a n d c . E. REESE (I949)J .

Physiol. Colloid Chem. 53, I426-1453.

Received February x98o. Accepted for publication September 198o.

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