Hydrophobization of ionic drugs for transport through membranes

Journal of Controlled Release, 6 (1987) 3-13 Elsevier Science Publishers B.V.. Amsterdam -

HYDROPHOBIZATION MEMBRANES*

OF IONIC

3

Printed

in The Netherlands

DRUGS

FOR TRANSPORT

THROUGH

Seung Jin Lee and Sung Wan Kim** Department (U.S.A.)

of Pharmaceutics

and Center for Controlled

Chemical Delivery,

University

of Utah, Salt Lake City, UT 84 1 12

The delivery of ionic drugs through hydrophobic membranes has not been successful due to their weak partitioning and low diffusiuity. In order to achieve transport of ionic drugs across hydrophobic membranes, lipophilization of the ionic drugs without modification of their chemical structures would be ideal. Studies of ion paired drugpermeation in nonaqueous media through model synthetic membranes were performed with the aim of lipophilization of ionic drugs for transport across hydrophobic barriers. The permeation experiments were conducted using hydrophobic polymer membranes, dense hydrophobic and hydrophobic-hydrophilic balanced membranes. It was found that the ion paired drugs attained lipophilic characteristics and consequently, had enhanced permeation through hydrophobic membranes. Both partition and pore mechanisms contributed to ion pair permeation through membranes.

INTRODUCTION

In the mechanistic viewpoint of solute permeation through membranes, the general understanding is that hydrophobic solutes can diffuse through both hydrophobic and hydrophilic membranes, while permeation of hydrophilic solutes occurs only through hydrophilic membranes. Although the transport of hydrophilic or ionic drugs across hydrophobic membranes has not yet been successfully achieved, finding a viable delivery method is important for several reasons. Firstly, the majority of drugs utilized in clinical settings are weak acids or bases, and are ionized at physiological pH. Also, the solubility *Paper presented at the Third International Symposium on Recent Advances in Drug Delivery Systems, February 24-27,1987, Salt Lake City, UT, U.S.A. **To whom correspondence should be sent.

0168-3659/87/$03.50

0 1987 Elsevier Science Publishers

of many drugs is low in aqueous medium, therefore they are prepared in ionic salt forms. Important biological membranes, such as skin and gastrointestinal membranes, preferentially allow the permeation of hydrophobic drugs [ 11. Several approaches have been investigated with the aim of enhancing ionic or hydrophilic drug permeation through hydrophobic membranes, including iontophoresis, prodrug design and ion pair formation as shown in Fig. 1. Iontophoresis enhances permeation of electrically charged (ionic) drugs into surface tissues by the application of an electrical current [ 21. Iontophoretic techniques have been developed recently and received considerable interest, especially in the field of transdermal delivery systems. Ionic drug delivery through the skin membrane is hindered due to the highly hydrophobic nature of stratum corneum. The application of an external electrical potential

B.V.

4

PERMEABLE PERMEABLE

HPB

MEMBRANE

PERMEABLE

RECENTAPPROACHES TO ACHIEVE TRANSPORT 1 IONTOPHORESIS

IMPERMEABLE

2 LIPOPHILIC

PRODRUGS

3 AQUEOUS

ION PAIR

ALL SUBJECT

NONAQUEOUS LIPOPHILIZATION

Fig.

1. Schematic

ION PAIR FORMATION

TO LIMITATIONS

FOR

OF IONIC DRUGS

representation

of solute

permeation

through membranes.

has resulted in enhanced permeation of many drugs through the skin. Although iontophoresis does have some advantages for externally controlled delivery of charged drugs through hydrophobic barriers, it has several drawbacks. Long-term application is difficult, and administration is limited to locally applied drugs since high doses require high current, which produces heat leading to tissue damage. Another approach for increasing ionic/bydrophilic drug permeation through hydrophobic membranes is prodrug design. The model prodrug for this system should be a drug which by chemical modification can be made more lipophilic and thus have greater permeation through hydrophobic membranes. The utilization of the prodrug approach in transdermal delivery systems was suggested by Higuchi et al. [ 31. It was reported that the permeability of some steroids across stratum corneum was increased by formation of an acetonide with the dihydroxyl group in the steroids [ 41. In prodrug delivery systems, simultaneous diffusion and enzymatic bioconversion occurs, to that, to acceptably delineate the processes involved, complicated physical models are necessary [ 51. Careful control of the bioconversion rate is also important since biological action is exerted by the parent drug. Also, pos-

sible chemical modification of the parent drug structure is limited and physiological evaluation of derivatized drug can be a long process. In spite of the difficulties, the prodrug approach is considered to be attractive in certain cases for the enhancement of ionic/hydrophilic drug transport through hydrophobic membranes. The concept of ion pair formation in aqueous systems has been proposed so that the drug ions may form aqueous ion pairs in the presence of large organic counter ions [ 6,7]. Evidence that the ionic drugs had improved permeability through biological membranes via ion pair formation was also reported [ 8-101. Jonkman reviewed the ion pair absorption hypotheses in gastrointestinal absorption [ 111. Tomlinson and Davis [ 12-141 contributed significantly to the understanding of ion pairing behavior. They observed that a large organic cation and anion form a stoichiometric ion pair complex. This complex possesses a certain solubility product above which micelle formation or further aggregation occurs. The solubility product decreased with an increase in ionic alkyl chain length, which is a determining factor in their hydrophobicity and critical micelle concentration [ 121. The free energy of ion pair formation was composed of two independent contributions, electrostatic interaction between charged head groups and hydrophobic interactions. Thus, as the number of methylene groups in the ions increases, both ion pair formation and partitioning into the oil phase were enhanced [ 131. The entropy change was found to be a dominating force in the formation of ion pair complexes induced by the solvophobic effect of large ions [ 141. Although the mechanistic concept of aqueous ion pair formation was elucidated, its general application for the transport of ionic drugs through hydrophobic membranes was limited. Aqueous ion pair formation requires a sufficient degree of hydrophobicity of the interacting drugs with counter ions. This creates a major limitation in the selection of appropriate drugs since the majority of ionic drugs do not have the

5

required hydrophobic structure. The counter ion should also contain a large hydrophobic group, i.e., carboxylate or quaternary ammonium ions with long alkyl chains. Another drawback in the aqueous ion pairing systems is that the ion pairs exist only within a very low concentration range because of the limited solubility of the two ions. At higher concentrations, the bulky hydrophobic ions form micelles that reduce the activity drastically and hinder flux of drug ions [ 15,161. Toxicity of counter ions must also be considered since they are delivered together with the drug ions in the form of an ion pair complex. Thus, despite the great interest in the physical chemistry of aqueous ion pairs, their application in drug delivery systems is somewhat limited. Therefore, new methods of ionic/hydrophilic drug transport through hydrophobic membranes still remain to be found. Ionic drugs form ion pairs in low dielectric nonaqueous media primarily via electrostatic interactions. The concept of ion pair formation was first introduced by Bjerrum [ 171. The major contribution to the binding energy between ions arises from coulombic energy which is given by E=Z1Z,e2/~r

(1)

where Z,e and Z,e are the ionic charges, r denotes the distance separating ions and E is the dielectric constant. Thus, it can be seen that the dielectric constant of the medium is an important factor influencing ion pair formation, although noncoulombic contributions such as solvation, polarizability of ions and hydrogen bonding, may also be involved. According to Bjerrum’s theory, ion pair formation is dependent upon the critical distance, cl, within which ions are stabilized as ion pairs; d is expressed as d=Z1Z2 e*/2 ckT

(2)

where k is Boltzmann’s constant and T is absolute temperature. This equation also demonstrates the importance of the dielectric constant

in ion pair formation. The thermal energy and electrostatic energy are equal at the critical distance. Therefore, expressions for the two energies were equated to derive eqn. 2. It can be deduced that in nonaqueous systems, where the solvent dielectric constants are less than 40, strong interactions between the ions lead to ion pairs as the predominant species f 18,191. The investigation of ion pairing phenomena has been advanced in the field of physical chemistry. In a study of the ion pairing behavior of sodium chloride in water-dioxane mixtures, a gradual increase in the concentration of ion pairs was observed with increasing dioxane content and only ion pairs were present in pure dioxane [ 201. Lee et al. [ 211 investigated the ion pairing behavior of ionic drugs utilizing conductivity, NMR and electromotive force. They reported that organic drug ions form electrically neutral ion pairs in low dielectric nonaqueous media and the ion pair formation occurs specifically between the charged sites of a drug ion and its counter ion. One hypothesis is that the ion paired drugs formed in nonaqueous systems will attain electrical neutrality and consequently, lipophilic characteristics. Hence, the ionic drugs may be readily transported across hydrophobic membrane barriers via ion pair formation. One way of visualizing the hypothesis of ion pair transport is in terms of the difference in the height of the energy barrier encountered by ions and ion pairs for permeation through membranes. This suggested hypothesis is supported by considering the energy of charging for ions [ 221. A spherically charged molecule with radius, a, in an infinite medium of dielectric constant E has a self-electrostatic free energy, E=e2/2ea, the Born energy of charging 123,241. Due to the inverse dependence of energy on the dielectric constant, large energy differences between low and high dielectric media exist. This causes a great energy barrier for ion partitioning and flux into hydrophobic membranes. The electrostatic charge of ions will be neutralized by the formation of ion pairs. Due

6

Fig. 2. Schematic of ion paired drug permeation hydrophobic membranes.

through

to the lowering of the energy barrier between the permeation medium and the membrane, the transport of ionic drugs through hydrophobic membranes will be enhanced. On the basis of this hypothesis, ion pairing systems utilizing nontoxic nonaqueous media were designed to achieve hydrophobization (lipophilization) of ionic drugs for transport through hydrophobic membranes. A schematic description of this system is given in Fig. 2. The advantage of the proposed system is a wide scope of applicability for ionic drugs without modification of drug structures. Membranes used for the investigation of the diffusion mechanisms of ion paired drugs include: silicone rubber (dense hydrophobic), 2-hydroxyethyl methacrylate (HEMA) /styrene copolymers (pHEMA/styrene, hydrophilic-hydrophobic), Celgard@ (porous hydrophobic) and p-HEMA membranes.

EXPERIMENTAL Preparation of polymer meation experiments

membranes

for per-

Silicone rubber membrane: a d~methylsiloxane prepolymer base was obtained commercially (Silastic @,382 Medical Grade Elastomer,

Dow Corning). Stannous octoate, was used as a cross-linking agent. The viscous prepolymer was placed in a beaker and the cross linker (0.2 w/w% ) was added. The solution was completely mixed immediately to ensure homogeneous curing. The mixture was degassed under vacuum to remove the air entrapped during the mixing process. Then, it was carefully placed between two polystyrene plates held apart with a spacer and allowed to cure at room temperature for 24 hours. After polymerization, the membrane was washed in chloroform/acetone f 1: 1 v/v% ) to remove unreacted compounds. p-HEMA/styrene membranes: medical grade HEMA monomer was obtained as a gift (Hydron Laboratories) and used without furStyrene monomer was ther purification. obtained commercially (Aldrich) and purified by distillation under reduced pressure. The pHEMA/styrene membranes were synthesized by free radical polymerization. 2,2’-azobisisobutyronitrile (Polysciences) was used as an initiator at a concentration of 7.84 mmol/l monomer and 0.3 mol% of ethyleneglycoldimethacrylate was used as a crosslinker. Several different compositions of the two monomers were mixed in glass vials, followed by addition of the initiator and crosslinker. The mixtures were purged with nitrogen to remove residual oxygen for 20 minutes and injected into a polymerization mold consisting of two polyethylene plates separated by a spacer. The polymerization was conducted for 5 days at 60°C in an oven. p-HEMA was obtained in a similar manner. After polymerization, the molds were opened and soaked in distilled water for 1 day. The membranes were removed and placed into a water/methanol (1: 1 v/v) mixture for 7 days to remove unreacted monomer. Porous polypropylene membrane: this membrane was obtained as a gift (Celgard@ 2400, Celanese) . The micropores in the asymmetric hydrophobic pol~ropylene network were developed by applying a stretching stress, the average pore size was specified at 0.1 pm [ 251.

Diffusion

experiments

Two compartment glass diffusion cells were used for the measurement of permeation coefficients. The compartments had a volume of 130 ml each and were separated by the polymer membrane with an effective area of 14.6 cm’. Both chambers were stirred at 1550 rpm for the duration of the experiment using glass stirrers to minimize the boundary layer effect. The polymer membranes were pre-equilibrated with a given media for 2 days. The receiver chamber was filled with a given solvent and a 1 mg/ml drug solution in the same solvent was placed in the donor chamber. At given times, 1 ml samples were withdrawn from the receiver chamber and replenished with fresh solvent. The drug concentration in the receiver samples was assayed spectrophotometrically ( Perkin-Elmer Lambda 7 UV/VIS Spectrometer). All diffusion experiments were conducted at 23°C. Partition coefficients were measured using a solution depletion technique which determines the equilibrated drug concentration in given volumes of polymer with drug solutions of known concentration. From the data obtained in the diffusion experiments, permeation coefficients were calculated from the following equation which was derived by modifying Fick’s law.

where C, is the solute concentration in the receiver chamber at a certain time t, C,, is the initial solute concentration in the donor chamber, A is the permeable area of membrane, U is the permeation coefficient, V is the compartment volume, and I is the thickness of the membrane. A plot of - ( VZ/2A)ln (1- 2C,/Co) versus t yields a straight line with a slope equal to the permeation coefficient. Diffusion coefficients, D, were calculated by dividing the permeation coefficient by the partition coefficient.

0

2

6

6

4

TIME

10

12

(days)

Fig. 3. Permeation of sodium salicylate through silicone rubber membrane in dioxane, ethanol and water.

RESULTS

AND DISCUSSION

Permeation experiments through the dense hydrophobic silicone rubber membrane with model ionic drugs sodium salicylate and sodium warfarin, were conducted to investigate the diffusion of ion paired drugs in several nonaqueous media. Water was employed as a reference system in which the drugs will exist as ionic species. As shown in Fig. 3, no permeation of sodium salicylate occurred in water. In contrast, significant permeation was observed in nonaqueous media, such as ethanol and dioxane. Similar results were obtained using another model drug, sodium warfarin, i.e., no permeation in the aqueous medium and significant permeation in the nonaqueous media, isopropanol and ethanol (Fig. 4). The ion paired drugs were electrically neutral and without an electrostatic energy term. Thus, the activation energy for the neutral ion pairs to partition into the hydrophobic membrane is much lower than for the ions. Consequently, the permeation of ion pairs through the membrane is greater than the permeation of ions. Supporting evidence can be found from

0.8

-

ISOPROPANOL

-

ETHANOL

-

WATER

0.6

0.4

0.2

0.0 0

10

20

30

TIME

40

50

60

(hrs)

Fig. 4. Permeation of sodium warfarin through silicone rubber membrane in isopropanol, ethanol and water.

numerous reports of permeation studies of both charged and uncharged solutes through silicone rubber membrane which was permeated only by uncharged solutes [ 261. These facts suggest that the ion paired drugs in the nonaqueous media diffused primarily via a partition type mechanism. This phenomenon is illustrated in Fig. 5. Higher permeability was observed in isopropanoi and dioxane than in ethanol. Two factors may contribute to this difference. These are the dielectric constants of the media and the swelling of the membrane. The dielectric constants

00 diffused

impermeable Fig. 5. Schematic illustration of ion paired drug permeation through silicone rubber (dense hydrophobic ) membrane.

of dioxane (E= 2 ) and isopropanol (E= 18.3) are lower than that of ethanol (E= 24.3). The lower dielectric media contains a higher concentration of ion pairs, a diffusable species, which leads to higher flux. The other factor was membrane swelling. The swelling ratios were about 18% in both dioxane and isopropanol and 3% in ethanol. The ion paired drugs were associated with the solvent and the ion pair stabilization was primarily due to coulombic forces. Thus, solvent partitioning was accompanied by ion pair permeation. Permeation occurred through the membrane, with a 3% swelling ratio, in ethanol. In this low swelling range, permeation has rarely been observed for hydrophilic solutes through a dense hydrogel, such as p-HEMA with 5 mol% crosslinking [ 271. This p-HEMA membrane allowed only hydrophobic solute permeation and showed 10% swelling in water. It is considered that pores were not present in the silicone rubber membrane with low ethanol swelling (3% ) . Therefore, permeation of sodium salicylate was primarily as neutral ion pairs via a partition mechanism. In the case of dioxane or isopropanol, the solvent partitioning into the membrane was 18%. Thus, permeation via pores is probably also involved. To further substantiate the diffusion mechanism involved in ion paired drug permeation, hydrophilic-hy~ophobic balanced membranes, p-HEMA/styrene, were selected. Model drugs included sodium warfarin, an ionic drug and warfarin, a neutral analog. Permeation studies with the model drugs were conducted in a model ion pairing medium, propylene glycol, and water. A plot of sodium warfarin diffusivity versus the membrane styrene composition is given in Fig, 6. The permeation of sodium warfarin in propylene glycol was enhanced by increasing membrane hydrophobicity up to 30% styrene. At higher styrene compositions (50%)) a decrease in diffusivity was observed. For the analysis of this result, the permeation system in propylene glycol can be described as follows:

9

-

0

10 STYRENE

20

WATER

30

COMPOSITION

Fig. 7. Mechanistic illustration tion through p-HEMA/styrene glycol.

40

50

(w/w%)

Fig. 6. Permeation of sodium warfarin through pHEMA/styrene membranes in propylene glycol and water.

(1) The polymer membrane contains three major components for drug permeation, the hydrophobic styrene, the relatively hydrophilic HEMA, and the solvent. The solvent phase may be divided into two regions, one is polymer associated medium and the other is bulk medium with fluctuating pores. Thus, it was expected that both partition and pore channels exist for drug permeation. (2) The pore volume fraction is approximately the same for all membranes, i.e., the membranes showed nearly equivalent swelling (73.5&1.1%). (3 ) Both ion paired drugs and ions coexist at equilibrium and both the ion paired and ionized drugs in propylene glycol could permeate through the pore channels. It was considered that the lipophilic ion pairs could also diffuse via the hydrophobic partition channels. As the hydrophobicity of the membrane increased, the ion pair permeability increased whereas, ion permeation gradually decreased. When the membrane was highly hydrophobic ( >40% styrene ratio), the permeability of ions dropped significantly, and therefore, the total permea-

of sodium warfarin permeamembranes in propylene

tion decreased. This fact may indicate the presence of a partition mechanism for lipophilic ion paired drug diffusion. Interpretation of permeation results is schematically illustrated in Fig. 7. The permeation behavior of sodium warfarin in water was considerably different (also see Fig. 6). The ion permeability markedly decreased with increasing styrene content. No permeation of ions was observed above 5% styrene ratio. The permeation was considered to occur primarily through the relatively hydrophilic HEMA or aqueous phase. The diffusion mechanisms were confirmed by permeation experiments with warfarin base, an intrinsically hydrophobic compound. In propylene glycol, a continuous increase in the diffusion rate of warfarin base with increased membrane hydrophobicity was observed (Fig. 8). This contrasting behavior as compared to Na-warfarin was due to the absence of ions in the permeation system of warfarin base. Since the diffusing entity was both hydrophobic and neutral, the permeation was enhanced as membrane hydrophobicity increased. This phenomenon is illustrated in Fig. 9. Aqueous permeation studies with warfarin were also conducted at a pH of 10, at which warfarin base is completely ionized ( pK, = 5.1) . The permeant species was identical to the case of aqueous sodium warfarin permeation (see Fig. 8). As expected, the results were similar to aqueous sodium warfarin permeation. Therefore, it was confirmed that the parti-

infers that the hole size affects the solute diffusivity through pores in the membrane and can be described by the following equation: lng=ln -B -

6-

0

PROPYLENE GLY WATER

4-

0

0

10

20

STYRENE

Fig. 8. Permeation styrene membranes

30

COMPOSITION

40

50

60

(w/w%)

of warfarin base through p-HEMA/in propylene glycol and water.

tion mechanism was operative in the permeation of ion paired drug through hydrophobic membranes. Mechanistic investigations of ion paired drug permeation were also performed based on the free volume theory developed by Yasuda et al. [ 28,291. This model is frequently used to identify the mechanism of solute diffusion through membranes. The free volume theory is based on the concept of “holes” in the membrane into which the solutes jump and diffuse. Conceptually, the larger solute molecules have fewer “holes” into which they can fit and therefore, permeate slower through the membranes. This

--

Fig. 9. Mechanistic illustration of warfarin permeation through p-HEMA/styrene membranes in propylene glycol.

y(P)

($)

(9)

(4)

where D denotes the solute diffusion coefficient through the membrane, D, is the self-diffusion coefficient, w( r2) is the probability function to find the hole for solute diffusion, Br2 is the proportionality factor to the cross-sectional area of the solute (xr’), V, is the free volume of solvent and H is the degree of solvation. This equation demonstrates the linear relationship between In ( D/Do) and solute cross-sectional area ( nr*) under the following conditions: (1) The solute permeates only through the bulk solvent phase, in which the fluctuating pores are developed. (2) The interaction between solute and polymer is not significant. Therefore, the linear solute cross-sectional area size dependence on membrane diffusion can be utilized as a criterion for determining if the pore mechanism is significant in a given system. Deviation from linearity is attributed to the presence of an operative partition mechanism. The rationale for the use of the free volume theory was based on the following facts: (1) ion and ion pairs are different in size. This difference is especially important in the case of ionic drug salts which form ion triplets. Therefore, the size effect is expected to be reflected in the permeability, if the pore mechanism is involved. (2) contributions from the partition mechanism for lipophilic ion paired drugs can be envisaged from diffusivity/drug size relationship. A schematic illustration describing the size factor is given in Fig. 10. The polymer membranes selected for these studies include: (1) Porous pol~ropylene (Celgard@ ) : a membrane with hydrophobic permanent pore channels only, ( 2) pHEMA/styrene: a membrane with both pore channels and partition channels.

11

0

0 \

m

Na-SALICYLATE

m

HYDRALAZINE HC, Ca-SACCHARIN

r’ 0” 0‘

Na-DICLOFENAC

\

-5.0

=

WARFARIN q Na-WARFARIN ’ \

-6.0

q

t

Fig. 10. Schematic illustration of solute molecular size effects on ionic drug permeation through membranes.

CHLORPROMAZINEHCI

-7.0

Permeation experiments through Celgard@ membrane were performed in propylene glycol. For this membrane, drug diffusion occurs by wetting the hydrophobic pores, without specific interactions. Figure 11 shows the linear relationship between In D and the square of ion pair radius. This indicates that the permeant species is an ion paired drug. If the relationship between In D/Doversus r2 is considered, however, the In D/Dovalues do not differ significantly between the drugs (not shown). Thus, only bulk medium exists in the membrane for the drug diffusion.

10

20

30

r* Fig. 11. Size dependence gardO membrane.

of drug permeation

through

Cel-

u

12

16

20

r* (A*) Fig. 12. Size dependence of ionized drug permeation HEMA membrane in water.

through

Also, this result manifests the functional differences between the permanent pores in this membrane and the fluctuating pores in swollen membranes (e.g., p-HEMA) . The diffusion in permanent pores is considered to be similar to self diffusion, and the permeation rate is retarded by membrane tortuosity. In fluctuating statistical pores, the diffusion is controlled by the probability of pore formation and the solute finding the pore. Permeation experiments based on the free volume theory were also conducted utilizing the p-HEMA/styrene (7: 3 w/w%) membrane in both aqueous and nonaqueous media. Since the ion paired drugs can also diffuse via pore channels, the permeation results may reflect the effect of the different ion pair sizes. Figure 12 shows the permeation results with ionic drugs of varying sizes through a p-HEMA membrane in water. The plot of In (D/Do) versus r2 by ionic size exhibits linearity, indicating the size dependence of solute diffusivity. Therefore, it was determined that ionized solutes permeated via a pore mechanism due to their hydrophilic characteristics. The permeation result of the ionic drugs in propylene glycol

12

CONCLUSION -0.1 Na-SALICYLATE

-0.3

z

t

-0.5

$ = -0.7 D

Ca-SACCHARIN -0.9 TERBUTALINE SO4 0

-1 .l 1

15

20

25

30

r2 (A*)

Fig. 13. Permeation of ion paired drugs with different sizes through p-HEMA/styrene (7: 3 w/w% ) membrane in propylene glycol.

through p-HEMA/styrene ( 7 : 3 w/w% ) membranes is presented in Fig. 13. In the plot of In D/D,, versus r2 for each ion pair, the permeation result demonstrated large deviations. This phenomenon suggests that ion paired drug also permeated through partition channels. Significant deviation from linearity was observed with drugs which form ion triplets, such as calcium saccharin and terbutaline sulfate. The size difference between ions and ion pairs for these drugs is large. The observed deviations indicated that the actual size of the ion triplets was even larger than the calculated value. This is probably due to solvent association between the two large ions of an ion triplet. Overall, the above size dependence studies provided additional evidence for ion paired drug permeation. In conclusion, the permeant species of ionic drugs in nonaqueous systems were found to be ion pairs and these ion paired drugs could diffuse via both partition and pore mechanisms.

These studies were based on the hypothesis that ion paired drugs achieve lipophilic characteristics which enables them to undergo enhanced permeation through hydrophobic membranes. Conclusions from these studies are summarized below: 1. Ion paired drugs can diffuse through dense hydrophobic polymer membranes, in which no ion permeation occurs. A partition mechanism is operative for ion pair permeation. 2. The lipophilic characteristics of ion paired drugs were ascertained from the permeation studies through hydrophobic hydrophilic balanced membranes. Ion paired drug permeation is enhanced by increases in membrane hydrophobicity and ionized drug species exhibit an opposite trend. 3. Permeation of water soluble drugs and ionic drugs through water swollen p-HEMA membrane shows drug sized dependence which indicates pore mechanisms. However, the ion paired drugs are found to diffuse via both partition and pore mechanisms. Overall, ion pair stabilization in nonaqueous systems is a useful method for the lipophilization of ionic drugs for the transport through hydrophobic membranes, thus making it a promising technique for delivery of ionic drugs.

ACKNOWLEDGEMENTS

This work was supported by the Ciba-Geigy Corporation. The authors wish to thank Drs. W.R. Good andT. Kurihara-Bergstrom for their valuable discussions. REFERENCES 1

G.S. Banker and C.T. Rhodes (Eds.) , Modern Pharmaceutics, Marcel Dekker, New York and Basel, 1979.

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