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Drug and excipient diffusion and solubility in acrylate adhesives measured by infrared-attenuated total reflectance (IR-ATR) spectroscopy
Journal of Controlled Release 61 (1999) 219–231
Drug and excipient diffusion and solubility in acrylate adhesives measured by infrared-attenuated total reflectance (IR-ATR) spectroscopy Adam S. Cantor* 3 M Pharmaceuticals, 3 M Center, Building 270 -4 S-02, St. Paul, MN 55144 -1000, USA Received 25 March 1999; received in revised form 20 March 1999; accepted 20 May 1999
Abstract Infrared-attenuated total reflectance (IR-ATR) was used to measure drug and excipient diffusion in acrylate pressuresensitive adhesives. The first part describes diffusion of drug and excipient from one adhesive layer to another. The IR-ATR spectrometer is used to continuously monitor the rate at which drug and excipient diffuse into the ‘receptor’ adhesive layer. In this way, the ability of the drug and / or excipient to leave an adhesive can be determined without any influence of receptor fluids or skin membranes. Data is reported here for terpineol and testosterone diffusion in isooctyl acrylate (IOA) and IOA–acrylic acid (AA) adhesives. It is shown that the diffusion rate is much higher in IOA adhesive than in IOA–AA adhesive. The second part describes the use of IR-ATR to measure the solubility of liquids in adhesives. In this method, a liquid excipient is placed in direct contact with an adhesive layer containing no excipient. The IR-ATR spectrometer is used to continuously monitor the rate at which excipient diffuses into the ‘receptor’ adhesive layer. At equilibrium, the IR spectrum can be compared to both the pure adhesive spectrum and the pure excipient spectrum to determine the solubility of the excipient in the adhesive. Data are reported here for terpineol in an IOA adhesive and for several liquids in an IOA–vinyl acetate adhesive. 1999 Elsevier Science B.V. All rights reserved. Keywords: Infrared; Drug; Diffusion; Pressure-sensitive adhesives
1. Introduction A factor of great importance in transdermal drug delivery (TDD) systems is the rate at which drug is able to permeate across the skin membrane and enter a patient’s bloodstream. The simplest model description of this delivery process involves two steps. The ability of the drug to move through and out of the *Tel.: 11-651-737-7524; fax: 11-651-737-7918. E-mail address: [email protected] (A.S. Cantor)
transdermal patch, followed by the ability of the drug to permeate through the skin membrane and thus reach the blood circulation. To directly measure drug delivery to the patient, however, requires dosing human subjects with active drugs and taking blood samples. For this reason, most TDD development work relies on simpler, in vitro tests to predict delivery performance. The two most common types of in vitro tests are penetration and dissolution tests. Penetration tests are sensitive to both the adhesive
0168-3659 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 99 )00119-4
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matrix and the membrane used (e.g., hairless mouse skin, human cadaver skin). Thus, if a low rate of delivery is measured in a penetration test, it is not clear whether this is due to the adhesive retarding release or if it is due to the membrane retarding permeation of the drug. Dissolution tests measure transport directly from a patch into a bath of receptor fluid. This is similar to a penetration test where the skin membrane is removed, so it is only sensitive to the ability of the mobile components to leave the patch. The main disadvantage of this test is the ability of the receptor fluid to influence the adhesive (e.g., through swelling) and thereby alter the rate of release. Infrared-attenuated total reflectance (IR-ATR) spectroscopy is well known as a powerful and convenient analytical tool and has been described in great detail elsewhere. Previous IR-ATR work has looked at water- or solvent-diffusion in semicrystalline or glassy polymers [1–5], drug diffusion in ointments [6] and polymer diffusion into other polymers [7]. IR-ATR has also been used to analyze concentrations of individual components in drugcontaining materials [8,9]. Diffusion of bovine serum albumin in a gel has been studied by using an IR microscope to measure diffusion in a long capillary [10]. Diffusion of a liquid into a pressure-sensitive adhesive forms the basis for a process to prepare transdermal patches [11]. This report describes two new uses for IR-ATR spectroscopy. The first part describes diffusion of drug and / or excipient from one pressure-sensitive adhesive layer to another. In essence, this is a ‘dry’ dissolution experiment. The receptor fluid in the dissolution experiment is replaced by a ‘receptor’ adhesive layer containing no drug and excipient. The IR-ATR spectrometer is used to continuously monitor the rate at which drug and excipient diffuse into the ‘receptor’ adhesive layer. In this way, the ability of the drug and / or excipient to leave an adhesive can be determined without any influence of receptor fluids or skin membranes. Data are reported here for terpineol and testosterone diffusion in isooctyl acrylate (IOA) and IOA–acrylic acid (AA) pressuresensitive adhesives. The second part describes the use of IR-ATR to measure the solubility of liquids in pressure-sensitive adhesives. In this method, a liquid excipient is placed
in direct contact with an adhesive layer containing no excipient. The IR-ATR spectrometer is again used to continuously monitor the rate at which excipient diffuses into the ‘receptor’ adhesive layer. At equilibrium, the IR spectrum can be compared to both the pure adhesive spectrum and the pure excipient spectrum, to determine the amount of excipient that is soluble in the adhesive. Data are reported here for terpineol in an IOA adhesive and for several liquids in an IOA–vinyl acetate (VOAc)– macromer pressure-sensitive adhesive.
2. Materials and methods
2.1. IR-ATR spectroscopy The permeation experiment was performed by preparing a layer of adhesive sandwiched between two release liners. One liner is removed and the adhesive is applied on top of the ATR crystal so that an initial spectrum can be recorded. The top release liner is then removed and a doped layer of adhesive (containing drug and / or excipient) is then placed on top of the first adhesive layer. As drug and / or excipient permeates through the bottom layer of adhesive and reaches the surface of the ATR crystal, the IR absorption spectrum changes. The Beer’s law relation between concentration and absorbance can then be used to determine the concentration of permeants at the ATR crystal surface as a function of time. In a variation of this experiment, a free liquid can also be placed on top of the first adhesive layer instead of a doped layer of adhesive. The experimental set-up involves reflecting an IR beam off the bottom of a flat crystal that has a high index of refraction. For the proper angles of reflection, a process know as total internal reflection takes place, and the entire IR beam is reflected. During this reflection, however, a small amount of the beam forms an evanescent wave that actually penetrates a small distance (of the order of one wavelength of IR light) above the top surface of the crystal. If an IR-absorbant material is placed on top of the crystal, then it will absorb portions of this evanescent wave, thereby attenuating the reflected beam. Thus, an IR absorption spectrum is obtained of the small layer
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(0.5 to 2.0 mm for the experimental conditions used here) of sample in contact with the top of the ATR crystal. For comparison, typical adhesive thickness in TDD tapes is 50 to 100 mm. If the small molecule permeates by Fickian diffusion, then mathematical descriptions are available to calculate the diffusion coefficient of the small molecule in the undoped adhesive matrix. A Nicolet Magna-IR 560 E.S.P. IR spectrophotometer with OMNIC 4.1a software was used for all experiments. The following conditions were used for all measurements: 32 scans with 4 cm 21 resolution, DTGS KBr detector, KBr beamsplitter, IR source, velocity50.6329, aperture5100, spectral range54000 to 650 cm 21 , no zero filling, HappGenzel apodization, Mertz phase correction, sample spacing set based on spectral range, low pass filters based on velocity. The ATR fixture had a ZnSe crystal (refractive index52.41) with an angle of reflection of 458. The temperature was not actively controlled, so the experiments were all run at a nominal room temperature of 218C. The sample chamber was purged with dry nitrogen and a purge time of 20 min was used before taking absorption measurements in static (non-timed) experiments. In the timed permeation experiments, the sample chamber had to be opened to apply the doped sample. Data collection was begun 1 min after applying the doped sample. Measurements during the first 20 min of permeation were only slightly influenced by a lack of complete purge. A background spectrum was collected where the absorbance due to lack of complete purge was measured in the absence of a sample. This background was used to correct the timed absorbance values. The correction was insignificant after 5 min at all wavelengths, and required only a small adjustment at shorter times for absorbances between 1600 and 1700 cm 21 . Spectra were automatically collected at fixed intervals (generally 1 to 10 min) during the length of each diffusion experiment using OMNIC series software. Experiments were continued either until the absorption spectrum became constant or had gone for one day in length without reaching equilibrium. Testosterone absorbance was measured at either 1663 (carbonyl) or 867 cm 21 (alkene). Terpineol absorbance was measured at either 799, 915
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or 950 cm 21 (alkene and alkanes). Both testosterone and terpineol absorb between 3100 and 3500 cm 21 (hydroxyl), so this absorbance was not used for samples containing both compounds. Under the conditions used here, the depth of penetration, g, of the IR beam was 0.39 mm at 685 cm 21 , 0.94 mm at 1663 cm 21 , and 1.99 mm at 3540 cm 21 . At a depth of 3g, the field strength is only 5% of the original intensity [6].
2.2. Dissolution /release testing A patch (5 cm 2 ) was cut from the coated tape and fastened to a steel plate using double-sided adhesive tape such that the adhesive layer was exposed to the release medium. The steel plate was immersed in a 30% ethyl alcohol aqueous release medium. The medium was maintained at 328C and stirred by means of a magnetic stirrer at moderate speed (75 rpm) throughout the experiment. At specified time points, a 2-ml volume of the release medium was removed and immediately replaced with 2 ml of fresh medium. The withdrawn medium was filtered through a 0.22-mm filter, to remove any particulate matter, then was assayed for drug content using high-performance liquid chromatography (HPLC).
2.3. In vitro skin penetration A Franz diffusion cell was used with a hairless mouse skin membrane. The release liner was removed from a 2.0-cm 2 patch and the patch was applied to the skin and pressed to cause uniform contact with the skin. The resulting patch / skin laminate was placed patch side up across the orifice of the lower portion of the diffusion cell. The diffusion cell was assembled and the lower portion was filled with 10 ml of warm (328C) receptor fluid so that the receptor fluid was in contact with the skin. The receptor fluid was stirred using a magnetic stirrer. The sampling port was covered except when in use. The cell was then placed in a constant temperature (32628C) and humidity (50610% relative humidity) chamber. The receptor fluid was stirred by means of a magnetic stirrer throughout the experiment, to ensure a uniform sample and a reduced diffusion barrier on the dermal side of the skin. The entire
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volume of receptor fluid was withdrawn at specified time intervals and immediately replaced with fresh fluid. The withdrawn fluid was filtered through a 0.45-mm filter and then analyzed for drug content using HPLC.
2.4. Materials a-Terpineol was of GC grade (Acros Organics), testosterone was of USP grade (Pharmacia Upjohn), ethanol was of reagent grade (Baker), isopropanol was of HPLC grade (Fisher), glycerol was of USP grade (EM Science), isopropyl myristate (Henkel) was of NF grade and methanol was of HPLC grade (Fisher). The IOA–AA pressure-sensitive adhesive was prepared by free-radical suspension polymerization of isooctyl acrylate and acrylic acid in a 94:6 ratio. A 1.0 L baffled reaction flask equipped with mechanical stirrer, condenser and inlet–outlet lines for vacuum and argon was charged with 450 g of deionized water and 6.0 g of ammonium lauryl sulfate (StandapolE A, Henkel). The reactor was degassed then refilled with argon and heated to 688C. A mixture containing 141 g of isooctyl acrylate, 9 g of acrylic acid and 0.71 g of benzoyl peroxide (Lucidol-70, Elf Atochem) was prepared in a jar. After the initiator dissolved, the mixture was charged to the reactor at 688C. The temperature of the reactor was then reset to 658C for 22 h. An argon purge was maintained during the polymerization. After 22 h, the suspension was cooled to ambient temperature. The reactor was then emptied, the suspension was coagulated with cetyl trimethyl ammonium chloride and redispersed in isopropanol before use. The IOA pressure-sensitive adhesive was prepared by free-radical suspension polymerization of isooctyl acrylate. A 1.0 L baffled reaction flask equipped with mechanical stirrer, condenser and inlet–outlet lines for vacuum and argon was charged with 390 g of deionized water and 8.4 g of ammonium lauryl sulfate (StandapolE A). The reactor was degassed then refilled with argon and heated to 688C. A mixture containing 210 g of isooctyl acrylate and 0.69 g of 2,29-azobis(2-methylbutanenitrile) (VazoE 67, DuPont) was prepared in a jar. After the initiator dissolved, the mixture was charged to the reactor at
688C. The temperature of the reactor was then reset to 608C for 22 h. An argon purge was maintained during the polymerization. After 22 h, the suspension was cooled to ambient temperature. The reactor was then emptied, the suspension was coagulated with isopropanol and redispersed in 89:11 (w / w) isopropanol–ethyl acetate before use. The IOA–VOAc–macromer adhesive was prepared by free-radical solution polymerization of isooctyl acrylate (IOA), vinyl acetate (VOAc) and macromer. The macromer was an acrylate-terminated polymethyl methacrylate with a molecular weight of approximately 8000 g / mol. A mixture containing 122.7 g of IOA, 80.4 g of VOAc, 8.5 g of macromer, 0.21 g of 2,29-azobis (2,4-dimethylpentanenitrile) and 238.5 g of ethyl acetate was prepared in a quart jar. The jar was purged with nitrogen gas, tightly sealed and placed in a rotating water bath at 458C for 24 h. After 24 h, the solution was cooled to ambient temperature. The adhesive was purified of residual monomers by coating on release liner and drying at 3008F for 10 min. The undoped IOA and IOA–AA adhesives were coated on Akrosil H2C / H4B differential release liner (coated on H2C, laminated to H4B). The undoped IOA adhesive was coated to 2.1 mil thickness from a 9.9% solids solution in 89:11 (w / w) ethyl acetate– isopropanol. The undoped IOA–AA adhesive was coated to 3.1 mil thickness from a 25.3% solids solution in isopropanol. The undoped adhesives were dried at 1108F for 4 min and 1858F for 6 min. The doped IOA formulation (115441-98-B) was coated to 3.1 mm thick from a 20% solids solution in 89:11 (w / w) ethyl acetate–isopropanol with a nominal formulation of 49.6:42.4:8.0 adhesive–terpineol– testosterone. The doped IOA–AA sample (11351254-5) was coated to 3.4 mil thick from a 10% solids solution in 87:13 (w / w) ethyl acetate–isopropanol and had a nominal formulation of 45.0:45.0:9.9 adhesive–terpineol–testosterone. The doped adhesives were dried at 1108F for 20 min. The IOA–VOAc–macromer adhesive was redissolved in ethyl acetate at 29.5% solids and coated and laminated on Daubert 164P release liner at a dried thickness of 3.5 mil. It was oven-dried at 1108F for 4 min and 1858F for 4 min. A comparison of an undoped IOA adhesive spectrum (bottom curve) and the doped adhesive spec-
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Fig. 1. IR spectrum of neat IOA adhesive compared to the spectrum of IOA adhesive with terpineol and testosterone.
trum (top curve) is shown in Fig. 1. Additional peaks due to terpineol or testosterone are identified.
2.5. Calculation of diffusion coefficient — undoped adhesive-doped adhesive experiment The theoretical rate of diffusion of a permeant from one finite layer into another finite layer has been determined previously [12]. This previous treatment explicitly solves for a three-layer system where the center layer is the doped layer and it is surrounded on each side by identical undoped layers (Fig. 2a). Diffusion is only considered perpendicular to the layers and the origin is set at the center of the doped layer. The diffusion is considered to be Fickian (i.e., it follows Eq. (1)) ≠C ≠ 2C ] 5 D ]] ≠t ≠z 2
(1)
Because of the symmetry of this construction, however, this also provides the solution for a two-layer system. In this case, the doped layer is now the top layer (and is one-half the thickness of the doped layer in the three-layer system) and one undoped layer is the bottom layer (Fig. 2b).
Fig. 2. (a) Schematic of a symmetric three-layer system for diffusion measurement. (b) Schematic of the two-layer system used in this work.
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224
After changing coordinates so that the origin is at the interface between the two layers, the following solution (Eq. (2)) is obtained. L1 5doped layer thickness L2 5undoped layer thickness the coordinate z5 2L2 is at the ATR crystaladhesive interface C(z 5 2 L2 ) ]]]] C0
OF S
(L2 1 2n(L1 1 L2 ) 1 2L1 ) 1 n 51` 5] erf ]]]]]]] Œ] 2 n 52` 4Dt (22n(L1 1 L2 ) 2 L2 ) 1 erf ]]]]]] Œ] 4Dt
S
DG
D (2)
Calculations were done in a MicrosoftE Excel spreadsheet. The terms from n5 24 to 14 were used. Terms from 14 and higher and 24 and lower contribute less than 0.01% to the total solution for the parameters used in this study. The error function, erf, was approximated by a series expansion (Eq. (3)) [13]. 2 erf(x) 5 ] Œ] p
SO `
1 x (2n11) ] ]]] (21)n n50 n! (2n 1 1)
D
(3)
The first 12 terms in the series were used, which gives an approximation that is valid within 0.1% unless uxu .2.1. For uxu .2.1, erf(x) was approximated as unity. Where appropriate, diffusion coefficients were determined by a least-squares fitting of the experimental data to the theoretically calculated concentration.
2.6. Solubility and diffusion coefficient — undoped adhesive–liquid experiment The solubility of a liquid in an adhesive can be determined at equilibrium when a free liquid layer is placed on top of the base adhesive layer. In schematic form, this is similar to the first experiment shown in Fig. 2b, except that the doped layer of adhesive is replaced by free liquid. There are important theoretical and practical differences in this type of experiment, compared to the previously described experiment with doped and
undoped adhesive layers. From a practical standpoint, it is important to be aware of the differences caused by having a free liquid present. The most obvious change is the need to use a trough ATR appliance to allow a layer of liquid to be placed on top of the layer of adhesive without allowing the liquid to flow away. The layer should be made thick enough so that the entire surface of the adhesive remains covered with free liquid despite any effects of permeation and evaporation. Evaporation was minimized by placing a polyester film over the top of the trough after loading of the permeant liquid. Another concern is that of imperfections in the adhesive film. In the previous experiment, a small tear or other opening in the undoped adhesive layer has little effect. With free liquid, imperfections in the adhesive layer can allow rapid permeation of the liquid to the ATR crystal surface. Also, the swelling of the adhesive was so large in one case that the adhesive buckled and lifted from the ATR crystal surface. In general, serious problems with sample deformation will only occur with highly soluble liquids. From a pharmaceutical formulation perspective, it is less important to be able to accurately measure excipient solubilities in an adhesive once the solubility is greater than 50–75%. Of some concern are the values obtained for excipients that are fairly insoluble in a particular adhesive. In these cases, it is important to be sure that the adhesive layer has no imperfections and covers the edges of the crystal sufficiently to prevent liquid from flowing around and under the adhesive layer. The theoretical treatment for this experiment differs from the previous undoped–doped layer experiment. The main difference is that the liquid layer is never depleted in this experiment. At all times, free liquid is maintained on top of the adhesive layer. A fairly simple approximation to the solution of the diffusion equation is given below [2]:
S
D SD
At 4 Dp 2 ln 1 2 ] 5 ln ] 2 ]] t A` p 4L 2
(4)
For the materials measured in this study, this equation is accurate, except at very short times. The
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absorbances, A, at times t and ` were directly equated to concentrations using Beer’s law. The actual concentration at equilibrium was determined by comparing the equilibrium absorbance, A ` , to the difference between the absorbance in the neat liquid and the absorbance in the undoped adhesive.
4. Results and discussion
4.1. Terpineol–testosterone diffusion in IOA and IOA– AA adhesives Fig. 3a–b shows the diffusion of terpineol (799 cm 21 ) and testosterone (1663 cm 21 ) in the IOA adhesive. Fig. 4a–b shows terpineol and testosterone diffusion in the IOA–AA adhesive. In each instance, the diffusion of both compounds was measured simultaneously. Diffusion measurements of the individual components have not yet been performed. It is anticipated that terpineol diffusion is unaffected by the presence of testosterone. Because of the high solubility of testosterone in terpineol, however, it is possible that the testosterone diffusion measured may be different than the diffusion that would be present in the adhesive alone. In the IOA adhesive, the permeation of terpineol and testosterone was seen to match very well to the theoretical prediction for a Fickian diffusion process (Fig. 3a,b). The terpineol diffusion coefficient, 3.13 10 28 cm 2 / s, was approximately ten-times faster than the testosterone diffusion coefficient, 4.9310 29 cm 2 / s. Complete equilibrium between the layers was seen after 200 to 300 min. Kokubo et al. [14] reported a diffusion coefficient of 3310 29 cm 2 / s for prostaglandin E1 (PGE1) in a 100% 2-ethyl hexyl acrylate (2-EHA) adhesive. This is of a similar magnitude to the value reported here for testosterone. On calculating molar volumes with the group contribution method proposed by Fedors [15], the molar volume of PGE1 (308.9 cm 3 / mol) is somewhat larger than that of testosterone (246.2 cm 3 / mol), so the lower diffusion coefficient is not surprising. The tenfold difference in diffusion coefficient between testosterone and terpineol is also consistent with the effect of molar volume that Morimoto et al. [16] reported for several drugs. Further analysis examining the effect of molar
Fig. 3. (a) Rate of diffusion of terpineol from an IOA–terpineol– testosterone formulation into an IOA adhesive with calculated fit. (b) Rate of diffusion of testosterone from an IOA–terpineol– testosterone formulation into an IOA adhesive with calculated fit.
volume on diffusion coefficient is given in the next section. In the IOA–AA adhesive, the permeation of terpineol and testosterone was significantly slower than the permeation in the IOA adhesive. The diffusion of each component in both adhesives is directly compared in Fig. 5. Neither component
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Fig. 5. Comparison of diffusion of terpineol and testosterone in both IOA and IOA–AA adhesives.
Fig. 4. (a) Rate of diffusion of terpineol from an IOA–AA– terpineol–testosterone formulation into an IOA–AA adhesive with calculated fit. (b) Rate of diffusion of testosterone from an IOA–AA–terpineol–testosterone formulation into an IOA–AA adhesive with calculated fit.
showed close agreement with the theoretical prediction for a Fickian diffusion process in the IOA–AA adhesive (Figs. 4a,b). Selecting a diffusion coefficient to match the onset of arrival at the ATR crystal gave values that were approximately one-third of the rate of diffusion in the IOA adhesive. However, after
the onset of signal due to the mobile molecules, the increase in concentration was much slower than that predicted for a Fickian diffusive process. Even after 24 h, the doped and undoped layers had not achieved equilibrium, with only 70 to 80% of the expected levels of the mobile molecules attained at the ATR crystal. The behavior in the IOA–AA adhesive contrasts strongly with results seen from standard dissolution testing of this adhesive. Dissolution testing was performed because the in vitro penetration experiments across hairless mouse skin showed much lower flux from the IOA–AA formulation than from the IOA formulation. The average in vitro flux from the IOA–AA formulation was approximately 5 mg / cm 2 / h, whereas the flux from the IOA formulation was approximately 20 mg / cm 2 / h. Since the drug and penetration enhancer levels were very similar, this suggested the possibility that the IOA–AA adhesive matrix was retarding drug delivery. Dissolution testing of the IOA– AA adhesive formulation using a water–ethanol medium as the dissolution medium, however, showed complete release of the testosterone within 15 to 30 min. The IR-ATR results, on the other hand, indicate that the low flux in the penetration experiment is caused by the IOA–AA matrix retarding drug release. The quick release in the dissolution
A.S. Cantor / Journal of Controlled Release 61 (1999) 219 – 231
experiment is undoubtedly due to the effect that the dissolution media has on swelling or otherwise extracting the testosterone from the adhesive matrix. Kokubo et al. [14] saw a reduction of the diffusion coefficient for PGE1 with increasing acrylic acid, but it was weaker than that seen here. Approximately 12% AA in the copolymer would have been needed to reduce the diffusion coefficient of PGE1 to onethird of the value with no AA in the copolymer. More importantly, the PGE1 diffusion remained Fickian following addition of acrylic acid to the copolymer.
4.2. Undoped adhesive–liquid: IOA adhesive with terpineol The IOA adhesive used in the previous experiment was used with terpineol for solubility determination. In this experiment, a free liquid layer of terpineol was placed on top of the base adhesive layer. The solubility of the liquid in the adhesive was then determined at equilibrium. Diffusion was monitored at both 915 cm 21 and 801 cm 21 , and agreement between the two peaks was quite good. The terpineol solubility was at least 85 to 90% (see Fig. 6). The experiment was terminated after 4 h, therefore, the
Fig. 6. Diffusion of neat methanol into IOA–VOAc–macromer adhesive with an approximate fit for the onset of diffusion.
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final equilibrium concentration may have been slightly higher. The rate of diffusion, however, did not match the prediction made by Fickian diffusion (see Eq. 4). Although a rate of diffusion of 3.1310 28 cm 2 / s (determined in the previous experiment) would be of the right magnitude, no meaningful fit for a Fickian diffusion coefficient could be made. The reason for the disagreement with Fickian diffusion was not investigated further. A likely explanation is that diffusion within the adhesive layer becomes significantly affected after large amounts of the small-molecule permeant is absorbed into the adhesive. In this experiment, the first data point was not collected until the concentration of terpineol at the ATR crystal was 40%. Since diffusion in the pure adhesive is likely to be significantly different than diffusion in a 60:40 mixture of adhesive and excipient, one should not expect a single diffusion coefficient to accurately describe the entire permeation process.
4.3. Undoped adhesive–liquid: IOA–VOAC– macromer with several liquids The IOA–VOAc–macromer adhesive was used for solubility and diffusion measurements with several small molecule liquids. For most liquids, the solubility could be monitored at more than one wavelength. In order to keep the figures legible, data from only two wavelengths are shown for each liquid. The agreement in solubility and diffusion measurements between different wavelengths was quite good. For the highly soluble liquids studied here, the permeation rate was quite fast, with complete equilibrium occurring within 2 h. This was seen for methanol, ethanol, isopropanol and isopropyl myristate (Figs. 6–8). Similar to the terpineol in the IOA adhesive experiment above, the rate of diffusion did not match the prediction made by Fickian diffusion (see Eq. (4)). As before, the reason is likely to be that the diffusion coefficient is dependent on the concentration of diffusant. With these liquids, however, several data points were collected at relatively short times. Although the entire sorption curve is not fit well by a Fickian diffusion prediction, it appears that the onset of sorption can be estimated to be Fickian. Because of the uncertainties in this approach
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Fig. 7. Diffusion of neat ethanol into IOA–VOAc–macromer adhesive with an approximate fit for the onset of diffusion.
due to the low number of data points fit, these data are presented as an estimated diffusion coefficient for the onset of sorption. It should be noted that further experiments performed at lower levels of the liquid
Fig. 8. Diffusion of neat isopropanol into IOA–VOAc–macromer adhesive with approximate fit for the onset of diffusion.
permeant would be necessary to establish that this estimated onset diffusion coefficient truly represents the initial diffusion rate of the permeant. Nevertheless, it is instructive to compare the order of magnitude of these estimated onset diffusion coefficients with free volume theory. Because of the uncertainties in estimating a diffusion coefficient for the onset of permeation, the liquid sorption samples were also evaluated by determining the length of time for the samples to reach either 50% or 80% (t-50% or t-80%) of the maximum concentration (see Table 1). A solubility of only 0.8 to 0.9% was measured for glycerol (Fig. 9). This represents close to a lower limit of sensitivity for this technique. The diffusion rate was also much slower. Although somewhat noisy, the data for glycerol were consistent with a Fickian diffusion model. In contrast to the cases of the highly soluble permeants, the final adhesive– glycerol mixture is not very different from the initial undoped adhesive. A comparison of the solubilities of the different liquids is shown in Fig. 10. Not surprisingly, increasing polarity leads to lower solubility in the largely non-polar adhesive (Table 1). As described above, the diffusion did not generally fit a Fickian model. The estimates of the diffusion coefficient for the onset of permeation, however, show that the initial diffusion is fastest for methanol and decreases with increasing alcohol size. Comparison of either the diffusion coefficient or the estimated diffusion coefficient at onset to the molar volume of the diffusants is shown in Fig. 11. There is good agreement with free volume theory that predicts a linear relationship between log D and the molar volume of the diffusant for all of the molecules with one hydroxyl group. Isopropyl myristate had a diffusion coefficient that was much higher than predicted. This is probably due to the lack of the hydroxyl functionality. Morimoto et al. [16] have shown that acrylic acid has a strong influence towards reducing diffusion coefficients for diffusants containing strong functional groups. The difference seen here between IPM and the hydroxyl-containing diffusants is quite interesting, because the adhesives used here had no strong functional groups. It appears that the hydroxyl interaction with the ester groups present in the
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Table 1 Diffusant
Solubility
MW (g / mol)
Molar vol. (cm 3 / mol)
t-50% (min)
t-80% (min)
Layer thickness (mm)
D or D aonset [310 8 cm 2 / s]
MeOH EtOH Glycerol IPA Terpineol b Testosterone b IPM
34–36% 56–60% 0.8–0.9% 80–851% 85–901% n.a. 601%*
32 46 92 60 154 288 270
43.5 59.6 61.1 76 162.6 246.2 310.7
1.3 3.3 68 4.0 7.2 38.6 *
5.9 8.6 170 14.6 22.2 89.7 *
3.5 3.5 3.5 3.5 2.1 2.1 3.5
18 a 15 a 0.64 12 a 3.1 0.5 *
*Adhesive lifted off the crystal; upper limit of solubility not determined. Diffusion coefficient, t-50% and t-80% values similar to those for IPA prior to adhesive lifting. a Donset estimated to fit the initial onset of permeation for these liquids. b Values measured in IOA adhesive.
acrylate adhesive is strong enough to significantly reduce the rate of diffusion. Glycerol had a diffusion coefficient that was much lower than predicted, which suggests that the additional hydroxyl groups also have a strong influence on the diffusion rate. A similar comparison of the t-50% or t-80% times (scaled by the square of the absorbing layer thickness) is shown in Fig. 12. The relationship to molar volume is very similar to that seen with the diffusion coefficients and estimated onset diffusion coefficients
Fig. 9. Diffusion of neat glycerol into IOA–VOAc–macromer adhesive with calculated fit.
for the permeants with a single hydroxyl group. The same conclusions as described above regarding glycerol and isopropyl myristate are also seen with this approach.
5. Conclusions Using IR-ATR spectroscopy to measure diffusion of small molecules in adhesives has been demon-
Fig. 10. Comparison of diffusion of several liquids into IOA– VOAc–macromer adhesive.
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Fig. 11. Comparison of diffusion coefficients and estimated onset diffusion coefficients for several liquids with their calculated molar volumes.
strated. This can be done without any influence from a liquid receptor medium. This allows for a clear distinction to be made between rate limitation of
Fig. 12. The t-50% and t-80% times (the times to reach 50 or 80% of the maximum concentration in the base adhesive) for several liquids compared with their calculated molar volumes.
delivery caused by the adhesive matrix and rate limitation caused by the skin membrane. The only major requirement to use this method is the need for suitable IR absorbances to allow spectral differentiation between the adhesive and the diffusing substances. The measured diffusion coefficients were similar in magnitude to those measured elsewhere in acrylate adhesives [14,16]. They were much faster than those typically seen in glassy polymers [1–3] (order of 10 210 to 10 211 cm 2 / s), but were slower than those seen in ointments [6] (2–5310 27 cm 2 / s) for similar small molecules. In particular, this method was applied to a comparison of IOA and IOA–AA pressure-sensitive adhesives. The IOA–AA adhesive showed poor delivery of testosterone across hairless mouse skin in penetration studies, whereas the IOA adhesive showed acceptable delivery. A dissolution experiment suggested that testosterone was released freely from the IOA–AA adhesive, but, based on the IR results, it appears that the release in the dissolution experiment was strongly influenced by the receptor medium. The IR measurement was able to show that the poor delivery from the IOA–AA adhesive was due to the rate-limiting nature of the adhesive. In addition, the experiment was able to show that terpineol diffusion was substantially faster than testosterone diffusion, which may help to provide insight into the testosterone delivery profile obtained with this system. An IR-ATR method for determination of the solubility of liquid excipients in adhesives was also demonstrated. This method allows for relatively accurate quantitative determinations of solubility for liquids in adhesives. Although the liquids did not show Fickian diffusion as they reached high concentrations in the adhesive, there was a clear dependence of the rate of permeation on the molar volume for several hydroxyl-containing diffusants. Changes in diffusant functionality, however, had a significant effect on the permeation rate. An important advantage for both of these uses of IR-ATR spectroscopy is the ability to perform these measurements on the actual thin adhesive films used in transdermal tapes. In addition, simultaneous detection of two or more different diffusing molecules can be done in some cases.
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Acknowledgements I would like to thank John A. Guertin and Jim K. Lundberg for assistance with IR measurements; ThuVan Tran for preparation of IOA and IOA–AA pressure-sensitive adhesives; Pat A. Kimbrough for preparation of IOA and IOA–AA adhesive formulations; Ruth A. James for preparation of IOA–VOAc– macromer pressure-sensitive adhesive.
References [1] N.E. Schlotter, P.Y. Furlan, Small molecule diffusion in polyolefins monitored using the infrared evanescent field, Vibrational Spectrosc. 3 (1992) 147–153. [2] G.T. Fieldson, T.A. Barbari, The use of FTi.r.-a.t.r. spectroscopy to characterize penetrant diffusion in polymers, Polymer 34 (9) (1993) 1146–1153. [3] G.T. Fieldson, T.A. Barbari, Analysis of diffusion in polymers using attenuated total reflectance Fourier-transform infrared spectroscopy, Polym. Mater. Sci. Eng. 71 (1994) 150–151. [4] N.E. Schlotter, Using vibrational spectroscopies to probe the diffusion of small molecules in polymer films, Polym. Prepr., Am. Chem. Soc. Div. Polym. Chem. 32 (3) (1991) 681–682. [5] T. Nguyen, D. Bentz, E. Byrd, Method for measuring water diffusion in a coating applied to a substrate, J. Coatings Technol. 67 (844) (1995) 37–46. [6] D.E. Wurster, V. Buraphacheep, J.M. Patel, The determination of diffusion coefficients in semisolids by Fourier transform infrared (FT-IR) spectroscopy, Pharm. Res. 10 (4) (1993) 616–620.
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[7] J.G. van Alsten, S.R. Lustig, Polymer mutual diffusion measurements using infrared ATR spectroscopy, Macromolecules 25 (1992) 5069–5073. [8] U.P. Fringeli, In situ infrared attenuated total reflection (IR ATR) spectroscopy: A complementary analytical tool for drug design and drug delivery, Chimia 46 (1992) 200–214. [9] D.D. Dunuwila, L.B. Carroll II, K.A. Berglund, An investigation of the applicability of attenuated total reflection infrared spectroscopy for measurement of solubility and supersaturation of aqueous citric acid solutions, J. Crystal Growth 137 (1994) 561–568. [10] R.E. Cameron, M.A. Jalil, A.M. Donald, Diffusion of bovine serum albumin in amylopectin gels measured using Fourier transform infrared microspectroscopy, Macromolecules 27 (1994) 2708–2713. [11] P.E. Price Jr., P.J. Northey, C.A. Miller, 3M Technical Report No. 6870-601412-001, 3M Pharmaceuticals, St. Paul, MN, 1992. [12] J. Comyn, Polymer permeability, in: J. Comyn (Ed.), Introduction to Polymer Permeability and the Mathematics of Diffusion, Elsevier Applied Science, London, 1985, p. 9. [13] W.H. Beyer (Ed.), CRC Standard Math Tables, 25th ed., CRC Press, Boca Raton, FL, 1979, p. 415. [14] T. Kokubo S, K. Sugibayashi, Y. Morimoto, Diffusion of drug in acrylic-type pressure-sensitive adhesive matrices. I. Influence of physical property of the matrices on the drug diffusion, J. Control. Release 17 (1991) 69–78. [15] R.F. Fedors, A method for estimating both the solubility parameters and molar volumes of liquids, Polym. Eng. Sci. 14 (2) (1974) 147–154. [16] Y. Morimoto, T. Kokubo, K. Sugibayashi, Diffusion of drug in acrylic-type pressure-sensitive adhesive matrices. II. Influence of interaction, J. Control. Release 18 (1992) 113– 122.
Drug and excipient diffusion and solubility in acrylate adhesives measured by infrared-attenuated total reflectance (IR-ATR) spectroscopy Adam S. Cantor* 3 M Pharmaceuticals, 3 M Center, Building 270 -4 S-02, St. Paul, MN 55144 -1000, USA Received 25 March 1999; received in revised form 20 March 1999; accepted 20 May 1999
Abstract Infrared-attenuated total reflectance (IR-ATR) was used to measure drug and excipient diffusion in acrylate pressuresensitive adhesives. The first part describes diffusion of drug and excipient from one adhesive layer to another. The IR-ATR spectrometer is used to continuously monitor the rate at which drug and excipient diffuse into the ‘receptor’ adhesive layer. In this way, the ability of the drug and / or excipient to leave an adhesive can be determined without any influence of receptor fluids or skin membranes. Data is reported here for terpineol and testosterone diffusion in isooctyl acrylate (IOA) and IOA–acrylic acid (AA) adhesives. It is shown that the diffusion rate is much higher in IOA adhesive than in IOA–AA adhesive. The second part describes the use of IR-ATR to measure the solubility of liquids in adhesives. In this method, a liquid excipient is placed in direct contact with an adhesive layer containing no excipient. The IR-ATR spectrometer is used to continuously monitor the rate at which excipient diffuses into the ‘receptor’ adhesive layer. At equilibrium, the IR spectrum can be compared to both the pure adhesive spectrum and the pure excipient spectrum to determine the solubility of the excipient in the adhesive. Data are reported here for terpineol in an IOA adhesive and for several liquids in an IOA–vinyl acetate adhesive. 1999 Elsevier Science B.V. All rights reserved. Keywords: Infrared; Drug; Diffusion; Pressure-sensitive adhesives
1. Introduction A factor of great importance in transdermal drug delivery (TDD) systems is the rate at which drug is able to permeate across the skin membrane and enter a patient’s bloodstream. The simplest model description of this delivery process involves two steps. The ability of the drug to move through and out of the *Tel.: 11-651-737-7524; fax: 11-651-737-7918. E-mail address: [email protected] (A.S. Cantor)
transdermal patch, followed by the ability of the drug to permeate through the skin membrane and thus reach the blood circulation. To directly measure drug delivery to the patient, however, requires dosing human subjects with active drugs and taking blood samples. For this reason, most TDD development work relies on simpler, in vitro tests to predict delivery performance. The two most common types of in vitro tests are penetration and dissolution tests. Penetration tests are sensitive to both the adhesive
0168-3659 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 99 )00119-4
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matrix and the membrane used (e.g., hairless mouse skin, human cadaver skin). Thus, if a low rate of delivery is measured in a penetration test, it is not clear whether this is due to the adhesive retarding release or if it is due to the membrane retarding permeation of the drug. Dissolution tests measure transport directly from a patch into a bath of receptor fluid. This is similar to a penetration test where the skin membrane is removed, so it is only sensitive to the ability of the mobile components to leave the patch. The main disadvantage of this test is the ability of the receptor fluid to influence the adhesive (e.g., through swelling) and thereby alter the rate of release. Infrared-attenuated total reflectance (IR-ATR) spectroscopy is well known as a powerful and convenient analytical tool and has been described in great detail elsewhere. Previous IR-ATR work has looked at water- or solvent-diffusion in semicrystalline or glassy polymers [1–5], drug diffusion in ointments [6] and polymer diffusion into other polymers [7]. IR-ATR has also been used to analyze concentrations of individual components in drugcontaining materials [8,9]. Diffusion of bovine serum albumin in a gel has been studied by using an IR microscope to measure diffusion in a long capillary [10]. Diffusion of a liquid into a pressure-sensitive adhesive forms the basis for a process to prepare transdermal patches [11]. This report describes two new uses for IR-ATR spectroscopy. The first part describes diffusion of drug and / or excipient from one pressure-sensitive adhesive layer to another. In essence, this is a ‘dry’ dissolution experiment. The receptor fluid in the dissolution experiment is replaced by a ‘receptor’ adhesive layer containing no drug and excipient. The IR-ATR spectrometer is used to continuously monitor the rate at which drug and excipient diffuse into the ‘receptor’ adhesive layer. In this way, the ability of the drug and / or excipient to leave an adhesive can be determined without any influence of receptor fluids or skin membranes. Data are reported here for terpineol and testosterone diffusion in isooctyl acrylate (IOA) and IOA–acrylic acid (AA) pressuresensitive adhesives. The second part describes the use of IR-ATR to measure the solubility of liquids in pressure-sensitive adhesives. In this method, a liquid excipient is placed
in direct contact with an adhesive layer containing no excipient. The IR-ATR spectrometer is again used to continuously monitor the rate at which excipient diffuses into the ‘receptor’ adhesive layer. At equilibrium, the IR spectrum can be compared to both the pure adhesive spectrum and the pure excipient spectrum, to determine the amount of excipient that is soluble in the adhesive. Data are reported here for terpineol in an IOA adhesive and for several liquids in an IOA–vinyl acetate (VOAc)– macromer pressure-sensitive adhesive.
2. Materials and methods
2.1. IR-ATR spectroscopy The permeation experiment was performed by preparing a layer of adhesive sandwiched between two release liners. One liner is removed and the adhesive is applied on top of the ATR crystal so that an initial spectrum can be recorded. The top release liner is then removed and a doped layer of adhesive (containing drug and / or excipient) is then placed on top of the first adhesive layer. As drug and / or excipient permeates through the bottom layer of adhesive and reaches the surface of the ATR crystal, the IR absorption spectrum changes. The Beer’s law relation between concentration and absorbance can then be used to determine the concentration of permeants at the ATR crystal surface as a function of time. In a variation of this experiment, a free liquid can also be placed on top of the first adhesive layer instead of a doped layer of adhesive. The experimental set-up involves reflecting an IR beam off the bottom of a flat crystal that has a high index of refraction. For the proper angles of reflection, a process know as total internal reflection takes place, and the entire IR beam is reflected. During this reflection, however, a small amount of the beam forms an evanescent wave that actually penetrates a small distance (of the order of one wavelength of IR light) above the top surface of the crystal. If an IR-absorbant material is placed on top of the crystal, then it will absorb portions of this evanescent wave, thereby attenuating the reflected beam. Thus, an IR absorption spectrum is obtained of the small layer
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(0.5 to 2.0 mm for the experimental conditions used here) of sample in contact with the top of the ATR crystal. For comparison, typical adhesive thickness in TDD tapes is 50 to 100 mm. If the small molecule permeates by Fickian diffusion, then mathematical descriptions are available to calculate the diffusion coefficient of the small molecule in the undoped adhesive matrix. A Nicolet Magna-IR 560 E.S.P. IR spectrophotometer with OMNIC 4.1a software was used for all experiments. The following conditions were used for all measurements: 32 scans with 4 cm 21 resolution, DTGS KBr detector, KBr beamsplitter, IR source, velocity50.6329, aperture5100, spectral range54000 to 650 cm 21 , no zero filling, HappGenzel apodization, Mertz phase correction, sample spacing set based on spectral range, low pass filters based on velocity. The ATR fixture had a ZnSe crystal (refractive index52.41) with an angle of reflection of 458. The temperature was not actively controlled, so the experiments were all run at a nominal room temperature of 218C. The sample chamber was purged with dry nitrogen and a purge time of 20 min was used before taking absorption measurements in static (non-timed) experiments. In the timed permeation experiments, the sample chamber had to be opened to apply the doped sample. Data collection was begun 1 min after applying the doped sample. Measurements during the first 20 min of permeation were only slightly influenced by a lack of complete purge. A background spectrum was collected where the absorbance due to lack of complete purge was measured in the absence of a sample. This background was used to correct the timed absorbance values. The correction was insignificant after 5 min at all wavelengths, and required only a small adjustment at shorter times for absorbances between 1600 and 1700 cm 21 . Spectra were automatically collected at fixed intervals (generally 1 to 10 min) during the length of each diffusion experiment using OMNIC series software. Experiments were continued either until the absorption spectrum became constant or had gone for one day in length without reaching equilibrium. Testosterone absorbance was measured at either 1663 (carbonyl) or 867 cm 21 (alkene). Terpineol absorbance was measured at either 799, 915
221
or 950 cm 21 (alkene and alkanes). Both testosterone and terpineol absorb between 3100 and 3500 cm 21 (hydroxyl), so this absorbance was not used for samples containing both compounds. Under the conditions used here, the depth of penetration, g, of the IR beam was 0.39 mm at 685 cm 21 , 0.94 mm at 1663 cm 21 , and 1.99 mm at 3540 cm 21 . At a depth of 3g, the field strength is only 5% of the original intensity [6].
2.2. Dissolution /release testing A patch (5 cm 2 ) was cut from the coated tape and fastened to a steel plate using double-sided adhesive tape such that the adhesive layer was exposed to the release medium. The steel plate was immersed in a 30% ethyl alcohol aqueous release medium. The medium was maintained at 328C and stirred by means of a magnetic stirrer at moderate speed (75 rpm) throughout the experiment. At specified time points, a 2-ml volume of the release medium was removed and immediately replaced with 2 ml of fresh medium. The withdrawn medium was filtered through a 0.22-mm filter, to remove any particulate matter, then was assayed for drug content using high-performance liquid chromatography (HPLC).
2.3. In vitro skin penetration A Franz diffusion cell was used with a hairless mouse skin membrane. The release liner was removed from a 2.0-cm 2 patch and the patch was applied to the skin and pressed to cause uniform contact with the skin. The resulting patch / skin laminate was placed patch side up across the orifice of the lower portion of the diffusion cell. The diffusion cell was assembled and the lower portion was filled with 10 ml of warm (328C) receptor fluid so that the receptor fluid was in contact with the skin. The receptor fluid was stirred using a magnetic stirrer. The sampling port was covered except when in use. The cell was then placed in a constant temperature (32628C) and humidity (50610% relative humidity) chamber. The receptor fluid was stirred by means of a magnetic stirrer throughout the experiment, to ensure a uniform sample and a reduced diffusion barrier on the dermal side of the skin. The entire
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volume of receptor fluid was withdrawn at specified time intervals and immediately replaced with fresh fluid. The withdrawn fluid was filtered through a 0.45-mm filter and then analyzed for drug content using HPLC.
2.4. Materials a-Terpineol was of GC grade (Acros Organics), testosterone was of USP grade (Pharmacia Upjohn), ethanol was of reagent grade (Baker), isopropanol was of HPLC grade (Fisher), glycerol was of USP grade (EM Science), isopropyl myristate (Henkel) was of NF grade and methanol was of HPLC grade (Fisher). The IOA–AA pressure-sensitive adhesive was prepared by free-radical suspension polymerization of isooctyl acrylate and acrylic acid in a 94:6 ratio. A 1.0 L baffled reaction flask equipped with mechanical stirrer, condenser and inlet–outlet lines for vacuum and argon was charged with 450 g of deionized water and 6.0 g of ammonium lauryl sulfate (StandapolE A, Henkel). The reactor was degassed then refilled with argon and heated to 688C. A mixture containing 141 g of isooctyl acrylate, 9 g of acrylic acid and 0.71 g of benzoyl peroxide (Lucidol-70, Elf Atochem) was prepared in a jar. After the initiator dissolved, the mixture was charged to the reactor at 688C. The temperature of the reactor was then reset to 658C for 22 h. An argon purge was maintained during the polymerization. After 22 h, the suspension was cooled to ambient temperature. The reactor was then emptied, the suspension was coagulated with cetyl trimethyl ammonium chloride and redispersed in isopropanol before use. The IOA pressure-sensitive adhesive was prepared by free-radical suspension polymerization of isooctyl acrylate. A 1.0 L baffled reaction flask equipped with mechanical stirrer, condenser and inlet–outlet lines for vacuum and argon was charged with 390 g of deionized water and 8.4 g of ammonium lauryl sulfate (StandapolE A). The reactor was degassed then refilled with argon and heated to 688C. A mixture containing 210 g of isooctyl acrylate and 0.69 g of 2,29-azobis(2-methylbutanenitrile) (VazoE 67, DuPont) was prepared in a jar. After the initiator dissolved, the mixture was charged to the reactor at
688C. The temperature of the reactor was then reset to 608C for 22 h. An argon purge was maintained during the polymerization. After 22 h, the suspension was cooled to ambient temperature. The reactor was then emptied, the suspension was coagulated with isopropanol and redispersed in 89:11 (w / w) isopropanol–ethyl acetate before use. The IOA–VOAc–macromer adhesive was prepared by free-radical solution polymerization of isooctyl acrylate (IOA), vinyl acetate (VOAc) and macromer. The macromer was an acrylate-terminated polymethyl methacrylate with a molecular weight of approximately 8000 g / mol. A mixture containing 122.7 g of IOA, 80.4 g of VOAc, 8.5 g of macromer, 0.21 g of 2,29-azobis (2,4-dimethylpentanenitrile) and 238.5 g of ethyl acetate was prepared in a quart jar. The jar was purged with nitrogen gas, tightly sealed and placed in a rotating water bath at 458C for 24 h. After 24 h, the solution was cooled to ambient temperature. The adhesive was purified of residual monomers by coating on release liner and drying at 3008F for 10 min. The undoped IOA and IOA–AA adhesives were coated on Akrosil H2C / H4B differential release liner (coated on H2C, laminated to H4B). The undoped IOA adhesive was coated to 2.1 mil thickness from a 9.9% solids solution in 89:11 (w / w) ethyl acetate– isopropanol. The undoped IOA–AA adhesive was coated to 3.1 mil thickness from a 25.3% solids solution in isopropanol. The undoped adhesives were dried at 1108F for 4 min and 1858F for 6 min. The doped IOA formulation (115441-98-B) was coated to 3.1 mm thick from a 20% solids solution in 89:11 (w / w) ethyl acetate–isopropanol with a nominal formulation of 49.6:42.4:8.0 adhesive–terpineol– testosterone. The doped IOA–AA sample (11351254-5) was coated to 3.4 mil thick from a 10% solids solution in 87:13 (w / w) ethyl acetate–isopropanol and had a nominal formulation of 45.0:45.0:9.9 adhesive–terpineol–testosterone. The doped adhesives were dried at 1108F for 20 min. The IOA–VOAc–macromer adhesive was redissolved in ethyl acetate at 29.5% solids and coated and laminated on Daubert 164P release liner at a dried thickness of 3.5 mil. It was oven-dried at 1108F for 4 min and 1858F for 4 min. A comparison of an undoped IOA adhesive spectrum (bottom curve) and the doped adhesive spec-
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223
Fig. 1. IR spectrum of neat IOA adhesive compared to the spectrum of IOA adhesive with terpineol and testosterone.
trum (top curve) is shown in Fig. 1. Additional peaks due to terpineol or testosterone are identified.
2.5. Calculation of diffusion coefficient — undoped adhesive-doped adhesive experiment The theoretical rate of diffusion of a permeant from one finite layer into another finite layer has been determined previously [12]. This previous treatment explicitly solves for a three-layer system where the center layer is the doped layer and it is surrounded on each side by identical undoped layers (Fig. 2a). Diffusion is only considered perpendicular to the layers and the origin is set at the center of the doped layer. The diffusion is considered to be Fickian (i.e., it follows Eq. (1)) ≠C ≠ 2C ] 5 D ]] ≠t ≠z 2
(1)
Because of the symmetry of this construction, however, this also provides the solution for a two-layer system. In this case, the doped layer is now the top layer (and is one-half the thickness of the doped layer in the three-layer system) and one undoped layer is the bottom layer (Fig. 2b).
Fig. 2. (a) Schematic of a symmetric three-layer system for diffusion measurement. (b) Schematic of the two-layer system used in this work.
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224
After changing coordinates so that the origin is at the interface between the two layers, the following solution (Eq. (2)) is obtained. L1 5doped layer thickness L2 5undoped layer thickness the coordinate z5 2L2 is at the ATR crystaladhesive interface C(z 5 2 L2 ) ]]]] C0
OF S
(L2 1 2n(L1 1 L2 ) 1 2L1 ) 1 n 51` 5] erf ]]]]]]] Œ] 2 n 52` 4Dt (22n(L1 1 L2 ) 2 L2 ) 1 erf ]]]]]] Œ] 4Dt
S
DG
D (2)
Calculations were done in a MicrosoftE Excel spreadsheet. The terms from n5 24 to 14 were used. Terms from 14 and higher and 24 and lower contribute less than 0.01% to the total solution for the parameters used in this study. The error function, erf, was approximated by a series expansion (Eq. (3)) [13]. 2 erf(x) 5 ] Œ] p
SO `
1 x (2n11) ] ]]] (21)n n50 n! (2n 1 1)
D
(3)
The first 12 terms in the series were used, which gives an approximation that is valid within 0.1% unless uxu .2.1. For uxu .2.1, erf(x) was approximated as unity. Where appropriate, diffusion coefficients were determined by a least-squares fitting of the experimental data to the theoretically calculated concentration.
2.6. Solubility and diffusion coefficient — undoped adhesive–liquid experiment The solubility of a liquid in an adhesive can be determined at equilibrium when a free liquid layer is placed on top of the base adhesive layer. In schematic form, this is similar to the first experiment shown in Fig. 2b, except that the doped layer of adhesive is replaced by free liquid. There are important theoretical and practical differences in this type of experiment, compared to the previously described experiment with doped and
undoped adhesive layers. From a practical standpoint, it is important to be aware of the differences caused by having a free liquid present. The most obvious change is the need to use a trough ATR appliance to allow a layer of liquid to be placed on top of the layer of adhesive without allowing the liquid to flow away. The layer should be made thick enough so that the entire surface of the adhesive remains covered with free liquid despite any effects of permeation and evaporation. Evaporation was minimized by placing a polyester film over the top of the trough after loading of the permeant liquid. Another concern is that of imperfections in the adhesive film. In the previous experiment, a small tear or other opening in the undoped adhesive layer has little effect. With free liquid, imperfections in the adhesive layer can allow rapid permeation of the liquid to the ATR crystal surface. Also, the swelling of the adhesive was so large in one case that the adhesive buckled and lifted from the ATR crystal surface. In general, serious problems with sample deformation will only occur with highly soluble liquids. From a pharmaceutical formulation perspective, it is less important to be able to accurately measure excipient solubilities in an adhesive once the solubility is greater than 50–75%. Of some concern are the values obtained for excipients that are fairly insoluble in a particular adhesive. In these cases, it is important to be sure that the adhesive layer has no imperfections and covers the edges of the crystal sufficiently to prevent liquid from flowing around and under the adhesive layer. The theoretical treatment for this experiment differs from the previous undoped–doped layer experiment. The main difference is that the liquid layer is never depleted in this experiment. At all times, free liquid is maintained on top of the adhesive layer. A fairly simple approximation to the solution of the diffusion equation is given below [2]:
S
D SD
At 4 Dp 2 ln 1 2 ] 5 ln ] 2 ]] t A` p 4L 2
(4)
For the materials measured in this study, this equation is accurate, except at very short times. The
A.S. Cantor / Journal of Controlled Release 61 (1999) 219 – 231
225
absorbances, A, at times t and ` were directly equated to concentrations using Beer’s law. The actual concentration at equilibrium was determined by comparing the equilibrium absorbance, A ` , to the difference between the absorbance in the neat liquid and the absorbance in the undoped adhesive.
4. Results and discussion
4.1. Terpineol–testosterone diffusion in IOA and IOA– AA adhesives Fig. 3a–b shows the diffusion of terpineol (799 cm 21 ) and testosterone (1663 cm 21 ) in the IOA adhesive. Fig. 4a–b shows terpineol and testosterone diffusion in the IOA–AA adhesive. In each instance, the diffusion of both compounds was measured simultaneously. Diffusion measurements of the individual components have not yet been performed. It is anticipated that terpineol diffusion is unaffected by the presence of testosterone. Because of the high solubility of testosterone in terpineol, however, it is possible that the testosterone diffusion measured may be different than the diffusion that would be present in the adhesive alone. In the IOA adhesive, the permeation of terpineol and testosterone was seen to match very well to the theoretical prediction for a Fickian diffusion process (Fig. 3a,b). The terpineol diffusion coefficient, 3.13 10 28 cm 2 / s, was approximately ten-times faster than the testosterone diffusion coefficient, 4.9310 29 cm 2 / s. Complete equilibrium between the layers was seen after 200 to 300 min. Kokubo et al. [14] reported a diffusion coefficient of 3310 29 cm 2 / s for prostaglandin E1 (PGE1) in a 100% 2-ethyl hexyl acrylate (2-EHA) adhesive. This is of a similar magnitude to the value reported here for testosterone. On calculating molar volumes with the group contribution method proposed by Fedors [15], the molar volume of PGE1 (308.9 cm 3 / mol) is somewhat larger than that of testosterone (246.2 cm 3 / mol), so the lower diffusion coefficient is not surprising. The tenfold difference in diffusion coefficient between testosterone and terpineol is also consistent with the effect of molar volume that Morimoto et al. [16] reported for several drugs. Further analysis examining the effect of molar
Fig. 3. (a) Rate of diffusion of terpineol from an IOA–terpineol– testosterone formulation into an IOA adhesive with calculated fit. (b) Rate of diffusion of testosterone from an IOA–terpineol– testosterone formulation into an IOA adhesive with calculated fit.
volume on diffusion coefficient is given in the next section. In the IOA–AA adhesive, the permeation of terpineol and testosterone was significantly slower than the permeation in the IOA adhesive. The diffusion of each component in both adhesives is directly compared in Fig. 5. Neither component
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Fig. 5. Comparison of diffusion of terpineol and testosterone in both IOA and IOA–AA adhesives.
Fig. 4. (a) Rate of diffusion of terpineol from an IOA–AA– terpineol–testosterone formulation into an IOA–AA adhesive with calculated fit. (b) Rate of diffusion of testosterone from an IOA–AA–terpineol–testosterone formulation into an IOA–AA adhesive with calculated fit.
showed close agreement with the theoretical prediction for a Fickian diffusion process in the IOA–AA adhesive (Figs. 4a,b). Selecting a diffusion coefficient to match the onset of arrival at the ATR crystal gave values that were approximately one-third of the rate of diffusion in the IOA adhesive. However, after
the onset of signal due to the mobile molecules, the increase in concentration was much slower than that predicted for a Fickian diffusive process. Even after 24 h, the doped and undoped layers had not achieved equilibrium, with only 70 to 80% of the expected levels of the mobile molecules attained at the ATR crystal. The behavior in the IOA–AA adhesive contrasts strongly with results seen from standard dissolution testing of this adhesive. Dissolution testing was performed because the in vitro penetration experiments across hairless mouse skin showed much lower flux from the IOA–AA formulation than from the IOA formulation. The average in vitro flux from the IOA–AA formulation was approximately 5 mg / cm 2 / h, whereas the flux from the IOA formulation was approximately 20 mg / cm 2 / h. Since the drug and penetration enhancer levels were very similar, this suggested the possibility that the IOA–AA adhesive matrix was retarding drug delivery. Dissolution testing of the IOA– AA adhesive formulation using a water–ethanol medium as the dissolution medium, however, showed complete release of the testosterone within 15 to 30 min. The IR-ATR results, on the other hand, indicate that the low flux in the penetration experiment is caused by the IOA–AA matrix retarding drug release. The quick release in the dissolution
A.S. Cantor / Journal of Controlled Release 61 (1999) 219 – 231
experiment is undoubtedly due to the effect that the dissolution media has on swelling or otherwise extracting the testosterone from the adhesive matrix. Kokubo et al. [14] saw a reduction of the diffusion coefficient for PGE1 with increasing acrylic acid, but it was weaker than that seen here. Approximately 12% AA in the copolymer would have been needed to reduce the diffusion coefficient of PGE1 to onethird of the value with no AA in the copolymer. More importantly, the PGE1 diffusion remained Fickian following addition of acrylic acid to the copolymer.
4.2. Undoped adhesive–liquid: IOA adhesive with terpineol The IOA adhesive used in the previous experiment was used with terpineol for solubility determination. In this experiment, a free liquid layer of terpineol was placed on top of the base adhesive layer. The solubility of the liquid in the adhesive was then determined at equilibrium. Diffusion was monitored at both 915 cm 21 and 801 cm 21 , and agreement between the two peaks was quite good. The terpineol solubility was at least 85 to 90% (see Fig. 6). The experiment was terminated after 4 h, therefore, the
Fig. 6. Diffusion of neat methanol into IOA–VOAc–macromer adhesive with an approximate fit for the onset of diffusion.
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final equilibrium concentration may have been slightly higher. The rate of diffusion, however, did not match the prediction made by Fickian diffusion (see Eq. 4). Although a rate of diffusion of 3.1310 28 cm 2 / s (determined in the previous experiment) would be of the right magnitude, no meaningful fit for a Fickian diffusion coefficient could be made. The reason for the disagreement with Fickian diffusion was not investigated further. A likely explanation is that diffusion within the adhesive layer becomes significantly affected after large amounts of the small-molecule permeant is absorbed into the adhesive. In this experiment, the first data point was not collected until the concentration of terpineol at the ATR crystal was 40%. Since diffusion in the pure adhesive is likely to be significantly different than diffusion in a 60:40 mixture of adhesive and excipient, one should not expect a single diffusion coefficient to accurately describe the entire permeation process.
4.3. Undoped adhesive–liquid: IOA–VOAC– macromer with several liquids The IOA–VOAc–macromer adhesive was used for solubility and diffusion measurements with several small molecule liquids. For most liquids, the solubility could be monitored at more than one wavelength. In order to keep the figures legible, data from only two wavelengths are shown for each liquid. The agreement in solubility and diffusion measurements between different wavelengths was quite good. For the highly soluble liquids studied here, the permeation rate was quite fast, with complete equilibrium occurring within 2 h. This was seen for methanol, ethanol, isopropanol and isopropyl myristate (Figs. 6–8). Similar to the terpineol in the IOA adhesive experiment above, the rate of diffusion did not match the prediction made by Fickian diffusion (see Eq. (4)). As before, the reason is likely to be that the diffusion coefficient is dependent on the concentration of diffusant. With these liquids, however, several data points were collected at relatively short times. Although the entire sorption curve is not fit well by a Fickian diffusion prediction, it appears that the onset of sorption can be estimated to be Fickian. Because of the uncertainties in this approach
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Fig. 7. Diffusion of neat ethanol into IOA–VOAc–macromer adhesive with an approximate fit for the onset of diffusion.
due to the low number of data points fit, these data are presented as an estimated diffusion coefficient for the onset of sorption. It should be noted that further experiments performed at lower levels of the liquid
Fig. 8. Diffusion of neat isopropanol into IOA–VOAc–macromer adhesive with approximate fit for the onset of diffusion.
permeant would be necessary to establish that this estimated onset diffusion coefficient truly represents the initial diffusion rate of the permeant. Nevertheless, it is instructive to compare the order of magnitude of these estimated onset diffusion coefficients with free volume theory. Because of the uncertainties in estimating a diffusion coefficient for the onset of permeation, the liquid sorption samples were also evaluated by determining the length of time for the samples to reach either 50% or 80% (t-50% or t-80%) of the maximum concentration (see Table 1). A solubility of only 0.8 to 0.9% was measured for glycerol (Fig. 9). This represents close to a lower limit of sensitivity for this technique. The diffusion rate was also much slower. Although somewhat noisy, the data for glycerol were consistent with a Fickian diffusion model. In contrast to the cases of the highly soluble permeants, the final adhesive– glycerol mixture is not very different from the initial undoped adhesive. A comparison of the solubilities of the different liquids is shown in Fig. 10. Not surprisingly, increasing polarity leads to lower solubility in the largely non-polar adhesive (Table 1). As described above, the diffusion did not generally fit a Fickian model. The estimates of the diffusion coefficient for the onset of permeation, however, show that the initial diffusion is fastest for methanol and decreases with increasing alcohol size. Comparison of either the diffusion coefficient or the estimated diffusion coefficient at onset to the molar volume of the diffusants is shown in Fig. 11. There is good agreement with free volume theory that predicts a linear relationship between log D and the molar volume of the diffusant for all of the molecules with one hydroxyl group. Isopropyl myristate had a diffusion coefficient that was much higher than predicted. This is probably due to the lack of the hydroxyl functionality. Morimoto et al. [16] have shown that acrylic acid has a strong influence towards reducing diffusion coefficients for diffusants containing strong functional groups. The difference seen here between IPM and the hydroxyl-containing diffusants is quite interesting, because the adhesives used here had no strong functional groups. It appears that the hydroxyl interaction with the ester groups present in the
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Table 1 Diffusant
Solubility
MW (g / mol)
Molar vol. (cm 3 / mol)
t-50% (min)
t-80% (min)
Layer thickness (mm)
D or D aonset [310 8 cm 2 / s]
MeOH EtOH Glycerol IPA Terpineol b Testosterone b IPM
34–36% 56–60% 0.8–0.9% 80–851% 85–901% n.a. 601%*
32 46 92 60 154 288 270
43.5 59.6 61.1 76 162.6 246.2 310.7
1.3 3.3 68 4.0 7.2 38.6 *
5.9 8.6 170 14.6 22.2 89.7 *
3.5 3.5 3.5 3.5 2.1 2.1 3.5
18 a 15 a 0.64 12 a 3.1 0.5 *
*Adhesive lifted off the crystal; upper limit of solubility not determined. Diffusion coefficient, t-50% and t-80% values similar to those for IPA prior to adhesive lifting. a Donset estimated to fit the initial onset of permeation for these liquids. b Values measured in IOA adhesive.
acrylate adhesive is strong enough to significantly reduce the rate of diffusion. Glycerol had a diffusion coefficient that was much lower than predicted, which suggests that the additional hydroxyl groups also have a strong influence on the diffusion rate. A similar comparison of the t-50% or t-80% times (scaled by the square of the absorbing layer thickness) is shown in Fig. 12. The relationship to molar volume is very similar to that seen with the diffusion coefficients and estimated onset diffusion coefficients
Fig. 9. Diffusion of neat glycerol into IOA–VOAc–macromer adhesive with calculated fit.
for the permeants with a single hydroxyl group. The same conclusions as described above regarding glycerol and isopropyl myristate are also seen with this approach.
5. Conclusions Using IR-ATR spectroscopy to measure diffusion of small molecules in adhesives has been demon-
Fig. 10. Comparison of diffusion of several liquids into IOA– VOAc–macromer adhesive.
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Fig. 11. Comparison of diffusion coefficients and estimated onset diffusion coefficients for several liquids with their calculated molar volumes.
strated. This can be done without any influence from a liquid receptor medium. This allows for a clear distinction to be made between rate limitation of
Fig. 12. The t-50% and t-80% times (the times to reach 50 or 80% of the maximum concentration in the base adhesive) for several liquids compared with their calculated molar volumes.
delivery caused by the adhesive matrix and rate limitation caused by the skin membrane. The only major requirement to use this method is the need for suitable IR absorbances to allow spectral differentiation between the adhesive and the diffusing substances. The measured diffusion coefficients were similar in magnitude to those measured elsewhere in acrylate adhesives [14,16]. They were much faster than those typically seen in glassy polymers [1–3] (order of 10 210 to 10 211 cm 2 / s), but were slower than those seen in ointments [6] (2–5310 27 cm 2 / s) for similar small molecules. In particular, this method was applied to a comparison of IOA and IOA–AA pressure-sensitive adhesives. The IOA–AA adhesive showed poor delivery of testosterone across hairless mouse skin in penetration studies, whereas the IOA adhesive showed acceptable delivery. A dissolution experiment suggested that testosterone was released freely from the IOA–AA adhesive, but, based on the IR results, it appears that the release in the dissolution experiment was strongly influenced by the receptor medium. The IR measurement was able to show that the poor delivery from the IOA–AA adhesive was due to the rate-limiting nature of the adhesive. In addition, the experiment was able to show that terpineol diffusion was substantially faster than testosterone diffusion, which may help to provide insight into the testosterone delivery profile obtained with this system. An IR-ATR method for determination of the solubility of liquid excipients in adhesives was also demonstrated. This method allows for relatively accurate quantitative determinations of solubility for liquids in adhesives. Although the liquids did not show Fickian diffusion as they reached high concentrations in the adhesive, there was a clear dependence of the rate of permeation on the molar volume for several hydroxyl-containing diffusants. Changes in diffusant functionality, however, had a significant effect on the permeation rate. An important advantage for both of these uses of IR-ATR spectroscopy is the ability to perform these measurements on the actual thin adhesive films used in transdermal tapes. In addition, simultaneous detection of two or more different diffusing molecules can be done in some cases.
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Acknowledgements I would like to thank John A. Guertin and Jim K. Lundberg for assistance with IR measurements; ThuVan Tran for preparation of IOA and IOA–AA pressure-sensitive adhesives; Pat A. Kimbrough for preparation of IOA and IOA–AA adhesive formulations; Ruth A. James for preparation of IOA–VOAc– macromer pressure-sensitive adhesive.
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