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Quantitative Rate Measurement of the Hydroxide Driven Dissolution of an Enteric Drug Coating Using Atomic Force Microscopy Giles H. W. Sanders, Jonathan Booth, and Richard G. Compton* Physical and Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford OX1 3QZ, United Kingdom Received November 12, 1996. In Final Form: April 16, 1997X The hydroxide-driven dissolution of the polymer hydroxypropyl methylcellulose phthalate (HPMCP) in aqueous solution is studied using atomic force microscopy. The novel technique of employing the surfaceaveraged z-piezo voltage as a direct measure of the mean absolute surface height is described, so as, after appropriate calibration, to permit the ready inference of dissolution fluxes. In the case of interest the following dissolution rate law was established: j/g‚cm-2‚s-1 ) 105.0[OH-] over the pH range 8.0-9.2, where j is the flux of the dissolving polymer and [OH-] is measured in mol cm-3.
Introduction Atomic force microscopy (AFM) has been widely employed to image solid/liquid interfaces at scales ranging from the micron level downwards.1-7 Of particular interest and possibly greatest challenge are systems in which reaction occurs at the interface, leading to erosion or loss of the solid phase. Work carried out to date in this area includes studies of crystallization,1,2,6 dissolution,1,2,4,5 and polymer degradation3,7 and has revealed the structural features associated with the reactions of interest. For example the movement of steps across a crystal surface can be identified as a mechanism of crystal growth or dissolution.1,2,6 In this case, where the reaction is associated with a clear feature, comparison of sequences of images may permit rates of reaction to be estimated. In contrast many materials, especially polymers, give relatively featureless AFM images. In this letter we report the development of a new technique in which the surfaceaveraged z-piezo voltage is monitored as a function of time to provide a measure of the mean absolute position of the surface and thus a quantitative estimate of the rate of growth or erosion of a solid. This will be shown to be a reliable, convenient, and rapid method for the direct measurement of interfacial kinetics and to be especially helpful for reactions that occur relatively uniformly over the solid surface. Although commercial AFM instruments record data as z voltage positions, the images produced are presented as heights relative to the lowest point in the image by the software. This leads to the need for off line computer processing to access the raw data. This not only is time consuming but also requires knowledge of the file formats used. The method presented here overcomes such difficulties by providing a simple route to access the raw data on line. This enables the user to rapidly and easily monitor surface kinetic rates in real time. By having direct access to the real sample z position, the user can also rapidly identify problems occurring due to z-drift that would otherwise go unnoticed prior to image processing. X
Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) Hillner, P. E.; Manne, S.; Gratz, A. J.; Hansma, P. K. Geology, 1992, 20, 359. (2) Hall, C.; Cullen, D. AICHE J. 1996, 42, 232. (3) Shakesheff, K. M.; Davies, M. C.; Domb, A.; Jackson, D. E; Roberts, C. J.; Tendler, S. J. B.; Williams, P. M. Macromolecules, 1995, 28, 1108. (4) Heaton, J. S.; Engstrom, R. C. Environ. Sci. Technol. 1994, 28, 1747. (5) Sollbo¨hmer, O.; May, K. P.; Anders, M.; Thin Solid Films 1995, 264, 176. (6) Carter, P. W.; Ward, M. D. J. Am. Chem. Soc., 1993, 115, 11521. (7) Chen, X.; Shakesheff, K. M.; Davies, M. C.; Heller, J.; Roberts, C. J.; Tendler, S. J. B.; Williams, P. M. J. Phys. Chem. 1995, 99, 11537.
S0743-7463(96)01094-3 CCC: $14.00
The technique has clear advantages over other techniques used to measure surface kinetics, in particular the channel flow cell (CFC), ellipsometry, and surface plasmon resonance (SPR). In the case of the CFC, surface kinetic data can be reliably obtained, but this method is only viable in cases where a suitable detector can be identified. Ellipsometry and SPR provide highly surface sensitive surface data, but the analysis of such to produce quantitative kinetic data is highly complex. Furthermore these techniques can only be used on thin films, unlike the technique presented here that can be used on any type of sample without any specialized preparation. Furthermore none of the above techniques can alone supply topographic data. In this note the z-piezo technique is applied to study the dissolution of hydroxypropyl methylcellulose phthalate (HPMCP, grade HP55) in weakly basic solution. This is
an enteric coating agent used to protect drugs from degradation by gastric acid or to prevent them from causing side effects in the stomach, and it has been widely employed by the pharmaceutical industry since its introduction into the market in 1971.8 Although the material is robust in aqueous acidic media, it is known to undergo rapid dissolution in base as a result of its conversion into an anionic form through deprotonation;9 the aim of the experiments reported here is to quantify this dissolution rate and the influence of pH in particular. Experimental Section A Topometrix TMX 2010 Discoverer atomic force microscope, operating in contact mode, was employed to image the surfaces of the HPMCP substrates. A commercial Topometrix liquid cell (8) Shin-Etsu, Tokyo, Japan, Technical Bulletin. (9) Deutsch, D. Glaxo-Welcome Research, Ware, Hertfordshire, personal communication.
© 1997 American Chemical Society
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Figure 1. Dissolution of HPMCP in pH 9.2 buffer solution. The first image was taken ca. 3 min after introduction of alkaline solution, and successive images were taken at 50 s intervals. The images are shaded from the left and have a typical height range between 3000 and 4000 nm. was used, without modification, for in situ AFM imaging. No tip-induced damage, such as sratching, of the samples was apparent in any of the recorded images. HPMCP (grade HP55) was obtained from Shin Etsu, Tokyo, Japan. This had a weight average molecular weight of 8.4 × 104, as determined by gel permeation chromatography.8 Samples were prepared by drop casting solutions of HPMCP dissolved in acetone onto PTFE. Once the acetone had evaporated a film of HPMCP remained. Typically this permitted the formation of films of thickness up to ca 0.5 mm. This was then removed from the PTFE, cut in ca. 10 mm × 10 mm pieces, and affixed to an AFM sample holder using araldite. Prior to undertaking any dissolution experiments, the samples were soaked in water for several hours to ensure that the substrates were fully saturated with water so that contributions to height changes during AFM imaging from polymer swelling were negligible relative to the rate of dissolution. All experiments were conducted using triply-distilled deionized water of resistivity greater than 107 Ω cm and AnalaR grade buffers covering the pH range 8.0-9.2. Commercial pH 8 (borate) and pH 9.2 (phosphate) buffers were employed along with borax/ hydrochloric acid buffers made up to pH 8.4 and 8.8.
Results and Discussion HPMCP surfaces were examined using AFM in an aqueous environment. After pretreatment to fully swell the polymer with pure water (see above) several images were taken until any drift on the x-, y-, and z-piezo scanner tubes was eliminated and their output minimized. Buffer solutions were then flowed into the liquid cell, and after ca. 10 mL had passed through the cell, the flow was stopped. Image sequences (typified by Figures 1 and 2) of the dissolving surfaces were recorded continuously, at 50 s intervals, corresponding to a scan rate of 10 Hz and a resolution of 200 × 200 data points per image. For quantitative experiments a scan area of 20 × 20 µm2 was employed. In all cases two sorts of experiments were undertaken: first the recording of conventional topographical images and second the monitoring of the absolute z-piezo voltage during scanning. The latter was recorded
by scaling down the z-piezo voltage using a potential divider, and feeding it to an external input channel of the electronic control unit of the AFM, which permitted an absolute voltage map of the scanned area to be generated. Calibration of the voltage then permitted real drops or increases in height to be measured. Calibration of the potential divider was performed by measuring output voltage as a function of known input voltage and yielded a voltage height conversion constant of 0.275 V/µm when combined with scanner calibration data. This was confirmed by imaging a test grid, with a known precisely defined thickness of 2400 Å, and measuring the z-piezo voltage changes between topographical maxima and minima. In this way the height of the polymer surface could be measured throughout the dissolution period in the presence of base. Examination of Figures 1 and 2 shows images. The polymer structure is evident, but the features are relatively unchanged with time except for the growth of pinholes in Figure 2. However the latter constitute a negligible contribution to the overall dissolution flux as monitored using the z-piezo voltage method. In all experiments the latter showed a steady and near linear increase of voltage with time, corresponding to expansion of the z-piezo to maintain feedback as the polymer surface dissolved. The magnitude of the rate of voltage change in combination with the known10 density of HPMCP (1.17 g cm-3) permitted the flux (g cm-2 s-1) of dissolving polymer to be quantified. This was investigated particularly as a function of pH. Figure 3 shows the variation of the z-piezo voltage with time for three representative experiments in which the polymer was exposed to first pure water, second an aqueous solution of 1.0 M KCl, and last a solution (10) Charters, J. Glaxo-Welcome Research, Ware, Hertfordshire, personal communication. (11) Shakesheff, K. M.; Davies, M. C.; Heller, J.; Roberts, C. J.; Tendler, S. J. B.; Williams, P. M. Langmuir 1995, 11, 2547.
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Figure 2. Dissolution of HPMCP in pH 8.0 buffer solution containing 0.86 M NaCl. The first image was taken ca. 3 min after introduction of alkaline solution, and successive images were taken at 50 s intervals. The images are shaded from the left and have a typical height range of up to 1000 nm.
Figure 4. Plot showing the flux of dissolving polymer as a function of the hydroxide ion concentration. Figure 3. Plot of the surface-averaged z-piezo voltage against time for the exposure of HPMCP to solutions containing (a) pure water (O), (b) 1.0 M aqueous KCl (0), and (c) 1.0 M aqueous KCl buffered at pH 8.0 (4). The voltage is recorded relative to the initially recorded value.
buffered at pH 8 also containing 1.0 M KCl. The first two experiments show only a tiny dissolution rate and confirm both that the polymer has been fully swollen with water and that the voltage drift is negligible (2.5 × 10-5 V s-1) as measured for the calibration grid. The third experiment shows the significant effect of increasing the hydroxide ion concentration, which is further emphasized by Figure 4 which shows the dissolution flux measured using the z-piezo method as a function of [OH-] only in buffered solutions. Note that the polymer was preswelled, as in the absence of OH-, so that this flux represents a pure dissolution flux, assuming the swelling characteristics of the polymer are unchanged on adding pH 8 or 9.2 buffer to the 1 M KCl solution; otherwise, it represents a net balance between dissolution and any continued swelling.
From Figure 4 the dissolution flux clearly increases linearly with added hydroxide over the pH range studied. The interpretation of this rate law is open; however, one possibility is that since the deprotonation of COOH groups is thought to drive the dissolution, then the rate of diffusion of hydroxide ions into the polymer may control the observed rate. In this case the observed flux would be given by
flux ∝ [OH-]/δ where δ is a reaction layer thickness within the film given by
δ ∝ (D/k)0.5 D is the hydroxide diffusion coefficient in the film, and k is a pseudo-first-order rate constant which describes the reaction of OH- within protonated carboxylate groups. However, regardless of the physical mechanism, the rate
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law as determined by z-piezo voltage measurements provides a direct measure of the sought rate of dissolution. Conclusions The z-piezo technique provides a simple and readily implemented method for the direct determination of net rates of solid growth or erosion. HPMCP dissolution in aqueous base has been found to be hydroxide driven with a rate law of the form j/gm‚ cm-2‚s-1 ) 105[OH-]. The ease of this technique to provide surface kinetic data has been ably demonstrated and points toward the need for commercial SPM manufacturers to allow direct on line access to the z-piezo voltage,
enabling the instrument to be employed as a uniquely powerful tool to provide simultaneous surface kinetic and topographical data. Acknowledgment. We thank EPSRC for financial support through the ROPA scheme, Zeneca (Blackley, Manchester) and EPSRC for support for J.B. via a CASE studentship, and Glaxo (Ware) for a Prize Scholarship for G.H.W.S. Interesting discussions with John Atherton, Colin Brennan, Barry A. Coles, and David Deutsch are gratefully noted. LA961094M
