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Determination of Water Penetration and Drug Concentration Profiles in HPMC-Based Matrix Tablets by Near Infrared Chemical Imaging
Determination of Water Penetration and Drug Concentration Profiles in HPMC-Based Matrix Tablets by Near Infrared Chemical Imaging WEIYONG LI, ABRAHAM WOLDU, LOLA ARABA, DENITA WINSTEAD Chemical and Pharmaceutical Development, Johnson & Johnson Pharmaceutical Research & Development, LLC, Welsh & McKean Roads, Spring House, Pennsylvania 19477 Received 13 October 2009; revised 15 December 2009; accepted 16 December 2009 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.22084 ABSTRACT: This work describes methodologies based on near infrared chemical imaging (NIR CI) and chemometric data analysis for studying hydration behaviors of prolonged release tablets, which contain a high solubility drug at high load and a hydrophilic polymer hydroxypropylmethylcellulose (HPMC). Hydration studies were performed by suspending the tablets in water at ambient temperature. The hydrated tablets were then dissected and scanned by NIR CI. Single wavelength images were obtained for accurately measuring radial dimension of the gel layer and size of the tablet core. By performing a principal component analysis (PCA), the phenomenon of polymer phase transition from the glassy state to rubbery state was detected and visualized. Partial least squares (PLS) models were created for quantitative analysis of the active pharmaceutical ingredient (API) and relative concentration of water in the hydrated tablets. The API concentration profiles are suitable for defining the swelling front in hydrated tablets. Because the NIR CI results are pixel-specific and each pixel has its unique coordinates, it is feasible to analyze and present the results according to spatial locations. The physical and chemical changes at the swelling/diffusion fronts can be demonstrated by overlaying the PCA and PLS results, which shed light on the release mechanism. ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3081–3088, 2010
Keywords: controlled release; hydrogels; hydration; near infrared spectroscopy; image analysis; principal component analysis; partial least squares
INTRODUCTION Prolonged-release (PR) drug delivery systems are gaining increased attention in the pharmaceutical industry because of their safety profiles and patient compliance advantages compared with the immediate-release (IR) products. Amongst a variety of PR systems, water-swellable matrix systems, particularly the ones containing hydroxypropylmethylcellulose (HPMC), are widely used for their simplicity in formula compositions and low cost in manufacturing. These PR systems usually are provided as tablets for oral administration. On the other hand, drug release mechanisms of these PR tablets can be complicated and affected by chemical, physical, and physiological factors. Generally, retarded drug release from the matrix PR tablets is realized due to formation of the gel layer after they are in contact with water.
Correspondence to: Weiyong Li (Telephone: 1-215-628-5122; Fax: 1-215-628-5897; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 3081–3088 (2010) ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association
To understand the drug release kinetics and mechanisms from the hydrophilic matrices, different technologies including mechanical measurements,1,2 optical microscopy,3–5 NMR imaging,6,7 and Rutherford backscattering spectrometry,8 have been used to evaluate the drug release characteristics of these products. Research reports on water penetration, gel layer formation, gel layer erosion, and drug diffusion have been published. Colombo et al. studied the relationship between water penetration and drug dissolution in highly loaded swellable matrix tablets. In their experiments, a special device consisting of two Plexiglass discs joined by means of four stainless steel screws was used.1,9 The see-through glass discs allowed identification and measurements of three boundaries, which were named the swelling, diffusion, and erosion fronts. It was also confirmed that in swellable matrix tablets drug release depended on the dynamics of gel layer thickness. Moussa et al.5 used image analysis to study water transport and dimensional changes of the gel layer and tablet core in the early stages of hydration in cross-linked amylose matrices. In their study, the images were converted into a discrete number of pixels, which were assigned
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numeric locations and gray levels. A total of 256 gray levels were used. By using the imaging method, they were able to observe a water front preceding the glassy–rubbery polymer (swelling) front even in the early stages of hydration. Based on the Colombo et al. method, Ferrero et al. investigated the release mechanisms of two different matrix tablets consisting of sodium carboxymethylcellulose (NaCMC) or hydroxypropylcellulose methylmethacrylate (HCMMAL). Two different drug release kinetics were observed. One was considered relaxation-controlled whereas the other diffusion-controlled.10 This article describes novel methods for characterizing swellable matrix tablets using near infrared chemical imaging (NIR CI) along with chemometric data analysis. NIR CI is a relatively new technology that has been used for pharmaceutical product and process characterizations, including homogeneity of powdered materials and granulations,11 content uniformity of tablets,12 dissolution behaviors of tablets,13 etc. In this study, attributes of hydrated matrix tablets related to prolonged release of a highly water-soluble active pharmaceutical ingredient (API) were investigated using NIR CI. Based on the NIR spectra, water penetration, polymer phase transition (PPT) from the glassy state to rubbery state, and relative water concentration can be determined and visualized. Results from this study confirm some of the qualitative observations reported in the literature.9,14 More importantly, the results also provide quantitative information with regard to water and API concentrations in the hydrated matrix tablets, which forms a foundation for better understanding of drug release mechanisms for this class of pharmaceutical products.
EXPERIMENTAL Materials HPMC with a commercial name of METOLOSE was purchased from ShinEtsu (Tokyo, Japan). Magnesium stearate was purchased from Merck KGaA (Darmstadt, Germany). This study involves a proprietary API under development by Johnson & Johnson Pharmaceutical Research & Development, LLC (JJPRD). Matrix Tablet Preparation The PR tablets of 250 mg strength (API ¼ 42%, w/w) were prepared through a direct compression process. The API, HPMC, and microcrystalline cellulose (MCC) were blended in a 40 L Bohle bin blender for 10 min at 25 rpm. Magnesium stearate was then added and the powder mixture was blended for 5 more minutes. Tablets were manufactured by a rotary tablet press Manesty Beta Press (Thomas EngineerJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
ing, Hoffman Estates, IL) with 7 mm 17 mm capsule shaped tooling at the speed of 40 rpm. Matrix Tablet Hydration PR tablets were suspended in distilled water at ambient temperature. Each of the tablets was held upright using a reshaped paper clip. The swelled tablets were first dried with a soft tissue and then dissected along the radial direction at the middle point using a stainless steel surgical razor blade. After dissecting, the samples were scanned immediately by NIR chemical imaging. Near Infrared Chemical Imaging A Spectral Dimensions Sapphire/NIRCI-2450 system (Malvern Instruments, Columbia, MD) equipped with a focal plane array detector consisting of 320 256 pixels was used in this study. A lens with 35-mm/ pixel resolution allowed scan of the dissected tablets with a field of view (FOV) of 11.1 mm 8.9 mm. Spectra were collected from 1200 to 2400 nm in 10-nm increments and eight co-additions. For each sample scanned, 81,920 spectra were collected to form a socalled data cube, in which the x and y axes record physical location of the sample by pixels and the z-axis contains the pixel-specific spectral data. Definition of Data Cubes For concise discussions, the following data cubes are defined: R-cube—containing untreated raw NIR spectra. 1D-cube—containing S. Golay 1st derivative spectra. 2D-cube—containing S. Golay 2nd derivative spectra. S-cube—containing principal component analysis (PCA) scores after PCA. C-cube—containing concentration information after partial least squares (PLS) regression. TP-cube—containing reduced number of pixels by truncation. TS-cube—containing truncated spectra. To derive a TP-cube for measuring gel layer thickness, core size in a hydrated tablet or dimension of the PPT zone, a slice of the corresponding image with 30-pixel in width (1.05 mm) and 285 pixels in length (9.98 mm) was taken. The rectangle-shaped slice passed through the center point of the original image and was directed in parallel to either the x- or y-axis. In order to perform numerical calculations, the TP-cube was transferred to a Microsoft spreadsheet to form a 30-column by 285-row data matrix. The values were averaged in each row. Distance calculations and graphic plotting were performed based on the average values unless otherwise specified. DOI 10.1002/jps
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Data Cube Calculations The NIR-CI data cubes were processed using the chemical imaging software ISys (version 3.5.0) provided by the instrument vendor. The R-cubes were background corrected to reflectance (R) and converted to log10(1/R) or absorbance, followed by multi-step pretreatments including masking, wavelength interpolation (mathematically change the wavelength interval from 10 to 5 nm), standard normal variate (SNV) normalization and S. Golay smoothing (filter length ¼ 9, filter order ¼ 2). Then the 1D- or 2D-cubes were obtained by applying the S. Golay 1st (filer length ¼ 9, filter order ¼ 2; for quantitative analysis of the API) or 2nd (filter length ¼ 9, order ¼ 3; for qualitative and quantitative analysis of water) derivative algorithms. Each of the 1D- or 2D-cube contained 241 single wavelength images. Principal Component Analysis (PCA) To perform PCA for hydrated tablets, the 2D-cubes were converted to TS-cubes by truncating the 2nd derivative spectra using a wavelength range of 1230– 1500 nm. Six principal components were used in the analysis. An S-cube was obtained for each hydrated tablet, which contained six PCA score images.
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hydrated tablet after PLS prediction, which contained one concentration image.
RESULTS AND DISCUSSION The main focus of this work is on developing methods for measuring radial dimensions of the gel layer and tablet core, characterizing the glassy to rubbery transition of the hydrophilic polymer, and quantifying API and relative water contents in hydrated matrix tablets using single wavelength images, as well as PCA and PLS algorithms based on NIR CI data. Hydration kinetics of the PR tablets is also briefly discussed. Determination of Gel Layer and Tablet Core Dimensions by Single Wavelength Images Figure 1A is a single wavelength image (at 1380 nm, 1st overtone of water) derived from the 2D-cube of HYD1. The image shows the radial cross section of the hydrated tablet. Based on the amount of water, three distinctive regions are present in the image: the yellow-to-red colored region represents the gel layer (high amount of water); the light-blue colored ‘‘ring’’
Partial Least Squares Regression (PLS) For quantitative analysis of the API in hydrated tablets (e.g., HYD1 ¼ 1 h hydration), a PLS calibration model was built. To build the model, first the 1Dcube of an API drug substance sample was converted to a TS-cube (wavelength range 2000–2350 nm), which was then further converted to a TP-cube with a size of 2 mm 1 mm (FOV) to simplify chemometrics calculations without causing increased errors in prediction. This cube was used as a calibration sample for establishing the PLS model. For PLS prediction of hydrated tablets, the 1D-cubes were converted to TS-cubes (wavelength range 2000– 2350 nm) before applying the PLS calibration model. A C-cube was obtained for each hydrated tablet after PLS prediction, which contained one concentration image. For quantitative analysis of water in hydrated tablets, the 2D-cube of a HYD12 tablet (12 h hydration) was first converted to a TS-cube (wavelength range 1230–1500 nm), which was then further converted to a TP-cube with a size of 2 mm 1 mm (FOV). This cube was used as a calibration sample with the assumption of 100% hydration for establishing the PLS calibration model. For PLS prediction of relative water content in hydrated tablets, the 2D-cubes of hydrated tablets were converted to TS-cubes (wavelength range 1230–1500 nm) before applying the PLS calibration model. A C-cube was obtained for each DOI 10.1002/jps
Figure 1. Single wavelength image (A) and the corresponding 2nd derivative spectra (B) of a 1-h hydrated PR tablet (HYD1) showing the gel layer (in yellow to red), swelling area (in light blue), and tablet core (in dark blue). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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represents the classic swelling/diffusion fronts9 (medium amount of water); the dark-blue colored region represents the tablet core (low amount of water). There are three distinctive groups of NIR spectra corresponding to the three regions. A small set of spectra from each region, colored accordingly, are presented in Figure 1B. This simple method based on single wavelength images can be used for determining thickness of the gel layer and size of the remaining tablet core in hydrated tablets. The method for deriving the suitable TP-cubes for measuring the gel layer and tablet core dimensions are described in the Experimental Section. Each pixel is equivalent to a distance of 0.035 mm. This method is generally applicable to swellable matrix tablets. However, the method does not adequately characterize the classic swelling/ diffusion fronts in the hydrated matrix tablets. In addition, the spectra in the light blue region do not explain the chemical and physical changes at the swelling/diffusion fronts. More suitable methods are needed for those purposes. Determination of the PPT Zone by PCA For further investigation of the classic swelling/ diffusion fronts, PCA was conducted according to the procedure described in the Experimental Section. The TS-cubes (wavelength range 1230–1500 nm) were derived from the 2D-cubes of hydrated tablets and used for PCA. Each of the TS-cubes contained 55 single wavelength images (one every 5 nm). PCA is a dimension-reduction algorithm that can be used to describe variances in a large collection of spectrumbased images. Variances in the pixel-specific spectra are re-expressed using only a few latent variables or principal components (PCs). These PCs are ranked according to the total percentage of spectral variances that they explain and they are orthogonal to each other. A set of loading vectors and scores are calculated for each PC. The results are presented using score images. For the same sample HYD1, three PCs were needed to account for 99% of the variances in the TS-cube. The results were saved as an S-cube, which contained six score images (only the first three are meaningful), each corresponding to a PC. As expected, score images of PC1 and PC2 described the gel layer and core (images not shown here), respectively. The score image of PC3 (Fig. 2A), however, shows a red-colored ring that is not present in the single wavelength image (Fig. 1A). This region is believed to be related to the glassy-to-rubbery phase transfer of the polymer HPMC, which has been proposed in the literature.9 The loading plots in Figure 3B support this conclusion. It should be pointed out that the loading plots are not necessarily equivalent to NIR spectra. Nevertheless, they may contain the same explainable information. The JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
Figure 2. PC3 score image (A), loading plots (B), and loading plot of PC03 compared with 2nd derivative spectra of API, MCC, and HPMC (C) after principal component analysis performed for HYD1. The red colored area in (A) showing the polymer phase transition from the glassy state to rubbery state.
loading plot of PC1 (in black, associated with the gel layer) shows a band at 1385 nm, which can be attributed to the 1st overtone of water. On the other side, the loading plot of PC2 (in blue, associated with the core) shows a band at 1460 nm, which can be attributed to the ROH functional groups in HPMC (and MCC). Interestingly, the 1460 nm band is not present in the loading plot of PC1, indicating completion of the hydration process for HPMC in DOI 10.1002/jps
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Figure 3. Determination of API concentration profiles: (A) concentration image of HYD1, and (B) the corresponding 1st derivative spectra in tablet core (in yellow to red), at the swelling front (light blue), and in the gel layer (dark blue) for HYD1; (C) 1st derivative spectra of the API, MCC, and HPMC; (D) the expanded API concentration profiles at the swelling front for samples HYD1, 2, 3, 4, and 6.
the gel layer. The loading plot of PC3 (in red) does have the 1460 nm band as well as a shifted water band at 1400 nm, indicating the transition of the hydrophilic polymer from the glassy state to rubbery state. Figure 2C compares the loading plot of PC3 with 2nd derivative spectra of the API, MCC, and HPMC. The PC3 loading plot and spectrum of HPMC show good alignments in peaks and troughs (e.g., the valleys at 1430 and 1480 nm) but significant differences in band intensities, which further support the notion regarding the PPT. Difference between the NIR spectra in Figure 1B and the corresponding loading plots in Figure 2B implies that the PPT zone shown in Figure 2A cannot be easily detected using single wavelength images. Even the more powerful PLS regression method is not suitable simply because of the difficulty in identifying suitable calibration samples. Determination of API Concentration Profiles by PLS PCA was able to detect the PPT zone in hydrated matrix tablets. In this section, a PLS model is used DOI 10.1002/jps
for quantitative determination of API concentration profiles, particularly at the classic swelling/diffusion fronts. The calibration model was based on a sample of authentic drug substance in a powder form (see the Experimental Section for details). Therefore, the model is intended for quantifying API in the solid core and other regions where solid drug substance is still present. The model is not applicable for API dissolved in water. A spectra range of 2000– 2350 nm was chosen to minimize the impact of the strong water bands (the first overtone at 1400 nm and the combination band at 1900 nm). Again the same sample HYD1 is used to demonstrate the PLS method and the concentration image is presented in Figure 3A, which shows three distinctive regions: the yellow-to-red colored region demonstrates nominal concentration of API in the core; the light-blue colored ring shows a lower API concentration in the region; a blue-colored gel layer shows absence of the API. Three small sets of spectra were obtained from the 1D-cube of HYD1, colored accordingly to represent the three locations (Fig. 3B). Spectra from the core show a strong absorption band at 2145 nm that is JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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specifically related to the API. This band shows lower intensity in spectra of the swelling/diffusion fronts and is not present in spectra of the gel layer. First derivative spectra of neat components, including the API, MCC, and HPMC, are shown Figure 3C. The features of the spectra show significant differences between the API and excipients, which ensure specificity of the calibration model. To closely look at API concentration profiles in the light-blue region, the TP-cubes were derived from the C-cubes of samples HYD1, 2, 3, 4, and 6. The average API concentrations were obtained according to the method described in the Experimental Section. The plots in Figure 3D demonstrate API concentration profiles (w/w, %) in the light-blue region for tablets with different degree of hydration. These plots span the distance between the edge of the core where the API concentrations start to decrease consistently and the edge of the gel layer where the (w/w, %) API concentrations (in solid state) reach zero. The distance varied from 0.6 mm (HYD1) to 1.4 mm (HYD6). For tablets suspended in water for more than 6 h, the API concentration profiles in the abovementioned region became noisy and difficult to measure. It should be pointed out that Figure 3A does not show a color gradient to human eyes in the light-blue region, which implies that the classic methods had their limitations. On the contrary, the NIR CI methods allow more objective data analysis. Figure 3D can be used to define the spectrum-based swelling front, which is intuitively set at the point of distance ¼ 0. This front has an obvious physical meaning and can be measured accurately. On the other side, it is not obvious to define the diffusion front based on the NIR CI/PLS results because diffusion may happen at any point along the curves in Figure 3D. More work is needed to see if the diffusion front needs to be separately defined. Determination of Relative Water Concentration by PLS Another important aspect in characterizing hydrated matrix tablets is quantitative analysis of water, which affects the drug release in many different ways. In developing a PLS model for this purpose, identifying suitable calibration samples was not straightforward: first, the amount of water in the hydro-gel of a fully hydrated tablet may be not constant; secondly, the amount of water in hydrated tablets is difficult to quantify due to the mass exchanges between the hydrated tablets and water. In this study, an HYD12 sample was arbitrarily selected, which was assumed to have reached 100% hydration. With this assumption, the method was developed to evaluate the relative water concentration in different regions of a hydrated tablet. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
Figure 4. Determination of relative water concentration: (A) concentration image of sample HYD1; (B) relative water concentration profiles of samples HYD1, 3, 6, and 10.
The PLS model was created using the procedures described in the Experimental Section. A C-cube was generated for each sample analyzed. Figure 4A shows a concentration image of the same sample HYD1. Interestingly, only two colored regions can be observed for HYD1: the yellow-to-red colored region shows the gel layer (high amount of water); the blue colored region shows the tablet core (low amount of water). The classic swelling/diffusion fronts are not clearly shown in this image. To closely look at water profiles across the entire tablet, the TP-cubes were derived from the C-cubes of HYD1, 3, 6, 10, and the average water concentration profiles were obtained according to the method described in the Experimental Section. Figure 4B shows the relative water concentration profiles of these tablets. There are a few interesting observations from Figure 4B: (a) water content in the gel layer is relatively constant, indicating the rate of hydration is faster than the rate of water penetration; (b) the relative water content in the core is relatively low but it increases with time, probably because of penetration of water vapor; (c) a very steep gradient of water concentration between the core and gel layer is observed for HYD1, which explains the observations in Figure 4A. The gradient becomes more moderate for samples HYD6 and 10. DOI 10.1002/jps
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Front Movement Kinetics In the aforementioned discussions, the results from single wavelength images, PCA and PLS regressions were described without considering their interrelationships. With the available imaging analysis software, it is feasible not only to apply multiple chemometric algorithms on the same data cube for assessing different attributes of the same sample, but also to coordinate the data analysis and presentation pixel by pixel. This is because every pixel in a data cube has its own coordinates and the pixel-specific information can be easily accessed and compared even though different chemometric algorithms have been used. To take this advantage, Figure 5 overlays the relative water concentration, API concentration, and PPT zone to demonstrate physical changes within the hydrated tablets (samples HYD 1, 3, and 6). In all cases, the water penetration front and polymer transition region seems to move in a synchronized fashion. The plots also indicate that the dissolution of API happens in the PPT zones, which becomes much broader for the 6 h sample (Fig. 5C). Plots in Figure 6A demonstrate increase of the gel layer thickness (in blue), decrease of the tablet core size (in red), and dimensional change of the PPT zone with time. A liner relationship can be observed between the dimensional changes of gel layer and tablet core versus hydration time in the first 7 h. The gel layer thickness and core size data were obtained from the C-cubes of API concentration profiles after the PLS predictions. Each data point shown in Figure 6 was the average of three individual determinations. The tablet core disappeared after 10 h. The PPT zone, determined by the PCA method, shows a steady increase in dimension for the first 4 h and then levels off. As pointed out by other researchers, these results are critical for understanding drug release of the PR tablets.1,9,10,14 Details on how to relay these observations to drug release behavior of the product (e.g., through dissolution testing) are out of the scope of this article and will be discussed in a separate publication. Plots in Figure 6B demonstrate the relative water content in the gel layer and tablet core as a function of time. During the hydration study, it was observed that the tablet retained its shape for up to at least 24 h. It is expected that as the hydration time increases, the hydro-gel will slowly lose its strength. Interestingly, Figure 6B does not show a dramatic change in relative water content in the gel layer for tablets suspended in water for up to 10 h. On the other side, relative water content in the tablet core increased from about 10% to 40% (relative to the water content in the gel layer). After 10 h, the tablet core became very small and materials in the core DOI 10.1002/jps
Figure 5. Overlay of API concentration profile, relative water concentration profile, and the PPT zone for samples (A) HYD1, (B) HYD3, and (C) HYD6.
became loose but maintained their solid state. Studies are on-going to develop PLS models for measuring absolution concentration of water in hydrated tablets. The information will enable calculation of locationspecific API concentrations for better understanding and modeling of drug release from the matrix-based pharmaceutical products. The absolution method will also enable quantitative measurement and comparison of physical properties among matrix tables with different polymer compositions and drug release characteristics. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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mechanisms of swellable matrix tablets, which will result in the design, development, and manufacture of better prolonged release pharmaceutics.
REFERENCES
Figure 6. Dimensional change of the gel layer, tablet core, and PPT zone (A), as well as relative water concentration in the gel layer and tablet core (B) as a function of hydration time.
CONCLUSION NIR CI in combination with chemometric data analysis is a powerful tool for characterization and quantitative analysis of hydrated matrix tablets. Dimensions of the gel layer and tablet core can be accurately measured using single wavelength images and PLS regression. Phenomenon of the glassy– rubbery phase transfer of the hydrophilic polymer can be detected and visualized by PCA. API concentration profiles can be used to define a more meaningful polymer swelling front. Relative concentration of water in the gel layer, at the swelling front, and in the core can be determined by PLS regression. The introduction of these methods should facilitate studies on better understanding of drug release
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1. Colombo P, Gazzaniga A, Caramella C, Conte U, La Manna A. 1987. In vitro programmable zero-order release drug delivery system. Acta Pharm Technol 33:15–20. 2. Konard R, Christ A, Zessin G, Cobet U. 1998. The use of ultrasound and penetrometer to characterize the advancement of swelling and eroding fronts in HPMC matrices. Int J Pharm 163:123–131. 3. Thomas N, Windle AH. 1978. Transport of methanol in poly(methylmethacrylate). Polymer 19:255–265. 4. Gao P, Meury H. 1996. Swelling of hydroxypropyl methylcellulose matrix tablets. 1. Characterization of swelling using a novel optical imaging method. J Pharm Sci 52:1145–1149. 5. Moussa IS, Lenaerts V, Cartilier LH. 1998. Image analysis studies of water transport and dimensional changes occurring in the early stages of hydration in cross-linked amylose matrices. J Control Rel 52:63–70. 6. Weisenberg LA, Koenig JL. 1990. An NMR imaging study of methanol desorption from partially swollen PMMA rods. Macromolecules 23:2454–2459. 7. Rajabi-Siahboomi AR, Bowtell RW, Mansfield P, Henderson A, Davies MC, Melia CD. 1994. Structure and behavior in hydrophilic matrix sustained release dosage forms: 2. NMR-imaging studies of dimensional changes in the gel layer and core of HPMC tablets undergoing hydration. J Control Release 31: 121–128. 8. Mills PJ, Palmstrom CJ, Kramer EJ. 1986. Concentration profiles of non-Fickian diffusants in glassy polymers by Rutherford backscattering spectrometry. J Mater Sci 21:1479–1486. 9. Colombo P, Bettini R, Santi P, De Ascentiis A, Peppas NA. 1996. Analysis of the swelling and release mechanisms from drug delivery system with emphasis on drug solubility and water transport. J Control Release 39:231–237. 10. Ferrero C, Munoz-Ruiz A, Jimenez-Castellanos MR. 2000. Fronts movement as a useful tool for hydrophilic matrix release mechanism elucidation. Int J Pharm 202:21–28. 11. Li W, Woldu A, Kelly R, McCool J, Bruce R, Rasmussen H, Cunningham J, Winstead D. 2008. Measeurement of drug agglomerates in powder blending simulation samples by near infrared chemical imaging. Int J Pharm 350:369–373. 12. Lee E, Huang WX, Chen P, Lewis EN, Vivlecchia RV. 2006. High throughput analysis of pharmaceutical tablet content uniformity by near-infrared chemical imaging. Spectroscopy 21:22. 13. Roggo Y, Jent N, Edmond A, Chalus P, Ulmschneider M. 2005. Characterizing process effects on pharmaceutical solid forms using near-infrared spectroscopy and infrared imaging. Eur J Pharm Biopharm 61:100–110. 14. Lee PI, Kim C. 1991. Probing the mechanisms of drug release from hydrogels. J Control Release 16:229–236.
DOI 10.1002/jps
Keywords: controlled release; hydrogels; hydration; near infrared spectroscopy; image analysis; principal component analysis; partial least squares
INTRODUCTION Prolonged-release (PR) drug delivery systems are gaining increased attention in the pharmaceutical industry because of their safety profiles and patient compliance advantages compared with the immediate-release (IR) products. Amongst a variety of PR systems, water-swellable matrix systems, particularly the ones containing hydroxypropylmethylcellulose (HPMC), are widely used for their simplicity in formula compositions and low cost in manufacturing. These PR systems usually are provided as tablets for oral administration. On the other hand, drug release mechanisms of these PR tablets can be complicated and affected by chemical, physical, and physiological factors. Generally, retarded drug release from the matrix PR tablets is realized due to formation of the gel layer after they are in contact with water.
Correspondence to: Weiyong Li (Telephone: 1-215-628-5122; Fax: 1-215-628-5897; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 3081–3088 (2010) ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association
To understand the drug release kinetics and mechanisms from the hydrophilic matrices, different technologies including mechanical measurements,1,2 optical microscopy,3–5 NMR imaging,6,7 and Rutherford backscattering spectrometry,8 have been used to evaluate the drug release characteristics of these products. Research reports on water penetration, gel layer formation, gel layer erosion, and drug diffusion have been published. Colombo et al. studied the relationship between water penetration and drug dissolution in highly loaded swellable matrix tablets. In their experiments, a special device consisting of two Plexiglass discs joined by means of four stainless steel screws was used.1,9 The see-through glass discs allowed identification and measurements of three boundaries, which were named the swelling, diffusion, and erosion fronts. It was also confirmed that in swellable matrix tablets drug release depended on the dynamics of gel layer thickness. Moussa et al.5 used image analysis to study water transport and dimensional changes of the gel layer and tablet core in the early stages of hydration in cross-linked amylose matrices. In their study, the images were converted into a discrete number of pixels, which were assigned
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numeric locations and gray levels. A total of 256 gray levels were used. By using the imaging method, they were able to observe a water front preceding the glassy–rubbery polymer (swelling) front even in the early stages of hydration. Based on the Colombo et al. method, Ferrero et al. investigated the release mechanisms of two different matrix tablets consisting of sodium carboxymethylcellulose (NaCMC) or hydroxypropylcellulose methylmethacrylate (HCMMAL). Two different drug release kinetics were observed. One was considered relaxation-controlled whereas the other diffusion-controlled.10 This article describes novel methods for characterizing swellable matrix tablets using near infrared chemical imaging (NIR CI) along with chemometric data analysis. NIR CI is a relatively new technology that has been used for pharmaceutical product and process characterizations, including homogeneity of powdered materials and granulations,11 content uniformity of tablets,12 dissolution behaviors of tablets,13 etc. In this study, attributes of hydrated matrix tablets related to prolonged release of a highly water-soluble active pharmaceutical ingredient (API) were investigated using NIR CI. Based on the NIR spectra, water penetration, polymer phase transition (PPT) from the glassy state to rubbery state, and relative water concentration can be determined and visualized. Results from this study confirm some of the qualitative observations reported in the literature.9,14 More importantly, the results also provide quantitative information with regard to water and API concentrations in the hydrated matrix tablets, which forms a foundation for better understanding of drug release mechanisms for this class of pharmaceutical products.
EXPERIMENTAL Materials HPMC with a commercial name of METOLOSE was purchased from ShinEtsu (Tokyo, Japan). Magnesium stearate was purchased from Merck KGaA (Darmstadt, Germany). This study involves a proprietary API under development by Johnson & Johnson Pharmaceutical Research & Development, LLC (JJPRD). Matrix Tablet Preparation The PR tablets of 250 mg strength (API ¼ 42%, w/w) were prepared through a direct compression process. The API, HPMC, and microcrystalline cellulose (MCC) were blended in a 40 L Bohle bin blender for 10 min at 25 rpm. Magnesium stearate was then added and the powder mixture was blended for 5 more minutes. Tablets were manufactured by a rotary tablet press Manesty Beta Press (Thomas EngineerJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
ing, Hoffman Estates, IL) with 7 mm 17 mm capsule shaped tooling at the speed of 40 rpm. Matrix Tablet Hydration PR tablets were suspended in distilled water at ambient temperature. Each of the tablets was held upright using a reshaped paper clip. The swelled tablets were first dried with a soft tissue and then dissected along the radial direction at the middle point using a stainless steel surgical razor blade. After dissecting, the samples were scanned immediately by NIR chemical imaging. Near Infrared Chemical Imaging A Spectral Dimensions Sapphire/NIRCI-2450 system (Malvern Instruments, Columbia, MD) equipped with a focal plane array detector consisting of 320 256 pixels was used in this study. A lens with 35-mm/ pixel resolution allowed scan of the dissected tablets with a field of view (FOV) of 11.1 mm 8.9 mm. Spectra were collected from 1200 to 2400 nm in 10-nm increments and eight co-additions. For each sample scanned, 81,920 spectra were collected to form a socalled data cube, in which the x and y axes record physical location of the sample by pixels and the z-axis contains the pixel-specific spectral data. Definition of Data Cubes For concise discussions, the following data cubes are defined: R-cube—containing untreated raw NIR spectra. 1D-cube—containing S. Golay 1st derivative spectra. 2D-cube—containing S. Golay 2nd derivative spectra. S-cube—containing principal component analysis (PCA) scores after PCA. C-cube—containing concentration information after partial least squares (PLS) regression. TP-cube—containing reduced number of pixels by truncation. TS-cube—containing truncated spectra. To derive a TP-cube for measuring gel layer thickness, core size in a hydrated tablet or dimension of the PPT zone, a slice of the corresponding image with 30-pixel in width (1.05 mm) and 285 pixels in length (9.98 mm) was taken. The rectangle-shaped slice passed through the center point of the original image and was directed in parallel to either the x- or y-axis. In order to perform numerical calculations, the TP-cube was transferred to a Microsoft spreadsheet to form a 30-column by 285-row data matrix. The values were averaged in each row. Distance calculations and graphic plotting were performed based on the average values unless otherwise specified. DOI 10.1002/jps
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Data Cube Calculations The NIR-CI data cubes were processed using the chemical imaging software ISys (version 3.5.0) provided by the instrument vendor. The R-cubes were background corrected to reflectance (R) and converted to log10(1/R) or absorbance, followed by multi-step pretreatments including masking, wavelength interpolation (mathematically change the wavelength interval from 10 to 5 nm), standard normal variate (SNV) normalization and S. Golay smoothing (filter length ¼ 9, filter order ¼ 2). Then the 1D- or 2D-cubes were obtained by applying the S. Golay 1st (filer length ¼ 9, filter order ¼ 2; for quantitative analysis of the API) or 2nd (filter length ¼ 9, order ¼ 3; for qualitative and quantitative analysis of water) derivative algorithms. Each of the 1D- or 2D-cube contained 241 single wavelength images. Principal Component Analysis (PCA) To perform PCA for hydrated tablets, the 2D-cubes were converted to TS-cubes by truncating the 2nd derivative spectra using a wavelength range of 1230– 1500 nm. Six principal components were used in the analysis. An S-cube was obtained for each hydrated tablet, which contained six PCA score images.
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hydrated tablet after PLS prediction, which contained one concentration image.
RESULTS AND DISCUSSION The main focus of this work is on developing methods for measuring radial dimensions of the gel layer and tablet core, characterizing the glassy to rubbery transition of the hydrophilic polymer, and quantifying API and relative water contents in hydrated matrix tablets using single wavelength images, as well as PCA and PLS algorithms based on NIR CI data. Hydration kinetics of the PR tablets is also briefly discussed. Determination of Gel Layer and Tablet Core Dimensions by Single Wavelength Images Figure 1A is a single wavelength image (at 1380 nm, 1st overtone of water) derived from the 2D-cube of HYD1. The image shows the radial cross section of the hydrated tablet. Based on the amount of water, three distinctive regions are present in the image: the yellow-to-red colored region represents the gel layer (high amount of water); the light-blue colored ‘‘ring’’
Partial Least Squares Regression (PLS) For quantitative analysis of the API in hydrated tablets (e.g., HYD1 ¼ 1 h hydration), a PLS calibration model was built. To build the model, first the 1Dcube of an API drug substance sample was converted to a TS-cube (wavelength range 2000–2350 nm), which was then further converted to a TP-cube with a size of 2 mm 1 mm (FOV) to simplify chemometrics calculations without causing increased errors in prediction. This cube was used as a calibration sample for establishing the PLS model. For PLS prediction of hydrated tablets, the 1D-cubes were converted to TS-cubes (wavelength range 2000– 2350 nm) before applying the PLS calibration model. A C-cube was obtained for each hydrated tablet after PLS prediction, which contained one concentration image. For quantitative analysis of water in hydrated tablets, the 2D-cube of a HYD12 tablet (12 h hydration) was first converted to a TS-cube (wavelength range 1230–1500 nm), which was then further converted to a TP-cube with a size of 2 mm 1 mm (FOV). This cube was used as a calibration sample with the assumption of 100% hydration for establishing the PLS calibration model. For PLS prediction of relative water content in hydrated tablets, the 2D-cubes of hydrated tablets were converted to TS-cubes (wavelength range 1230–1500 nm) before applying the PLS calibration model. A C-cube was obtained for each DOI 10.1002/jps
Figure 1. Single wavelength image (A) and the corresponding 2nd derivative spectra (B) of a 1-h hydrated PR tablet (HYD1) showing the gel layer (in yellow to red), swelling area (in light blue), and tablet core (in dark blue). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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represents the classic swelling/diffusion fronts9 (medium amount of water); the dark-blue colored region represents the tablet core (low amount of water). There are three distinctive groups of NIR spectra corresponding to the three regions. A small set of spectra from each region, colored accordingly, are presented in Figure 1B. This simple method based on single wavelength images can be used for determining thickness of the gel layer and size of the remaining tablet core in hydrated tablets. The method for deriving the suitable TP-cubes for measuring the gel layer and tablet core dimensions are described in the Experimental Section. Each pixel is equivalent to a distance of 0.035 mm. This method is generally applicable to swellable matrix tablets. However, the method does not adequately characterize the classic swelling/ diffusion fronts in the hydrated matrix tablets. In addition, the spectra in the light blue region do not explain the chemical and physical changes at the swelling/diffusion fronts. More suitable methods are needed for those purposes. Determination of the PPT Zone by PCA For further investigation of the classic swelling/ diffusion fronts, PCA was conducted according to the procedure described in the Experimental Section. The TS-cubes (wavelength range 1230–1500 nm) were derived from the 2D-cubes of hydrated tablets and used for PCA. Each of the TS-cubes contained 55 single wavelength images (one every 5 nm). PCA is a dimension-reduction algorithm that can be used to describe variances in a large collection of spectrumbased images. Variances in the pixel-specific spectra are re-expressed using only a few latent variables or principal components (PCs). These PCs are ranked according to the total percentage of spectral variances that they explain and they are orthogonal to each other. A set of loading vectors and scores are calculated for each PC. The results are presented using score images. For the same sample HYD1, three PCs were needed to account for 99% of the variances in the TS-cube. The results were saved as an S-cube, which contained six score images (only the first three are meaningful), each corresponding to a PC. As expected, score images of PC1 and PC2 described the gel layer and core (images not shown here), respectively. The score image of PC3 (Fig. 2A), however, shows a red-colored ring that is not present in the single wavelength image (Fig. 1A). This region is believed to be related to the glassy-to-rubbery phase transfer of the polymer HPMC, which has been proposed in the literature.9 The loading plots in Figure 3B support this conclusion. It should be pointed out that the loading plots are not necessarily equivalent to NIR spectra. Nevertheless, they may contain the same explainable information. The JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
Figure 2. PC3 score image (A), loading plots (B), and loading plot of PC03 compared with 2nd derivative spectra of API, MCC, and HPMC (C) after principal component analysis performed for HYD1. The red colored area in (A) showing the polymer phase transition from the glassy state to rubbery state.
loading plot of PC1 (in black, associated with the gel layer) shows a band at 1385 nm, which can be attributed to the 1st overtone of water. On the other side, the loading plot of PC2 (in blue, associated with the core) shows a band at 1460 nm, which can be attributed to the ROH functional groups in HPMC (and MCC). Interestingly, the 1460 nm band is not present in the loading plot of PC1, indicating completion of the hydration process for HPMC in DOI 10.1002/jps
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Figure 3. Determination of API concentration profiles: (A) concentration image of HYD1, and (B) the corresponding 1st derivative spectra in tablet core (in yellow to red), at the swelling front (light blue), and in the gel layer (dark blue) for HYD1; (C) 1st derivative spectra of the API, MCC, and HPMC; (D) the expanded API concentration profiles at the swelling front for samples HYD1, 2, 3, 4, and 6.
the gel layer. The loading plot of PC3 (in red) does have the 1460 nm band as well as a shifted water band at 1400 nm, indicating the transition of the hydrophilic polymer from the glassy state to rubbery state. Figure 2C compares the loading plot of PC3 with 2nd derivative spectra of the API, MCC, and HPMC. The PC3 loading plot and spectrum of HPMC show good alignments in peaks and troughs (e.g., the valleys at 1430 and 1480 nm) but significant differences in band intensities, which further support the notion regarding the PPT. Difference between the NIR spectra in Figure 1B and the corresponding loading plots in Figure 2B implies that the PPT zone shown in Figure 2A cannot be easily detected using single wavelength images. Even the more powerful PLS regression method is not suitable simply because of the difficulty in identifying suitable calibration samples. Determination of API Concentration Profiles by PLS PCA was able to detect the PPT zone in hydrated matrix tablets. In this section, a PLS model is used DOI 10.1002/jps
for quantitative determination of API concentration profiles, particularly at the classic swelling/diffusion fronts. The calibration model was based on a sample of authentic drug substance in a powder form (see the Experimental Section for details). Therefore, the model is intended for quantifying API in the solid core and other regions where solid drug substance is still present. The model is not applicable for API dissolved in water. A spectra range of 2000– 2350 nm was chosen to minimize the impact of the strong water bands (the first overtone at 1400 nm and the combination band at 1900 nm). Again the same sample HYD1 is used to demonstrate the PLS method and the concentration image is presented in Figure 3A, which shows three distinctive regions: the yellow-to-red colored region demonstrates nominal concentration of API in the core; the light-blue colored ring shows a lower API concentration in the region; a blue-colored gel layer shows absence of the API. Three small sets of spectra were obtained from the 1D-cube of HYD1, colored accordingly to represent the three locations (Fig. 3B). Spectra from the core show a strong absorption band at 2145 nm that is JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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specifically related to the API. This band shows lower intensity in spectra of the swelling/diffusion fronts and is not present in spectra of the gel layer. First derivative spectra of neat components, including the API, MCC, and HPMC, are shown Figure 3C. The features of the spectra show significant differences between the API and excipients, which ensure specificity of the calibration model. To closely look at API concentration profiles in the light-blue region, the TP-cubes were derived from the C-cubes of samples HYD1, 2, 3, 4, and 6. The average API concentrations were obtained according to the method described in the Experimental Section. The plots in Figure 3D demonstrate API concentration profiles (w/w, %) in the light-blue region for tablets with different degree of hydration. These plots span the distance between the edge of the core where the API concentrations start to decrease consistently and the edge of the gel layer where the (w/w, %) API concentrations (in solid state) reach zero. The distance varied from 0.6 mm (HYD1) to 1.4 mm (HYD6). For tablets suspended in water for more than 6 h, the API concentration profiles in the abovementioned region became noisy and difficult to measure. It should be pointed out that Figure 3A does not show a color gradient to human eyes in the light-blue region, which implies that the classic methods had their limitations. On the contrary, the NIR CI methods allow more objective data analysis. Figure 3D can be used to define the spectrum-based swelling front, which is intuitively set at the point of distance ¼ 0. This front has an obvious physical meaning and can be measured accurately. On the other side, it is not obvious to define the diffusion front based on the NIR CI/PLS results because diffusion may happen at any point along the curves in Figure 3D. More work is needed to see if the diffusion front needs to be separately defined. Determination of Relative Water Concentration by PLS Another important aspect in characterizing hydrated matrix tablets is quantitative analysis of water, which affects the drug release in many different ways. In developing a PLS model for this purpose, identifying suitable calibration samples was not straightforward: first, the amount of water in the hydro-gel of a fully hydrated tablet may be not constant; secondly, the amount of water in hydrated tablets is difficult to quantify due to the mass exchanges between the hydrated tablets and water. In this study, an HYD12 sample was arbitrarily selected, which was assumed to have reached 100% hydration. With this assumption, the method was developed to evaluate the relative water concentration in different regions of a hydrated tablet. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
Figure 4. Determination of relative water concentration: (A) concentration image of sample HYD1; (B) relative water concentration profiles of samples HYD1, 3, 6, and 10.
The PLS model was created using the procedures described in the Experimental Section. A C-cube was generated for each sample analyzed. Figure 4A shows a concentration image of the same sample HYD1. Interestingly, only two colored regions can be observed for HYD1: the yellow-to-red colored region shows the gel layer (high amount of water); the blue colored region shows the tablet core (low amount of water). The classic swelling/diffusion fronts are not clearly shown in this image. To closely look at water profiles across the entire tablet, the TP-cubes were derived from the C-cubes of HYD1, 3, 6, 10, and the average water concentration profiles were obtained according to the method described in the Experimental Section. Figure 4B shows the relative water concentration profiles of these tablets. There are a few interesting observations from Figure 4B: (a) water content in the gel layer is relatively constant, indicating the rate of hydration is faster than the rate of water penetration; (b) the relative water content in the core is relatively low but it increases with time, probably because of penetration of water vapor; (c) a very steep gradient of water concentration between the core and gel layer is observed for HYD1, which explains the observations in Figure 4A. The gradient becomes more moderate for samples HYD6 and 10. DOI 10.1002/jps
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Front Movement Kinetics In the aforementioned discussions, the results from single wavelength images, PCA and PLS regressions were described without considering their interrelationships. With the available imaging analysis software, it is feasible not only to apply multiple chemometric algorithms on the same data cube for assessing different attributes of the same sample, but also to coordinate the data analysis and presentation pixel by pixel. This is because every pixel in a data cube has its own coordinates and the pixel-specific information can be easily accessed and compared even though different chemometric algorithms have been used. To take this advantage, Figure 5 overlays the relative water concentration, API concentration, and PPT zone to demonstrate physical changes within the hydrated tablets (samples HYD 1, 3, and 6). In all cases, the water penetration front and polymer transition region seems to move in a synchronized fashion. The plots also indicate that the dissolution of API happens in the PPT zones, which becomes much broader for the 6 h sample (Fig. 5C). Plots in Figure 6A demonstrate increase of the gel layer thickness (in blue), decrease of the tablet core size (in red), and dimensional change of the PPT zone with time. A liner relationship can be observed between the dimensional changes of gel layer and tablet core versus hydration time in the first 7 h. The gel layer thickness and core size data were obtained from the C-cubes of API concentration profiles after the PLS predictions. Each data point shown in Figure 6 was the average of three individual determinations. The tablet core disappeared after 10 h. The PPT zone, determined by the PCA method, shows a steady increase in dimension for the first 4 h and then levels off. As pointed out by other researchers, these results are critical for understanding drug release of the PR tablets.1,9,10,14 Details on how to relay these observations to drug release behavior of the product (e.g., through dissolution testing) are out of the scope of this article and will be discussed in a separate publication. Plots in Figure 6B demonstrate the relative water content in the gel layer and tablet core as a function of time. During the hydration study, it was observed that the tablet retained its shape for up to at least 24 h. It is expected that as the hydration time increases, the hydro-gel will slowly lose its strength. Interestingly, Figure 6B does not show a dramatic change in relative water content in the gel layer for tablets suspended in water for up to 10 h. On the other side, relative water content in the tablet core increased from about 10% to 40% (relative to the water content in the gel layer). After 10 h, the tablet core became very small and materials in the core DOI 10.1002/jps
Figure 5. Overlay of API concentration profile, relative water concentration profile, and the PPT zone for samples (A) HYD1, (B) HYD3, and (C) HYD6.
became loose but maintained their solid state. Studies are on-going to develop PLS models for measuring absolution concentration of water in hydrated tablets. The information will enable calculation of locationspecific API concentrations for better understanding and modeling of drug release from the matrix-based pharmaceutical products. The absolution method will also enable quantitative measurement and comparison of physical properties among matrix tables with different polymer compositions and drug release characteristics. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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mechanisms of swellable matrix tablets, which will result in the design, development, and manufacture of better prolonged release pharmaceutics.
REFERENCES
Figure 6. Dimensional change of the gel layer, tablet core, and PPT zone (A), as well as relative water concentration in the gel layer and tablet core (B) as a function of hydration time.
CONCLUSION NIR CI in combination with chemometric data analysis is a powerful tool for characterization and quantitative analysis of hydrated matrix tablets. Dimensions of the gel layer and tablet core can be accurately measured using single wavelength images and PLS regression. Phenomenon of the glassy– rubbery phase transfer of the hydrophilic polymer can be detected and visualized by PCA. API concentration profiles can be used to define a more meaningful polymer swelling front. Relative concentration of water in the gel layer, at the swelling front, and in the core can be determined by PLS regression. The introduction of these methods should facilitate studies on better understanding of drug release
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1. Colombo P, Gazzaniga A, Caramella C, Conte U, La Manna A. 1987. In vitro programmable zero-order release drug delivery system. Acta Pharm Technol 33:15–20. 2. Konard R, Christ A, Zessin G, Cobet U. 1998. The use of ultrasound and penetrometer to characterize the advancement of swelling and eroding fronts in HPMC matrices. Int J Pharm 163:123–131. 3. Thomas N, Windle AH. 1978. Transport of methanol in poly(methylmethacrylate). Polymer 19:255–265. 4. Gao P, Meury H. 1996. Swelling of hydroxypropyl methylcellulose matrix tablets. 1. Characterization of swelling using a novel optical imaging method. J Pharm Sci 52:1145–1149. 5. Moussa IS, Lenaerts V, Cartilier LH. 1998. Image analysis studies of water transport and dimensional changes occurring in the early stages of hydration in cross-linked amylose matrices. J Control Rel 52:63–70. 6. Weisenberg LA, Koenig JL. 1990. An NMR imaging study of methanol desorption from partially swollen PMMA rods. Macromolecules 23:2454–2459. 7. Rajabi-Siahboomi AR, Bowtell RW, Mansfield P, Henderson A, Davies MC, Melia CD. 1994. Structure and behavior in hydrophilic matrix sustained release dosage forms: 2. NMR-imaging studies of dimensional changes in the gel layer and core of HPMC tablets undergoing hydration. J Control Release 31: 121–128. 8. Mills PJ, Palmstrom CJ, Kramer EJ. 1986. Concentration profiles of non-Fickian diffusants in glassy polymers by Rutherford backscattering spectrometry. J Mater Sci 21:1479–1486. 9. Colombo P, Bettini R, Santi P, De Ascentiis A, Peppas NA. 1996. Analysis of the swelling and release mechanisms from drug delivery system with emphasis on drug solubility and water transport. J Control Release 39:231–237. 10. Ferrero C, Munoz-Ruiz A, Jimenez-Castellanos MR. 2000. Fronts movement as a useful tool for hydrophilic matrix release mechanism elucidation. Int J Pharm 202:21–28. 11. Li W, Woldu A, Kelly R, McCool J, Bruce R, Rasmussen H, Cunningham J, Winstead D. 2008. Measeurement of drug agglomerates in powder blending simulation samples by near infrared chemical imaging. Int J Pharm 350:369–373. 12. Lee E, Huang WX, Chen P, Lewis EN, Vivlecchia RV. 2006. High throughput analysis of pharmaceutical tablet content uniformity by near-infrared chemical imaging. Spectroscopy 21:22. 13. Roggo Y, Jent N, Edmond A, Chalus P, Ulmschneider M. 2005. Characterizing process effects on pharmaceutical solid forms using near-infrared spectroscopy and infrared imaging. Eur J Pharm Biopharm 61:100–110. 14. Lee PI, Kim C. 1991. Probing the mechanisms of drug release from hydrogels. J Control Release 16:229–236.
DOI 10.1002/jps