Drug Mobilization from Lescol XL Tablets Using Two-Dimensional

Brief Article pubs.acs.org/molecularpharmaceutics

Direct Visualization of in Vitro Drug Mobilization from Lescol XL Tablets Using Two-Dimensional 19F and 1H Magnetic Resonance Imaging Chen Chen, Lynn F. Gladden, and Michael D. Mantle* Department of Chemical Engineering & Biotechnology, University of Cambridge, Cambridge, CB2 3RA, United Kingdom S Supporting Information *

ABSTRACT: This article reports the application of in vitro multinuclear (19F and 1H) two-dimensional magnetic resonance imaging (MRI) to study both dissolution media ingress and drug egress from a commercial Lescol XL extended release tablet in a United States Pharmacopeia Type IV (USP-IV) dissolution cell under pharmacopoeial conditions. Noninvasive spatial maps of tablet swelling and dissolution, as well as the mobilization and distribution of the drug are quantified and visualized. Two-dimensional active pharmaceutical ingredient (API) mobilization and distribution maps were obtained via 19F MRI. 19F API maps were coregistered with 1H T2-relaxation time maps enabling the simultaneous visualization of drug distribution and gel layer dynamics within the swollen tablet. The behavior of the MRI data is also discussed in terms of its relationship to the UV drug release behavior. KEYWORDS: magnetic resonance imaging, 19F MRI, USP-IV dissolution, radial FLASH, RARE, controlled release, multinuclear coimaging

1. INTRODUCTION For extended release drug delivery systems, pharmacopoeial dissolution testing becomes increasingly important as it is not only vital for quality control but also critical for formulation screening and bioequivalence evaluation.1,2 Currently, most dissolution studies are conducted using commercially available dissolution apparatus by following the protocols on local pharmacopoeias.3 However, the fundamental chemistry and physics that occur within a solid dosage form when subject to drug dissolution testing is not well understood as it is affected by many factors, such as excipient formulation, active pharmaceutical ingredients (API) properties, and manufacturing/processing conditions.2,3 A sound physical understanding of the mechanisms involved in polymer swelling and dissolution is a vital step toward developing comprehensive mathematical models, leading to more accurate predictions of the drug release kinetics from polymer matrices.4−6 Various characterization and imaging methods have been developed to investigate the drug release behavior, for example, NIR spectroscopy,7,8 FTIR spectroscopic imaging,9,10 Raman mapping,11,12 UV imaging,13,14 and magnetic resonance imaging (MRI).15,16 Among these, localized nuclear magnetic resonance (NMR) spectroscopy and magnetic resonance imaging (MRI) techniques are well-established tools for noninvasive investigations of pharmaceutical systems in situ.16−22 Magnetic resonance provides quantitative information, that is, water concentration,20,23−25 water self-diffusivity,20,24,26 and polymer concentration,24,26 as well as API diffusivity and concentration22,27 during the whole drug release process, so that these parameters © 2013 American Chemical Society

can be used in formulation design and for testing the mathematical models describing the kinetic processes of drug release.5 In pharmaceutical compounds, fluorine has become a widespread and important component, as its introduction affects physical, adsorption, distribution, metabolism, and excretion properties of a lead compound.28 The percentage of fluorinated compounds in the pharmaceutical market has increased from 2% in 1970 to 18% in 2000. Currently, around 20% of all the pharmaceutical products contain at least one fluorine atom, including three of the top ten best sellers: Pfizer’s cholesterol lowering medicine, Lipitor, TAP’s proton pump inhibitor Prevacid, and GSK’s asthma treatment Seretide.28−30 Another example of a successful commercial fluorinated pharmaceutical is the cholesterol lowing agent Lescol which contains fluvastatin (sodium) as its API. An extended release (8 h) tablet formulation, Lescol XL, is available containing 80 mg of fluvastatin for oral administration. The extended release formulation results in better patient compliance and lower incidence of systemic adverse events.31 Recently Dahlberg et al. published results from spatially resolved 19F, 2H, and 1H NMR and MRI experiments examining model hydroxypropyl methylcellulose (HPMC) tablet disintegration and showed that the API recrystallization Received: Revised: Accepted: Published: 630

July 15, 2013 November 8, 2013 December 17, 2013 December 17, 2013 dx.doi.org/10.1021/mp400407c | Mol. Pharmaceutics 2014, 11, 630−637

Molecular Pharmaceutics

Brief Article

Figure 1. Two-dimensional slice selective 19F signal intensity maps of the tablet at different hydration times. FOV (field of view) = 25 mm × 25 mm, pixel resolution = 391 μm × 391 μm, slice thickness = 2.5 mm, temporal resolution = 13 min per image.

w/w), potassium bicarbonate (2.5% w/w), and Povidone (1.5% w/w). The tablet is coated with Opadry yellow (a polyvinyl alcohol based polymer). The tablet has a diameter of 10 ± 0.1 mm and thickness of 4.0 ± 0.2 mm. The dissolution media used in the experiments was 500 mL of 0.01 M phosphate buffer solution (PBS, pH = 7.4) prepared from a powder sachet (Sigma-Aldrich, USA). Following the method of Zhang et al., a standard USP-IV flow-through dissolution cell (i.d. 22.6 mm) (Sotax, Switzerland) was used for the tablet dissolution study under flowing conditions at 37 °C.27 A peristaltic pump (205S, Watson Marlow, USA) was used in the experiment, and the flow rate was set to 8 mL/min (see Supporting Information S1). Note the complete release of Lescol XL in this in vitro study is significantly longer than “8 h” stipulated by the manufacturer, which is based on in vivo study results. The accelerated drug release rate in vivo is due to the distinctive pH environments, ionic strength, mechanical stresses, and potential food effects in the GI tract. Following the method of Chen et al., a T2-pRARE (T2preconditioned Rapid Acquisition with Relaxation Enhancement) pulse sequence was used to acquire the quantitative spin−spin relaxation time (T2) maps of the dissolving tablet.24 The 1H T2-pRARE experiment was performed under flowing conditions at all times (8 mL/min). For these conditions the 1 H T2 images in the flowing regions outside the outer gel layer boundary are essentially insensitive to any flow related artifacts (see Supporting Information S2). The free water−gel layer was determined using histogram plots of the 1H T2 values from the 1 H T2-pRARE imaging data with T2 values above 3000 ms being assigned to free water and those below to the gel layer (see Supporting Information S2). 19F API images were acquired by FLASH (Fast Low Angle Shot) pulse sequences (echo time = 1.086 ms).32 A small excitation angle, 10°, is used to allow faster recovery of magnetization and reduction of repetition time to 100 ms. 128 scans were taken to achieve a reasonable signal-to-noise ratio (SNR). To further improve the SNR of the 19 F images, a radial coverage of k-space strategy was adopted, rather than the conventional Cartesian sampling strategy.33 Images were reconstructed using a filtered back projection method with a Ram-Lak filter.34,35 19F Radial FLASH was chosen over both 19F T2-pRARE imaging and conventional 19F

was related to the local hydration level and local mobility of the polymer matrix.22 They concluded that the amorphous drug could recrystallize over the course of dissolution either by nanoparticulate coalescence or via the ripening of crystalline grains.22 Zhang et al. were the first to publish both 19F and 1H MRI results using a commercial USP-IV dissolution apparatus under biorelevant conditions to study the behavior of dissolution media ingress and drug egress during the dissolution testing of Lescol XL tablets. One-dimensional (1D) MR 19F profiling was used to follow the mobilization and solubilization of fluvastatin within the solid dosage. The integrated 19F signal intensity was also correlated with the cumulative drug concentration release curve measured using inline UV−vis spectroscopy.27 While 1D 19F magnetic resonance profiling showed that solubilization and subsequent mobilization of the API correlated well with the UV−vis determined API release curves, it provided only limited insights into the drug release mechanisms from within the dosage form. This article augments the work of Zhang et al., and for the first time provides a detailed two-dimensional (2D) visualization of in situ drug behavior within the dosage form during dissolution test. This has been achieved by exploiting both 19F and 1H 2D slice selective MR imaging. In particular, we described how 19F MR imaging can be used to visualize the mobilization of sodium fluvastatin within a Lescol XL tablet during dissolution in a United States Pharmacopeia type IV (USP-IV) dissolution apparatus under biorelevant conditions. Co-registration of the 19F images with 1H T2-relaxation time images show the spatial location of the solubilized drug and its relationship to the gel layer formed within the Lescol XL tablet during dissolution. Moreover, the drug release profile obtained by conventional UV spectroscopy shows an anomalous release mechanism, which is discussed with respect to the MR observations.

2. MATERIALS AND METHODS A commercially available Lescol XL 80 mg tablet (Novartis, Switzerland) is an extended release formulation for the active ingredient fluvastatin sodium (84.24 mg, which corresponds to 80 mg of fluvastatin free acid). The other excipients used in the formulation include HPMC (K100LV, 30% w/w), microcrystalline cellulose (33% w/w), hydroxypropyl cellulose (5% 631

dx.doi.org/10.1021/mp400407c | Mol. Pharmaceutics 2014, 11, 630−637


Brief Article

Figure 2. Quantitative two-dimensional spin−spin relaxation time (T2) maps of the tablet at different hydration times. FOV = 25 mm × 25 mm, pixel resolution = 391 μm × 391 μm, slice thickness = 1 mm, temporal resolution = 3 min per image. Each image is taken approximately 10 min before that of Figure 1. Note that different color scales were used for the top and bottom rows to highlight the gel structure at different hydration times. 19

Cartesian FLASH imaging as it gave a superior signal-to-noise ratio for the imaging time chosen (13 min). A comparison of these three imaging techniques is shown in Figure S3 of the Supporting Information. For both 1H and 19F images, a 64 (x-read) × 64 (y-phase) data array was acquired with a field of view of 25 mm × 25 mm, yielding an in-plane pixel resolution of 391 μm × 391 μm. The slice thickness of 1H and 19F images are 1 mm and 2.5 mm, respectively. The difference in slice thickness did not affect the interpretation of the results (see Supporting Information S4). The temporal resolutions of 1 H and 19 F images are approximately 3 min and 13 min, respectively. For the particular formulation investigated, this study shows that the swelling and dissolution of the tablet is slow enough that the morphological change of the tablet within 13 min imaging time is minimal (see Supporting Information S4). The drug release profile was measured online with an ultraviolet/visible (UV−vis) spectrophotometer (Spectronic Unicam, UK) with a quartz cell (path length = 10 mm). At predetermined intervals, absorption was measured at a wavelength of 303 nm at a resolution of 1 nm, and the concentration of fluvastatin in solution was calculated using a prepared calibration curve (linearity checked between 0.01 mmol/L and 0.5 mmol/L). The measurements were carried out using VisionLite software (Thermo Scientific). Three repetitions were taken to take the average. The visual coregistration of MR images was completed using open source software ImageJ_Fiji (NIH, USA) (see Supporting Information S5).

F signal detected in these experiments arises solely from the dissolved (mobilized) fluvastatin drug that is held within the hydrated Lescol XL gel layer.27 No detectable signal can be attributed to the drug dissolved in the flowing media due to inflow/outflow (washout effects) of the dissolution media from the active slice within the MRI radio frequency coil. This is consistent with the study of Dahlberg et al., in which it is observed that the signal intensity of the dissolved flutamide in dissolution media is negligible.22 Also, no signal is detected from the solid state API in the dry core of the tablet due to the short T2* it possesses.22,27 Thus, the 19F images obtained can be uniquely used to monitor the dissolution, subsequent mobilization, and hence distribution of the nonsolid state API within the swelling polymeric matrix. FLASH imaging protocols are by their very nature essentially insensitive to T1 relaxation effects at low excitation flip angles (here 10°),36 and thus there will be little if any T1 contrast present in the 19F images shown here. 19F Bulk T1 measurement of the fluvastatin in Lescol XL tablet using a standard inversion recovery pulse sequence showed it to be essentially constant at approximately 500 ms over the dissolution period (see Supporting Information S6). Absolute quantification of the 19 F signal in terms of its relationship to actual fluvastatin concentration in this study is complicated not only by T2* relaxation contrast due to magnetic susceptibility differences at phase boundaries but also by the fact the we cannot access the pure API on its own to perform calibration tests. At present we cannot quantify T2* effects, and further extensive work is required to address this issue. However the 19F radial FLASH imaging was performed at the minimum possible echo time (1.086 ms) on our equipment and thus represents optimal conditions. As fluvastatin is not freely available it is not directly possible to assess the limits of detection (LOD) of the 19F signal from the fluvastatin in these experiments. However we have performed experiments on another similar 19F containing drug at a range of absolute concentrations (see Supporting Information S3) which show that for the acquisition parameters

3. RESULTS AND DISCUSSION 3.1. 19F API Mapping in Two Dimensions during Dissolution. Figure 1 shows the temporal evolution of the solubilization/mobilization of the 19F fluvastatin API within the system. We stress that while the system is surrounded by 1H containing PBS solution only the signals from 19F nuclei of the API are detected.22,27 Similar to the findings of Zhang et al., the 632



Brief Article

Figure 3. 19F and 1H coregistered maps of the tablet at different hydration times. FOV = 25 mm × 25 mm, pixel resolution = 391 μm × 391 μm, temporal resolution = 3 min (1H) and 13 min (19F), slice thickness = 1 mm (1H) and 2.5 mm (19F).

used in this study, radial FLASH can detect 19F concentrations between 30 and 45 mg/mL (or 0.011−0.017 mg/voxel). In the 19F API maps, the bright green areas correspond to the dissolved (mobilized) fluvastatin residing within the gel layer. At t = 1 h, a well-resolved “ring-like” structure surrounding the tablet is observed and corresponds to the accumulation of dissolved API. From t = 1−8 h, the dry core (shown as black areas within the ring structure) becomes more diffuse as more water penetrates into the dry core of the tablet and subsequently hydrates the API. From t = 8 h to t = 90 h the average 19F signal intensity starts to decrease due to (1) the dilution of local API concentration as a result of the increase in area and (2) the fact that API is constantly diffusing out of the gel layer into the surrounding flowing dissolution medium. In addition, from t = 13 h, the increase of the dark areas visible toward the center of the tablet corresponds to the air bubbles that are released during the dissolution process in agreement with the observations of Zhang et al.27 From t = 23 h, the circumference and intensity of the 19F signal decreases as the hydrated drug continues to diffuse in all directions within the gel layer and ultimately out into the bulk solution. After 90 h, no more 19F API signal is visible corresponding to complete release of API. 3.2. 1H PBS (Water) T2-Relaxation Time Imaging during Dissolution. To give complementary mechanistic insights into the fluvastatin drug release dynamics from Lescol XL tablet and the behavior of the water within the tablet, we now introduce the spatial distribution of water 1H T2-relaxation time images that highlight the location of the gel layer within the dosage form during the drug release process.27 Figure 2 shows a similar time series of 1H T2-relaxation time images from the exactly the same sample as that of Figure 1, where the difference in time (time offset) between each sequential 1H and 19 F image is approximately 10 min. As discussed by Zhang et al. the 1H images show three distinct regions: (i) the free-flowing dissolution medium as a high T2 relaxation time (depicted by the white region) surrounding the tablet and (ii) water that has penetrated the Lescol XL tablet as regions of blue and red (iii) dry core where the T2 relaxation time of the solid matrix is typically of the order of a few tens of micro seconds and thus cannot be

measured by the T2-pRARE technique. The dry core is specifically colored in gray for better contrast and has been determined by setting, to zero value, any pixels with a value lower than the five times the standard deviation of pure noise taken from the Fourier transform of the raw T2-pRARE image data. Note that at t = 13 h and t = 23 h, the gray area corresponds to the air bubbles trapped in the gel rather than the dry core, as the air void within the gel system shows no signal.25 Collectively the 1H images show a gel layer being formed with time that increases steadily in size up to t = 23 h. At times greater than 23 h there is little increase in the physical dimensions of the tablet, but an increase in surface roughness between the outer edge of the gel layer and free-flowing dissolution medium is evident in agreement with the observations of Zhang et al.27 Lighter areas (shown as red color) in the 1H images from t = 49 h to t = 107 h are due to three-dimensional ruptures in the gel layer that allow inhomogeneous liquid dissolution medium ingress into the tablet structure.37 Note the swelling tablet is restricted by the wall of the dissolution apparatus after 49 h upon dissolution, which may in turn affect the drug release rate. 3.3. 19F API and 1H T2-Relaxation Time Coregistered Map. In order to gain a better understanding of the physical behavior and interplay between water (1H) ingress and drug (19F) egress, a coregistration of the 19F drug images (Figure 1) with the 1H T2 relaxation time images (Figure 2) is shown in Figure 3. The merged images show the ingress of water into the tablet and egress of the API from the tablet simultaneously. Such information is critical to understand how the evolution of tablet structures affects the distribution of drug within the tablet. At t = 0.5 h, no 19F signal is observed, and the 1H T2 remains below detection limit of the T2-pRARE method24,27 indicating no significant water ingress due to the protection provided by the tablet coating, i.e. the API and excipients have yet to be significantly hydrated. After 2.5 h, substantial 19F signal from hydrated API is observed due to significant water penetration with simultaneous gel swelling, as seen from the coregistered 1 H T2 relaxation time map. Note for t = 1.0 and 2.5 h the “grey” dry core area shown in Figure 2 and the central “black” region encircled by the inner boundary of green pixels from the 19F 633



Brief Article

images, should also, within the LOD of 19F already discussed, have an equivalent size. However, the slightly smaller size of the black inner dry core visible in Figure 3 when compared with the equivalent gray dry core area shown in Figure 2 is likely due to the fact that reconstructed 19F radial FLASH data have a broader point spread function than the Cartesian sampled 1H T2-pRARE images.33 From t = 8 h onward, it is seen that the rate of increase in size of the gel layer has “overtaken” that of the API mobilization, and a clear distinction between the API outer boundary and gel layer is now visible where a significant proportion of the outer gel region is now depleted with respect to the API. The API “depletion region” increases in size as the gel expands. This is consistent with the findings reported by Dahlberg et al. from their 1D 19F and 1H profiling studies. They also observed that the dissolved API (flutamide in their study) is “left behind” by the “expanding and weakening” gel.22 In the coregistered maps (t = 13 and 23 h), it is seen the black dots from both 1H and 19F maps at the center of tablet match each other, which corresponds to the trapped air bubbles in the gel structure. Note that the color of API turns from green to light blue/cyan over the course of dissolution due to the merging of two RGB color schemes (see Supporting Information S5). Dahlberg et al. also investigated crystalline form of the API during drug release process by tracking the temporal evolution of bulk T1 and T2.22 We adopted a similar approach and found that highly soluble fluvastatin (sodium) does not recrystallize during the drug release process (see Supporting Information S6). 3.4. UV Drug Release Profiles. Figure 4 shows the in-line drug release profile of fluvastatin to the surrounding solution,

from HPMC compressed matrices under different pH and temperature.43 Escudero et al. used both the Korsmeyer− Peppas model and the Peppas−Sahlin model to rationalize the release of theophylline from HPMC-based matrices.46 In light of these recent studies, numerical fitting of the drug release profile in this study to the Korsmeyer−Peppas model35 shows the drug release adopts an anomalous release mechanism, which has been previously described by a combination of Fickian and Case II relaxation mechanisms together.5,48 The drug release data presented here are then analyzed in more detail using the heuristic model proposed by Peppas and Sahlin:49 Mt = k1t m + k 2t 2m M∞

(1)

where the first term k1t is the Fickian contribution, adopting a transport mechanism by which the drug release is primarily controlled by Fickian diffusion (F). The second term k2t2m is the Case-II relaxation contribution, which conveys the extent of drug released that is controlled by the relaxation of the polymeric chains (R). In this paper the exponent m has the value of m = 0.45 assuming a cylindrical shape of the Lescol XL tablet,49 and k1 and k2 are the release constants. Because this equation is derived with an assumption of “sink conditions”, that is, the drug solubility is five to ten times of the dissolved drug concentration,1 the first 60% of a full release curve is normally used in literature for numerical fitting and is adopted in this analysis. The release parameters of Lescol XL are summarized in Table 1. m

Table 1. Summary of Fitting Parameters to Peppas−Sahlin Model for Dataa Presented in Figure 1 m

2m

(Mt)/(M∞) = k1t + k2t

m

k1

k2

r2

0.45

0.052

0.012

0.996

a

Note that only 60% of the data (t = 0 to t = 72 h) was used for numerical fitting.

The ratio of relaxation (R) and Fickian (F) contributions is calculated as49 k R = 2 tm F k1 Figure 4. Drug release profile of fluvastatin from the Lescol XL obtained by UV spectroscopy. The error bars on the UV data were standard deviations derived from three repetitive measurements.

(2)

The Peppas−Sahlin equation and hence the correlation of the R/F ratio with drug release time have been extensively used to describe the drug release process and to elucidate the associated release mechanism.5,44,49−54 The Fickian and relaxation behavior of Lescol XL tablets are summarized in Figure 5. The results show that R/F ratio increases from 0 to 1.2 over 40 h upon dissolution, which corresponds to 60% of complete drug release. The significant change of R/F ratio suggests that the contribution of a Fickian like diffusion mechanism rapidly decreases, while polymer relaxation (and hence gel layer formation) plays an increasingly important role in the drug release process. The release mechanism shift, from Fickian like diffusion control to polymer relaxation (and hence gel layer) control, can be corroborated by the combined 2D MRI results obtained. In the first 1 h, the drug diffusion front matches closely with the thin gel layer front (Figure 3), indicative of good source/sink conditions for a Fickian like drug diffusion mechanism at this stage (R/F < 0.23 in Figure 5). From t = 1 h to t = 8 h, along with the rapid expansion of the gel layer, a gel

monitored by in-line UV spectroscopy measurements. The observed release rate in this study is comparable to that reported by Zhang et al., though in their study, fasted state simulated intestinal fluid (FaSSIF) and simulated gastric fluid (SGF) were used instead of PBS to mimic the GI tract environment. Zhang et al. also reported the drug release profile of fluvastatin from Lescol XL tablet in pure deionized water at 37 °C.38 The reported release rate is significantly slower than when using PBS, FaSSIF, and SGF, indicating the ionic strength and pH of the dissolution media plays a critical role in determining the release rate. Numerous recent studies of drug release from hydrophilic matrix use numerical fitting to empirical models to rationalize drug release mechanisms.39−47 Ferrero et al. used the Korsmeyer−Peppas model to characterize the caffeine release 634



Brief Article

two distinct regions: (i) between 8 < t < 25 h; and (ii) between 25 < t < 100 h. The average drug release rates of these two regions are 1.25 mg/h and 0.5 mg/h. The likely reason for this can again be explained by the switch from a diffusion controlled drug release process to a polymer relaxation controlled process as was shown in Figure 5. Before 25 h, Fickian diffusion is the dominant mechanism (R/F < 1), suggesting that the release rate is closely dependent on the API concentration gradient between the tablet and the dissolution media. The continuous release of API results in a decreasing concentration gradient, which leads to a rapid release rate decrease. On the other hand, after 25 h, polymer relaxation becomes the dominant process (R/F > 1), which means the release rate is less dependent on the API concentration gradient but more dependent on the relaxation process of the swollen polymer. Thus, the release rate decrease is slower at this stage. The two distinct release rate regions (i) and (ii) identified from the UV data Figure 6b are not evident in the 19F integrated MR signal intensity where a steady decrease in integrated 19F API signal is seen. There are two main reasons as to why these two different release rate regions are not evident from the MRI data: (1) due to the 19F MR limits of detection already discussed the 19F data have a much larger error than the calculated UV release data; and (2) the integrated 19F signal has not been corrected for T3* due to reasons already discussed.

Figure 5. Values of relaxation/Fickian (R/F) ratio as a function of drug release time based on eq 2.

layer becomes visible which is depleted in API. Because of this “depletion zone”, the source condition of API at the outer edge of the gel layer is no longer maintained as the API now has to diffuse further through the evolving gel layer to be subsequently released into the surrounding (sink) dissolution medium. Hence, the gel layer begins to significantly hinder the drug release by providing a physically larger distance, thereby providing an additional barrier to mass transport. Polymer relaxation starts to contribute to a greater extent at this stage, resulting in a rapid increase of R/F to 0.6 (Figure 5). After t = 8 h, the gel layer of the Lescol XL tablet is well-formed (Figure 3); the continuous physical expansion of the gel layer contributes to the further increase of R/F. After 26 h upon dissolution, R/F ratio exceeds 1, indicating that polymer relaxation, instead of diffusion, becomes the dominant factor controlling the drug release. Figure 6 compares the drug release data monitored by UV spectroscopy and the integrated 19F 2D MRI signal. Note the drug release rate in Figure 6b is calculated from the time derivative of the cumulative release data (a). In addition to the previous discussion regarding empirical drug release models, the UV drug release data can also be correlated with the integrated 19F MRI data. Figure 6a shows that the integrated 19 F MRI signal rapidly reaches a maximum at t = 8 h and then decreases at a steady rate to within the noise level at t = 100 h. Figure 6b, compares the rate of API release calculated from the cumulative UV drug release data with the rate of change of MRI signal and shows two interesting features: (1) the calculated UV drug release rate shows reaches a maximum at the same point in time as the maximum of the integrated 19F MRI signal at t = 8 h; (2) From t = 8 h onward the UV release rate curve shows

4. CONCLUSIONS In this study, the dissolution behavior of a commercial extended release formulation (Lescol XL 80 mg) in a USP-IV dissolution cell under pharmacopeial conditions was investigated. 19F FLASH techniques with radial coverage of k-space were used to obtain 2D images of the distribution of the fluorinated API (fluvastatin). These were correlated to the behavior of the tablet gel layer via simultaneous 2D 1H T2-relaxation time imaging. The results presented here are, to our best knowledge, the first report of 2D 19F imaging of the in vitro drug release process of a commercial tablet formulation. Co-registration of 19F and 1H images showed the visualization of drug egress and water ingress into the polymer matrix simultaneously. Collectively, these results give a more comprehensive understanding of the morphological changes of Lescol XL and provide new insights and information into drug release mechanisms that augment our interpretation of the conventional drug release profile obtained by UV−vis spectroscopy.

Figure 6. A comparison of the integration of the 19F 2D MRI signals with (a) cumulative drug release profiles monitored by UV and (b) the drug release rate calculated from the UV data in a. The error bar on MRI signals corresponds to the standard deviation of the noise. 635



■

Brief Article

(17) Melia, C. D.; Rajabi-Siahboomi, A. R.; Bowtell, R. W. Magnetic resonance imaging of controlled release pharmaceutical dosage forms. Pharm. Sci. Technol. Today 1998, 1, 32−39. (18) Richardson, J. C.; Bowtell, R. W.; Mäder, K.; Melia, C. D. Pharmaceutical applications of magnetic resonance imaging (MRI). Adv. Drug Delivery Rev. 2005, 57, 1191−209. (19) Metz, H.; Mäder, K. Benchtop-NMR and MRI–a new analytical tool in drug delivery research. Int. J. Pharmaceutics 2008, 364, 170−5. (20) Dorożyński, P. P.; Kulinowski, P.; Młynarczyk, A.; Stanisz, G. J. MRI as a tool for evaluation of oral controlled release dosage forms. Drug Discovery Today 2012, 17, 110−23. (21) Nott, K. P. Magnetic resonance imaging of tablet dissolution. Eur. J. Pharm. Biopharm. 2010, 74, 78−83. (22) Dahlberg, C.; Dvinskikh, S. V.; Schuleit, M.; Furó, I. Polymer swelling, drug mobilization and drug recrystallization in hydrating solid dispersion tablets studied by multinuclear NMR microimaging and spectroscopy. Mol. Pharmaceutics 2011, 8, 1247−56. (23) Hyde, T. M.; Gladden, L. F.; Payne, R. A nuclear magnetic resonance imaging study of the effect of incorporating a macromolecular drug in poly (glycolic acid-co-?-lactic acid). J. Controlled Release 1995, 36, 261−275. (24) Chen, Y. A. Y.; Hughes, L. P.; Gladden, L. F.; Mantle, M. D. Quantitative Ultra-Fast MRI of HPMC Swelling and Dissolution. J. Pharm. Sci. 2010, 99, 3462−3472. (25) Dahlberg, C.; Millqvist-fureby, A.; Schuleit, M.; Furó, I. Relationships between solid dispersion preparation process, particle size and drug release–an NMR and NMR microimaging study. Eur J Pharm Biopharm 2010, 76, 311−9. (26) Dahlberg, C.; Fureby, A.; Schuleit, M.; Dvinskikh, S. V.; Furó, I. Polymer mobilization and drug release during tablet swelling. A 1H NMR and NMR microimaging study. J. Controlled Release 2007, 122, 199−205. (27) Zhang, Q.; Gladden, L. F.; Avalle, P.; Mantle, M. D. In vitro quantitative ((1))H and ((19))F nuclear magnetic resonance spectroscopy and imaging studies of fluvastatin in Lescol XL tablets in a USP-IV dissolution cell. J. Controlled Release 2011, 156, 1−30. (28) Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 2007, 317, 1881−6. (29) Bégué, J.-P.; Bonnet-Delpon, D. Recent advances (1995−2005) in fluorinated pharmaceuticals based on natural products. J. Fluor. Chem. 2006, 127, 992−1012. (30) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.; Begue, J.P.; Daniele, B.-D. Bioorganic and Medicinal Chemistry of Fluorine; Wiley: New York, 2008; Vol. 37, pp 320−30. (31) Barilla, D.; Prasad, P.; Hubert, M.; Gumbhir-Shah, K. Steadystate pharmacokinetics of fluvastatin in healthy subjects following a new extended release fluvastatin tablet, Lescol XL. Biopharm. Drug Dispos. 2004, 25, 51−9. (32) Haase, A.; Frahm, J.; Matthaei, D.; Hänicke, W.; Merboldt, K.D.; Hanicke, W. FLASH imaging. Rapid NMR imaging using low flipangle pulses. J. Magn. Reson. 1986, 67, 258−266. (33) Haacke, E. M.; Brown, R.; Thompson, M.; Venkatesan, R. Magnetic resonance imaging: physical principles and sequence design; J. Wiley & Sons: New York, 1999. (34) Mistretta, C. a; Wieben, O.; Velikina, J.; Block, W.; Perry, J.; Wu, Y.; Johnson, K. Highly constrained backprojection for timeresolved MRI. Magn. Reson. Med. 2006, 55, 30−40. (35) Block, K. T.; Uecker, M.; Frahm, J. Undersampled radial MRI with multiple coils. Iterative image reconstruction using a total variation constraint. Magn. Reson. Med. 2007, 57, 1086−98. (36) Callaghan, P. T. Principles of nuclear magnetic resonance microscopy; Oxford University Press: Oxford, U.K., 1993. (37) Dahlberg, C.; Millqvist-Fureby, A.; Schuleit, M.; Furó, I. Polymer-drug interactions and wetting of solid dispersions. Eur. J. Pharm. Sci. 2010, 39, 125−33. (38) Zhang, Q. NMR and MRI Studies of Controlled Release Drug Delivery Systems; University of Cambridge: Cambridge, U.K., 2012; p 218.

ASSOCIATED CONTENT

S Supporting Information *

Schematics of the experimental setup, T2 maps of Lescol XL tablets at different hydration times, SNR images, 19F signal intensity maps, merge of RGB color schemes and example of the co-registration process, and evolution of 19F bulk T1 and T2 of the fluvastatin during drug release process. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +44-1223-766325. Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS M.D.M. and L.F.G. wish to thank the EPSRC for funding under Platform Grant (EP/F047991/1). REFERENCES

(1) Jennifer, D.; Kraemer, J. Pharmaceutical dissolution testing; Taylor & Francis Group: London, 2005. (2) Azarmi, S.; Roa, W.; Löbenberg, R. Current perspectives in dissolution testing of conventional and novel dosage forms. Int. J. Pharmaceutics 2007, 328, 12−21. (3) Dressman, J.; Krämer, J. Pharmaceutical dissolution testing; Taylor and Francis Group: London, 2005. (4) Siepmann, J.; Siepmann, F. Mathematical modeling of drug delivery. Int. J. Pharmaceutics 2008, 364, 328−43. (5) Siepmann, J.; Peppas, N. A. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv. Drug Delivery Rev. 2001, 48, 139−57. (6) Kaunisto, E.; Abrahmsen-Alami, S.; Borgquist, P.; Larsson, A.; Nilsson, B.; Axelsson, A. A mechanistic modelling approach to polymer dissolution using magnetic resonance microimaging. J. Controlled Release 2010, 147, 232−241. (7) Avalle, P.; Pygall, S. R.; Gower, N.; Midwinter, A. The use of in situ near infrared spectroscopy to provide mechanistic insights into gel layer development in HPMC hydrophilic matrices. Eur. J. Pharm. Sci. 2011, 43, 400−408. (8) Avalle, P.; Pygall, S. R.; Pritchard, J.; Jastrzemska, A. Interrogating erosion-based drug liberation phenomena from hydrophilic matrices using near infrared (NIR) spectroscopy. Eur. J. Pharm. Sci. 2013, 48, 72−79. (9) Kazarian, S. G.; van der Weerd, J. Simultaneous FTIR spectroscopic imaging and visible photography to monitor tablet dissolution and drug release. Pharm. Res. 2008, 25, 853−60. (10) Wray, P. S.; Clarke, G. S.; Kazarian, S. G. Dissolution of tabletin-tablet formulations studied with ATR-FTIR spectroscopic imaging. Eur. J. Pharm. Sci. 2013, 48, 748−57. (11) Gordon, K. C.; McGoverin, C. M. Raman mapping of pharmaceuticals. Int. J. Pharmaceutics 2011, 417, 151−62. (12) Sasić, S. Raman mapping of low-content API pharmaceutical formulations. I. Mapping of Alprazolam in Alprazolam/Xanax tablets. Pharm. Res. 2007, 24, 58−65. (13) Østergaard, J.; Meng-Lund, E.; Larsen, S. W.; Larsen, C.; Petersson, K.; Lenke, J.; Jensen, H. Real-time UV imaging of nicotine release from transdermal patch. Pharm. Res. 2010, 27, 2614−23. (14) Østergaard, J.; Ye, F.; Rantanen, J.; Yaghmur, A.; Larsen, S. W.; Larsen, C.; Jensen, H. Monitoring lidocaine single-crystal dissolution by ultraviolet imaging. J. Pharm. Sci. 2011, 100, 3405−3410. (15) Mantle, M. D. Quantitative magnetic resonance micro-imaging methods for pharmaceutical research. Int. J. Pharmaceutics 2011, 417, 173−95. (16) Mantle, M. D. NMR and MRI studies of drug delivery systems. Curr. Opin. Colloid Interface Sci. 2013, 18, 214−227. 636



Brief Article

(39) Jamzad, S.; Tutunji, L.; Fassihi, R. Analysis of macromolecular changes and drug release from hydrophilic matrix systems. Int. J. Pharmaceutics 2005, 292, 75−85. (40) Kiortsis, S.; Kachrimanis, K.; Broussali, T.; Malamataris, S. Drug release from tableted wet granulations comprising cellulosic (HPMC or HPC) and hydrophobic component. Eur. J. Pharm. Biopharm. 2005, 59, 73−83. (41) Baumgartner, S.; Pavli, M.; Kristl, J. Effect of calcium ions on the gelling and drug release characteristics of xanthan matrix tablets. Eur. J. Pharm. Biopharm. 2008, 69, 698−707. (42) Cahyadi, C.; Chan, L. W.; Colombo, P.; Heng, P. W. S. The butterfly effect: a physical phenomenon of hypromellose matrices during dissolution and the factors affecting its occurrence. Int. J. Pharmaceutics 2011, 406, 31−40. (43) Ferrero, C.; Massuelle, D.; Jeannerat, D.; Doelker, E. Towards elucidation of the drug release mechanism from compressed hydrophilic matrices made of cellulose ethers. III. Critical use of thermodynamic parameters of activation for modeling the water penetration and drug release processes. J. Controlled Release 2013, 170, 175−182. (44) Vendruscolo, C. W.; Andreazza, I. F.; Ganter, J. L. M. S.; Ferrero, C.; Bresolin, T. M. B. Xanthan and galactomannan (from M. scabrella) matrix tablets for oral controlled delivery of theophylline. Int. J. Pharmaceutics 2005, 296, 1−11. (45) Escudero, J. J.; Ferrero, C.; Jiménez-Castellanos, M. R. Compaction properties, drug release kinetics and fronts movement studies from matrices combining mixtures of swellable and inert polymers: effect of HPMC of different viscosity grades. Int. J. Pharmaceutics 2008, 351, 61−73. (46) Escudero, J. J.; Ferrero, C.; Jiménez-Castellanos, M. R. Compaction properties, drug release kinetics and fronts movement studies from matrices combining mixtures of swellable and inert polymers. II. Effect of HPMC with different degrees of methoxy/ hydroxypropyl substitution. Int. J. Pharmaceutics 2010, 387, 56−64. (47) Avalle, P.; Pygall, S. R.; Pritchard, J.; Jastrzemska, A. Interrogating erosion-based drug liberation phenomena from hydrophilic matrices using near infrared (NIR) spectroscopy. Eur. J. Pharm. Sci. 2013, 48, 72−79. (48) Korsmeyer, R. W.; Gurny, R.; Doelker, E.; Buri, P.; Peppas, N. A. Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharmaceutics 1983, 15, 25−35. (49) Peppas, N.; Sahlin, J. A simple equation for the description of solute release. III. Coupling of diffusion and relaxation. Int. J. Pharmaceutics 1989, 57, 169−172. (50) Colombo, P.; Catellani, P.; Peppas, N. Swelling characteristics of hydrophilic matrices for controlled release new dimensionless number to describe the swelling and release behavior. Int. J. Pharmaceutics 1992, 88, 99−109. (51) Bettini, R.; Colombo, P.; Massimo, G.; Catellani, P. L.; Vitali, T. Swelling and drug release in hydrogel matrices: polymer viscosity and matrix porosity effects. Eur. J. Pharm. Sci. 1994, 2, 213−219. (52) Ferrero, C.; Bravo, I.; Jiménez-Castellanos, M. R. Drug release kinetics and fronts movement studies from methyl methacrylate (MMA) copolymer matrix tablets: effect of copolymer type and matrix porosity. J. Controlled Release 2003, 92, 69−82. (53) Ozyazici, M.; Gökçe, E. H.; Ertan, G. Release and diffusional modeling of metronidazole lipid matrices. Eur. J. Pharm. Biopharm. 2006, 63, 331−9. (54) Wu, W. D.; Liu, W.; Selomulya, C.; Chen, X. D. On spray drying of uniform silica-based microencapsulates for controlled release. Soft Matter 2011, 7, 11416.

637


Drug Mobilization from Lescol XL Tablets Using Two-Dimensional

Recommend Documents