Identifying the mechanisms of drug release from amorphous solid dispersions using MRI and ATR-FTIR spectroscopic imaging.

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Contents lists available at ScienceDirect

International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

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Identifying the mechanisms of drug release from amorphous solid dispersions using MRI and ATR-FTIR spectroscopic imaging Katerina Pun9 cochová a,c , Andrew V. Ewing b , Michaela Gajdošová a , Nina Sarvašová a , pánek a, * Sergei G. Kazarian b, ** , Josef Beránek c , František Šte a b c

Department of Chemical Engineering, University of Chemistry and Technology Prague, Technická 3, 166 28 Prague 6, Czech Republic Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom Zentiva, k.s., U Kabelovny 130, Prague 10, Czech Republic

A R T I C L E I N F O

A B S T R A C T

Article history: Received 13 January 2015 Received in revised form 10 February 2015 Accepted 12 February 2015 Available online xxx

The dissolution mechanism of a poorly aqueous soluble drug from amorphous solid dispersions was investigated using a combination of two imaging methods: attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging and magnetic resonance imaging (MRI). The rates of elementary processes such as water penetration, polymer swelling, growth and erosion of gel layer, and the diffusion, release and in some cases precipitation of drug were evaluated by image analysis. The results from the imaging methods were compared with drug release profiles obtained by classical dissolution tests. The study was conducted using three polymeric excipients (soluplus, polyvinylpyrrolidone – PVP K30, hydroxypropylmethyl cellulose – HPMC 100M) alone and in combination with a poorly soluble drug, aprepitant. The imaging methods were complementary: ATR-FTIR imaging enabled a qualitative observation of all three components during the dissolution experiments, water, polymer and drug, including identifying structural changes from the amorphous form of drug to the crystalline form. The comparison of quantitative MRI data with drug release profiles enabled the different processes during dissolution to be established and the rate-limiting step to be identified, which – for the drug– polymer combinations investigated in this work – was the drug diffusion through the gel layer rather than water penetration into the tablet. ã 2015 Elsevier B.V. All rights reserved.

Keywords: FT-IR spectroscopy Magnetic resonance imaging Solid dispersion Dissolution rate Water penetration Spray drying

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1. Introduction

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There is a growing need to understand the stability and dissolution properties of dosage forms containing poorly watersoluble drugs (Siepmann et al., 2002) where the enhancement of dissolution rate is often achieved by forming an amorphous solid dispersion of the drug in a water-soluble polymer. Conventional dissolution testing of pharmaceutical formulations determines drug release from tablets or capsules based on measuring the concentration of the active pharmaceutical ingredient (API) in the dissolution medium as a function of time. Although this provides information about the overall rate of drug release, there is limited information about the underlying mechanism (Dressman et al., 1998) and the elementary phenomena that occur in the hydrated

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* Corresponding author. Tel.: +420 220 443 236. ** Corresponding author. Tel.: +44 20 7594 5574. E-mail addresses: [email protected] (S.G. Kazarian), pánek). [email protected] (F. Šte

tablet and in the diffusion boundary layer. Polymer hydration and dissolution rates can significantly influence the release rate of the API (Harland et al., 1988). The drug release from a polymer matrix involves several elementary processes (Fig. 1), namely water ingress, polymer swelling, drug diffusion and polymer chain disentanglement or erosion (Siepmann et al., 1999), each of which can in principle be rate-determining for the macroscopically observed drug release. The choice of suitable candidates (polymers, additives) for a pharmaceutical formulation should therefore be guided by the understanding of the dissolution mechanism and Q2 knowledge of the rate-limiting step during dissolution. After sufficient contact with water, a dry glassy polymer transforms into a wet rubbery state and molecules become relatively mobile. This transition creates a gel layer (Miller-Chou and Koenig, 2003). The gel layer is characterized by a concentration gradient of water, polymer and API, whereby the viscosity and chemical structure of the polymer regulates the penetration rate of the dissolution medium into the tablet and the diffusion and release rate of API from the tablet. There are important consequences of the positions and movement of the wetting front

http://dx.doi.org/10.1016/j.ijpharm.2015.02.035 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.

Please cite this article in press as: Pun9cochová, K., et al., Identifying the mechanisms of drug release from amorphous solid dispersions using MRI and ATR-FTIR spectroscopic imaging. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.02.035

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Fig. 1. Elementary processes and possible mechanisms of drug release from a swellable tablet compressed from spray-dried particles (solid dispersion of API in polymer). 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89

(a front between the dry core and the hydrated polymer), the diffusion front (a front between undissolved and dissolved API) and the erosion front (a front between the gel layer and the bulk dissolution medium). The position of the diffusion front in the gel layer during dissolution is related to the local drug dissolution rate in the gel (Colombo et al., 2000) and its diffusion transport through the gel, both of which depend on the local extent of polymer swelling. For a fast-diffusing, well-soluble API, the diffusion front can coincide with the wetting front and thus the rate of drug release would be controlled by that of water ingress. At the other limit, for an extremely slow-diffusing and/or poorly soluble API, the diffusion front can coincide with the erosion front and the rate of drug release would depend on the disentanglement rate of the polymer. In between these two limiting scenarios, the diffusion front lies within the gel layer and the rate of drug release would be controlled by the drug diffusion through the gel. Thus, the evolution of the gel-layer thickness and the positions of the different fronts directly determine the observed release rate of the API. However, conventional dissolution tests do not enable direct observation of phenomena in the gel layer. Several imaging-based analytical approaches are used nowadays to aid the investigation of the physical and chemical processes of dissolution, including attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging (Kazarian and Ewing, 2013; Van der Weerd and Kazarian, 2005), magnetic resonance imaging (MRI) (Mikac et al., 2011), UV imaging (Niederquell and Kuentz, 2014; Østergaard et al., 2010) and Raman spectroscopy (Windbergs et al., 2009). These techniques use different principles of measurement and provide different information about the mechanism of dissolution (Wray et al., Q3 2013); thus, using a combination of these approaches is often necessary in order to obtain a complete picture. ATR-FTIR imaging has a significant advantage of providing chemically specific information about the components within the formulation. It can simultaneously collect thousands of infrared spectra in a single measurement by using a focal plane array (FPA) detector. This provides information about the relative concentration of the individual components within the measured area. Hence, the spatial distribution of each component in a dissolving tablet can be shown in the resulting chemical images (Kazarian and Van der Weerd, 2008). Moreover, ATR-FTIR imaging can be used to study the stability of amorphous solid dispersions during dissolution. The structural changes of an amorphous form of a drug can be affected depending on the polymer present (Ewing et al., 2014; Chan and Kazarian, 2004). A possible limitation of ATR-FTIR spectroscopic imaging is the need to physically press the tablet against the ATR crystal. This can influence the observed rates of water penetration and gel layer formation because the tablet is in between the ATR crystal (at the bottom) and the dissolution cell

(on the top) meaning the dissolution media only contacts the sides of the tablet. On the other hand, in vitro MRI studies can be used to non-invasively measure the properties which influence drug release such as water penetration, polymer swelling and formation of the gel layer (Richardson et al., 2005). These two chemical imaging approaches have been used in combination to study the aggregation of asphaltenes, however not for the studies of pharmaceutical systems to date (Gabrienko et al., 2015). The aim of this work was to investigate the physical and chemical processes of dissolution in a detailed way using a combination of imaging methods, ATR-FTIR imaging and MRI, along with classical dissolution test, focusing on water penetration, polymer swelling, drug diffusion and precipitation, in order to explain the mechanisms during tablet dissolution and identify the major steps that affect drug release. Specifically, the release of a poorly water-soluble drug, aprepitant, from solid dispersion formulations containing several polymers (soluplus, polyvinylpyrrolidone – PVP K30, hydroxypropylmethyl cellulose - HPMC 100 M) was investigated. The results from the MRI and ATR-FTIR imaging methods were compared both qualitatively and quantitatively, and combined with the results from classical dissolution tests. The mechanisms of dissolution and the effect of different types of formulations have been explained.

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2. Materials and method

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2.1. Chemicals used

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The drug aprepitant (3-{[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluoro-phenyl)morpholin-4-yl] methyl}-4,5-dihydro-1H-1,2,4-triazol-5-one) was kindly provided

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Table 1 Structural formula and physico-chemical parameters of aprepitant (Knox et al., 2011).

Aprepitant

Molecular weight (g/mol) 534.4

Melting point ( C) 244–246

logP pKa 4.5

3.5, 9.6

Water solubility (20 C) (mg/ml) 0.02

Please cite this article in press as: Pun9 cochová, K., et al., Identifying the mechanisms of drug release from amorphous solid dispersions using MRI and ATR-FTIR spectroscopic imaging. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.02.035

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by Zentiva, k.s. (Prague, Czech Republic). Aprepitant is an antiemetic drug; its structural formula and physico-chemical characteristics are summarized in Table 1. Three different polymers were used as excipients. Poly(vinylpyrrolidone) K30 (PVP, molar weight Mw = 30 000 g/mol and glass transition temperature Tg = 164 C), obtained from BASF (Germany), is a water soluble polymer often used for increasing the dissolution rate of the active ingredient and improving the bioavailability of many poorly water soluble drugs (Gupta et al., 2004). Soluplus (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer, Mw = 90,000–140,000 g/mol, Tg = approx. 70 C), obtained from BASF (Germany), is a novel solubility enhancing excipient that contains both hydrophilic and hydrophobic parts and is capable of micelle formation in a solution (Linn et al., 2012). Hydroxypropylmethyl cellulose (HPMC, Mw = 90,000 g/mol, Tg = approx. 184 C) 100 M obtained from Shandong Head Co., Ltd., is a water-soluble cellulose ether derivative which is commonly used in the preparation of controlled release tablets. Its hydration and gel forming abilities are used to control drug release (Siepmann et al., 1999).

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2.2. Sample preparation

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The solid dispersions were prepared by spray drying, a solvent evaporation method based on the spraying of dissolved drug and polymeric carrier into the flow of heated inert gas to remove the solvent and create spherical micro-particles (Dhirendra et al., 2009). To form the starting solution, aprepitant (0.5–1.0 g) was dissolved in absolute ethanol, the solution was mixed at 40 C for about 15 min, and the required amount of polymer was then added to achieve a drug:polymer ratio of 1:3 w/w on a dry basis. After complete dissolution of the polymer, the solution was spray dried using the mini spray dryer B-290 (Buchi, Switzerland) with an inert loop. The temperature inside the drying chamber was kept at 77–78 C. The solid dispersion thus obtained was stored in vials in a freezer to reduce the risk of the drug crystallization during storage.

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2.3. Dissolution tests

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Conventional dissolution tests, similar to the United States Pharmacopeia (USP) standards, were carried out in order to complement the imaging studies and to determine the differences in the release rate of the API from solid dispersions in different polymers into the bulk. The dissolution tests were performed on both powder (to expose the supersaturated concentration and precipitation) and tablet samples (to provide direct comparison with imaging methods). Throughout this manuscript, “tablet” refers to experimental compacts formed directly from solid dispersion powders or from powders mixed with a disintegrant in the laboratory, i.e., these are not commercially formulated tablet

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products. Dissolution from powder was conducted by adding 160 mg of the spray-dried particles to 150 ml of dissolution medium. The dissolution media were aqueous buffers at pH 6.8 with 0.001% (w/v) Tween 20 and pH 2 with 0.001% (w/v) Tween 20. The rotational speed was 75 rpm and the dissolution profile was measured at 37 C. Dissolution from tablets was conducted by adding 160 mg tablets compacted at 8 kN from the spray dried powder and from spray dried powder mixed with 27.5% w/w disintegrant croscarmellose to 150 ml of pure water. The dissolution profile was measured at laboratory temperature. The concentration of aprepitant in the solution was determined using HPLC at predetermined time points.

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2.4. ATR-FTIR spectroscopy

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The Nicolet iZ10 Fourier transform infrared (FTIR) module with a ZnSe ATR accessory was used to measure single mid-IR spectra of the pure components and solid dispersions to determine the unique band of each component. Each spectrum represented 64 co-added scans measured with a spectral resolution of 4 cm 1 in the 3700–800 cm 1 range.

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2.5. ATR-FTIR spectroscopic imaging

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A continuous scan spectrometer Equinox (Bruker) mid-IR imaging system in ATR mode was used. The spectrometer used the Golden GateTM ATR imaging accessory (Specac) with a diamond internal reflection element (IRE) used in the IMAC macrochamber of the instrument. The FTIR images were acquired with FPA detector, composed of 64 64 individual elements (pixels). Each spectrum represented 32 co-added scans with at a spectral resolution of 8 cm 1. The image size was 635 mm 525 mm. ATRFTIR spectroscopic images were produced by plotting the distribution of integrated absorbance of the selected characteristic spectral bands of each component aprepitant, polymer and water. The high and low areas of absorbance are related to the relative concentration of the components and are represented by a color scale in the images, where the red/pink areas represent high concentration and blue areas represent low concentration areas. The generation of chemical images is illustrated in Fig. 2. The in situ dissolution behavior of pure polymers and solid dispersions was studied using a specifically designed flow cell that fits to the diamond IRE accessory (Van der Weerd and Kazarian, 2005). Tablets were formed in situ by direct compression of the Q4 spray-dried powder. Tablets were compacted at 120 cNm; they were cylindrical with a diameter of 3 mm and a mass of 21 mg. The dissolution medium was water at a flow rate of 5 ml/min and room temperature. Once water was added, consecutive FTIR images were acquired at 2 or 5 min intervals. FTIR spectroscopic images show the edge of the tablet to observe the positions of different dissolution fronts.

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Fig. 2. Schematic illustration of the generation of chemical images obtained by ATR-FTIR spectroscopy using an FPA detector. Each pixel of the detector measured a single Q8 spectrum corresponding to a particular location in the sample. The distribution of intergrated absorbance of characterisatics band for each compound was then plotted for all pixels to produce chemical images. (For interpretation of the references to color in the text, the reader is referred to the web version of this article.)


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Fig. 3. (a) Scheme of the MRI measurement set-up with a flow cell installed in the imaging coil, (b) example of a single slice of a partially swollen tablet inside the flow cell, (c) photograph of the flow cell.

Fig. 4. Example of image processing and evaluation of front movement. (a) Movement of the PVP erosion front and (b) water penetration front evaluated from a time series of ATR-FTIR images. (c) Movement of the water penetration front evaluated from MRI images (d) in the case of Soluplus.


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Fig. 5. Dissolution profiles of aprepitant from powders for solid dispersions with polymers soluplus and PVP, measured in (a) pH 2 solution (good solubility) and (b) pH 6.8 solution (poor solubility).

Fig. 6. Dissolution profiles of aprepitant from tablets for solid dispersions with polymers soluplus and PVP, measured in pure water. (a) Tablets formed by direct compression of solid dispersions, (b) tablets compressed from solid dispersions mixed with a disintegrant.

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2.6. Magnetic resonance imaging

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The MRI desktop system icon (Bruker), containing a cryogenfree 1 Tesla permanent magnet, was used in conjunction with a custom-built flow cell. MRI analysis was based on multi-slicemulti-echo (MSME) sequences of pulses where the concentration of mobile hydrogen protons was measured. The images were weighted by relaxation times T2. The echo time was 16 ms, repetition time 500 ms, number of averages 6, number of repetitions 1. The resolution of the images was 96 96 pixels for a field of view 1.5 cm 1.5 cm. The scheme of the MRI measurement set-up and the flow cell containing a tablet is illustrated in Fig. 3. The tablet was placed into the flow cell and fixed by a holder to prevent its movement in the flow of the dissolution medium. The holder was designed so as to minimize its contact area with the tablet. The first scan was used to localize the position of the tablet in the flow cell and choose the number, position and thickness of slices. An example of a single slice is shown in Fig. 3b. The scans were taken every 5 min and the dissolution medium (water) flow rate and temperature were identical to those used in the ATR-FTIR imaging.

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2.7. Image processing and analysis

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The images were analyzed using the software ImageJ (Rasband 1997–2014). The positions of the wetting and the erosion fronts, as

well as the widths of the gel layer were determined from the images as illustrated in Fig. 4. Taking PVP as an example (Fig. 4a and b), the distribution of PVP was obtained using its unique band 1295–1345 cm 1, whereas the band between 3300–3000 cm 1 was used to generate the FTIR chemical images for the distribution of water. A similar procedure was used for the evaluation of other components. The images were converted to 8-bit gray-scale levels such that a value of 0 corresponds to no component present in a given pixel and a value of 255 corresponds to a pure component (e.g., water) in the pixel. A series of line plots (typically 10) positioned at different locations perpendicular to the tablet edge was then generated from each image and the position of the corresponding front (e.g., the water penetration front) was defined by the coordinate of the first pixel on each line plot in which the gray-scale level exceeded a set threshold value. The threshold value was chosen as gfront = gmin + k(gmax – gmin) where gmin is the average gray-scale intensity of a line-segment positioned entirely in a component-poor area (e.g., dry core) and gmax is the average gray-scale intensity of a line-segment positioned entirely in a component-rich area (e.g., water surrounding the tablet). The value of k was chosen manually depending on the level of noise in the data, but was fixed for each time series. For example, a value of k = 0.05 would mean a threshold level 5% above the baseline that corresponds to zero concentration. The mean and the standard deviation of the front position were then evaluated from the 10 line-plots for each time interval.

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Fig. 7. Comparison of dissolution kinetics of pure polymers as indicated in the legend, evaluated from ATR-FTIR images (a) water penetration, (b) polymer erosion. The points are measured data, the lines represent linear regression. In all cases the front position is given as the relative distance from the original edge of the dry tablet (given as 0.0 mm). 261

3. Results and discussion

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3.1. Classical dissolution tests

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The dissolution rates of aprepitant:PVP and aprepitant:soluplus solid dispersions (produced by spray drying) were investigated first in the powder form and then in the form of tablets. The amorphous nature of the solid dispersions was confirmed by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis – see Supplementary Information. The dissolution from powder simulates the theoretical case of infinitely fast tablet disintegration. Aprepitant is not only a poorly water-soluble drug (class II according to the Biopharmaceutics Classification System (BCS) criteria), but also exhibits pH-dependent solubility. The dissolution tests were therefore carried out in both neutral and acidic pH, namely at pH 6.8 where aprepitant is poorly soluble and at pH 2 where aprepitant has a relatively higher solubility (Wu

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Table 2 Summary of erosion and water penetration rates evaluated for the three polymers by two imaging methods as indicated in the table. Erosion rate (ATR- Water penetration rate FTIR) (mm/h) (ATR-FTIR) (mm/h) 0.68 0.04 PVP Soluplus 0.33 0.02 HPMC 0.08 0.005

0.80 0.02 0.49 0.05 0.19 0.01

Water penetration rate (MRI) (mm/h) – 0.74 0.02 0.46 0.01

Fig. 8. Comparison of water penetration rates into the tablets made of pure polymers, evaluated by ATR-FTIR Imaging and MRI in the case of (a) soluplus and (b) HMPC.

et al., 2004). The dissolution profiles are shown in Fig. 5 with absolute concentrations on the y-axis (rather than the usual fraction of drug released) to highlight the difference in solubility in different pH environments. At pH 2 (relatively good drug solubility), the nature of the polymer does not appear to have much of an effect. The solid dispersion with soluplus shows initially a slightly slower dissolution rate, with a gradual release of API, which eventually achieves a higher concentration of dissolved API and appears to continue beyond 90 min of dissolution. The release from the PVP solid dispersion is initially faster but seems to attain a lower asymptotic value. This would indicate an initially faster hydration rate of PVP and a solubilisation effect of soluplus, respectively. At pH 6.8 (poor drug solubility), there is stark difference between drug release profiles from the two polymers. The solid dispersion of aprepitant:PVP achieves a very low asymptotic concentration already after 15 min (note: that the mass of the powder and the volume of the dissolution medium were the same as for pH 2). Soluplus significantly improves the apparent solubility of aprepitant compared to PVP. In the presence of soluplus, aprepitant achieves a maximum concentration after approx. 60 min, which is higher by almost a factor of 10 than in the case of PVP. However, this solution appears to be super-saturated with respect to aprepitant, which then begins to precipitate. This is manifested by a decrease of its concentration in the dissolution medium for times beyond 60 min (Fig. 5b).


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Fig. 9. (a) FTIR spectra of pure components used for the determination of specific band shift (1124 to 1143 cm 1) and presence of peak (1000 cm 1) confirming the crystalline form of aprepitant, (b) FTIR spectra of pure component compared to solid dispersion of aprepitant and soluplus.

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When dissolution tests at a neutral pH (i.e., conditions of poor aprepitant solubility) were carried out from tablets rather than powders, very different drug release profiles were obtained (Fig. 6). In cases where the tablets were directly compressed from the solid dispersion (Fig. 6a), drug release was extremely slow and the concentration of aprepitant barely reached measurable values at comparable times (60 min) for which its concentration had already peaked in the case of dissolution from powder. However, the release from the tablet was steady, reaching a value of approx. 2.5 mg/l after 8 h form the solid dispersion with soluplus, without precipitation. As in the case of dissolution from powder, soluplus enables a higher apprepitant concentration to be reached compared to PVP. In this case it is only by a factor of approximately 2 as opposed to a factor of 10 that was seen in the dissolution of the powder samples. The tablets did not disintegrate during the dissolution test, so aprepitant had to diffuse from the tablet through a gel layer. An intermediate scenario between dissolution from a nondisintegrating tablet and from a powder was achieved by forming tablets with a small quantity of disintegrant. The dissolution profile of aprepitant from those tablets is shown in Fig. 6b. There is a notable improvement in both the rate and the quantity of aprepitant released, which can be attributed to an enhancement of tablet wettability, manifested by extreme swelling and disintegration of the tablets. Again, the release of aprepitant is higher from the solid dispersion with soluplus compared to that with PVP (by a factor of approximately 4 in this case). Moreover, the formulation with PVP seems to reach a plateau where no more

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aprepitant is dissolving after approximately 120 min, while the drug still continues to be released from the formulation with soluplus, even after 140 min of the experiment. The study with conventional USP-type dissolution measurements revealed several trends: (i) in conditions of good API solubility, the hydrophilic polymer PVP leads to a faster initial release rate of the API; (ii) under conditions of poor API solubility, the amphiphilic polymer soluplus manifested its ability to solubilize the poorly water-soluble API. The ratio between the API concentration achieved by soluplus vs. PVP increased with decreasing disintegration time, being a factor of 2 faster for cases of no tablet disintegration, 4 faster for intermediate tablet disintegration, and 10 faster for dissolution from powder samples (infinitely fast disintegration); (iii) too fast API dissolution in the absence of diffusion across a gel layer can be detrimental to the overall dissolution due to the formation of locally supersaturated solution and precipitation of the API. While some ideas about the underlying mechanism of API dissolution and release can be inferred from the above observations, imaging methods can provide direct evidence and help confirm (or reject) assumptions made on the basis of the classical dissolution tests. An important question still remaining is whether the results from the imaging methods used, ATR-FTIR spectroscopic imaging and/or MRI, can be quantitatively correlated with the results of standard dissolution tests, and whether knowledge about the hydration, swelling and erosion of pure polymers can be used for the prediction of the API release rates.

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3.2. Dissolution kinetics of pure polymers–comparison of imaging methods

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The dissolution kinetics of pure polymers PVP, soluplus and also HPMC (as a representative of a high-viscosity hydrophilic polymer) was investigated using both imaging methods. The positions of the water penetration and polymer erosion fronts as function of time, evaluated from the ATR-FTIR images for all three polymers, are summarized in Fig. 7. The velocities of the water penetration and the polymer erosion fronts, obtained by linear regression of the data from Fig. 7, are given in Table 2. The three polymers show very different behavior during dissolution, each revealing different progress of the wetting and erosion fronts, and thus being suitable for different drug release mechanisms. Pure PVP has the fastest water penetration rate combined with the fastest dissolution rate, and essentially no swelling. The erosion front closely follows the wetting front, which means a gel layer is almost non-existent and the tablet radius shrinks from the initial contact with water. This can be explained by a hydrophilic character combined with a relatively low chain disentanglement threshold of PVP. In contrast, soluplus combines intermediate values of both wetting and disentanglement rates, which results in the gradual formation of a gel layer. However, the tablet still does not swell beyond its original perimeter. The formation of a gel layer can be important for the dissolution of poorly water-soluble drugs as the presence of the polymer at a relatively high concentration can help maintain the API in solution and inhibit its precipitation from a locally supersaturated state. Finally, HPMC 100K is a polymer with a high extent of swelling, forming a wide gel layer with an extremely slow dissolution. The swelling of the polymer is seen during the first 15 min where the gel layer expands and the tablet diameter increases, which was not the case of soluplus or PVP (Fig. 7b). The penetration of water is slightly slower, but comparable to, that of soluplus. The dissolution rate of pure polymers was also evaluated from images obtained by MRI and compared to those obtained by ATRFTIR spectroscopic imaging (Fig. 8). While the qualitative trends are the same, i.e., the rate of water penetration into soluplus is

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faster than into HPMC, there are quantitative differences between the water penetration rates obtained by each method. The slopes of the regression lines show the differences in the penetration of water to the tablet, also summarized in Table 2. Although the experimental conditions were identical (same compaction pressure, same dissolution medium and temperature), ATR-FTIR imaging shows a significantly slower penetration rate compared to that measured by MRI, by a factor of 1.5 time for soluplus and 2.4 times for HPMC. The cause of the slower water penetration rate observed in ATR-FTIR imaging experiments is most probably the fact that the tablet is physically pressed between the ATR diamond and the flow cell. The image shows a physical interface between a porous, water-wicking material (the tablet) and a non-porous, water-impermeable material (the ATR crystal), whereas in the case of MRI, the image shows a virtual slice fully immersed in the waterwicking material (the tablet). 3.3. ATR-FTIR imaging of aprepitant dissolution from solid dispersions Aprepitant has been shown to exist in three different structural forms: crystalline form I, crystalline form II, and amorphous form. As reported by Helmy et al. (2003), the crystalline and amorphous forms of aprepitant can be distinguished by infrared spectroscopy. ATR-FTIR imaging is able to observe the changes of a drug crystallinity during dissolution (Kazarian and Chan, 2003). The comparison of FTIR spectra of the amorphous and crystalline form of aprepitant is shown in Fig. 9 along with the spectra of PVP and soluplus for comparison. The crystalline form has a characteristic

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absorption band at 1000 cm 1 and a number of noticeable shifts at the lower-wavenumber region (1143 to 1124 cm 1), which do not overlap with any absorption bands of the polymers and can therefore be used as unique identification bands of aprepitant for the FTIR imaging data. The images of the dissolution of a solid dispersion containing aprepitant:soluplus (1:3) were generated by plotting the distribution of the integral absorbance of corresponding bands (1250 cm 1 for soluplus and 1110 cm 1 for aprepitant). The distribution of drug and polymer as a function of time during dissolution is shown in Fig. 10. The images of soluplus (Fig. 10a) show a continuous and smooth movement of the erosion front, which is also the case for the API. The crystalline form of the API is absent during the dissolution over the time-scale of the measurement. The gel layer releases the drug gradually and the presence of the amphiphilic polymer inhibits drug precipitation in the gel layer. The flow of the dissolution medium coupled with moderate release rate of the API ensures sink conditions and prevents the supersaturation in the solution outside of the gel layer to reach levels where the API would precipitate. The dissolution sequence for aprepitant:PVP is shown in Fig. 10b (using characteristic bands at 1410 cm 1 for PVP and 1110 cm 1 for aprepitant). In line with the behavior of pure polymer discussed in the previous section (cf. Fig. 7), the images reveal a significantly faster dissolution of PVP from the tablet edge, which is associated with a rapid initial release of the drug into solution. However, the rapid decrease of local PVP concentration in the solution adjacent to the receding tablet edge (there is no gel

Fig. 10. ATR-FTIR spectroscopic images of tablet dissolution for aprepitant:polymer solid dispersions, where the polymer is (a) soluplus and (b) PVP. Note the recrystallisation of aprepitant at 90 min in case (b) shown by the appearence of the yellow and red regions in the image. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)


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Fig. 11. FTIR spectra extracted from the area of precipitation seen in the images at 90 min of aprepitant shown in Fig. 10b. Spectral changes confirm the local recrystallization of aprepitant during the dissolution experiment. 448

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layer in this case), coupled with a high local concentration of aprepitant, leads to local super-saturation and eventually precipitation of the drug to its crystalline form shown by the appearance of the yellow and red regions in Fig. 10b at the time frame at 90 min. Thus, it can be proposed that in some cases a too fast dissolution of the polymer matrix can negatively influence the availability of a poorly water-soluble drug as it gives rise to high local supersaturation and consequently crystallization. This phenomenon can also account for and further explain the low aprepitant release observed during the classical dissolution tests (cf. Section 3.1, Fig. 5). The precipitation of the drug was confirmed by extracting FTIR spectra from the region of precipitation (the yellow and red regions in Fig 10b, frame t = 90 min). The relevant portion of the spectra is shown in Fig. 11. Initially, the absorbance decreases as a result of the dissolution process. However, when precipitation occurs, the absorbance starts to increase (phase change from solution to solid state). Moreover, the crystalline form is confirmed in the region of precipitation by the presence of a specific band 1000 cm 1 and by a shift of band from 1124 cm 1 to 1134 cm 1.

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3.4. Evaluation of front velocities from ATR-FTIR images

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The positions of the individual fronts were evaluated as function of time from the ATR-FTIR spectroscopic images and compared between the pure components and their solid dispersions. Fig. 12a shows the progress of the aprepitant dissolution front from solid dispersions in comparison to that of pure aprepitant. Since pure aprepitant is very poorly soluble in water at neutral pH, there is essentially no movement of the front corresponding to the pure drug. When aprepitant was formulated as a solid dispersion within a PVP matrix, its dissolution rate improved significantly and was initially even faster than in the case of a soluplus matrix (Fig. 12a). However, after approx. 30 min aprepitant began to precipitate and the initial slope indicative of fast drug release was no longer maintained. On the other hand, the solid dispersion with soluplus shows a gradual dissolution of aprepitant, which is sustained throughout the duration of the experiment. This is consistent with the observations made during the bulk dissolution tests (cf. Section 3.1). When comparing the erosion rate of the polymer matrix in the presence of aprepitant, there is a noticeable decrease in the erosion front velocity compared to the pure polymers in both cases, as shown in Fig. 12b for soluplus and 12c for PVP. The decrease of the polymer dissolution rate can be explained by the presence of the hydrophobic drug, which limits the surface area of polymer

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Fig. 12. Comparison of the front positions for pure components and components in solid disperisions (a) dissolution of aprepitant, (b) erosion of PVP, (c) erosion of soluplus, and (d) water ingress into a tablet. All data were evaluated from the ATRFTIR spectroscopic images.


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Fig. 13. Images of tablet dissolution obtained by MRI. (a) Aprepitant:soluplus solid dispersion, (b) aprepitant:soluplus solid dispersion with disintegrant (croscarmellose), (c) aprepitant:PVP solid dispersion, (d) aprepitant:PVP solid dispersion with disintegrant.

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effectively in contact with water. Also, the wetting properties are worse in the solid dispersions with aprepitant. Finally, the aprepitant–polymer interactions in the solid dispersion may contribute to the decrease in the dissolution rate of the polymer because they can reduce the number of functional groups that are able to interact with water. Aprepitant contains two hydrogen donors and five hydrogen acceptors that can interact with water or the polymer via hydrogen bonding. The shift of unique bands for each component is an indication of the involvement of the specific functional group in the interaction, as indicated in Fig. 9 and discussed in Section 3.3 above. The rate of water penetration into the polymer matrices with and without the drug is summarized in Fig. 12d. Pure PVP as well as

PVP in the solid dispersion have a linear progression of water penetration, due to the rapid erosion of PVP and essentially no gel layer formation, as was already discussed in the previous sections. On the other hand, soluplus has a non-linear water penetration, whereby the penetration rate decreases with time. This can be explained by the formation of a gel layer that acts as a diffusion barrier toward further water ingress into the tablet structure. The conclusion from the measurements discussed in this section (in combination with Section 3.1) is that a polymer that hydrates and dissolves very rapidly, PVP in this case, is not necessarily better for the formulation with a poorly soluble drug because although it can give an initially faster release rate of the API, this may be negated by the subsequent API recrystallisation.


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Fig. 14. Comparison of water penetration rates into tablets made from aprepitant: polymer solid dispersions (a) without disintegrant and (b) with disintegrant. All data points were evaluated from MRI images.

Water penetration into the soluplus-based formulation with disintegrant manifests a non-linear behavior with a lag phase (Fig. 14b). A crucial question with respect to the formulation component selection is whether there is a correlation between the water penetration rate into the tablets and the drug release rate, and if so, whether water penetration is the main factor that influences and controls drug release. To answer this question, the MRI study must be combined with the classical dissolution study discussed in Section 3.1. In the case of tablets without disintegrant, the water penetration rates were very similar (Fig. 14a) and so were the release rates of the API (Fig. 6a) over the same time interval, i.e., the first 100–150 min. It can be stated that in the early stages of tablet hydration, drug release is controlled by the availability of the dissolution medium. However, in later stages the API release from soluplus- and PVP-based formulations differed substantially, which cannot be attributed to the water penetration rates as there was no such dramatic difference in the hydration rates of the PVP and soluplus matrices. Thus, the drug diffusion through the gel layer must be the rate-controlling step in that case, and soluplus was clearly superior for aprepitant in this respect (Fig. 6a). In the presence of disintegrant, over the first 90 min the water penetration into the PVP-based tablet is faster than into the soluplus matrix (Fig. 14b), but the drug release rate shows exactly the opposite trend (Fig. 6b). Although a larger volume of the tablet was hydrated in the case of PVP compared to soluplus and therefore a larger quantity of the drug had access to the dissolution medium, this was not reflected in the drug release rate. Aprepitant: soluplus:crosscarmelose formulations had a superior dissolution profile in spite of having a slower water penetration rate. This could mean that the physico-chemical properties of the polymer played the most important role in drug solubility enhancement. Although the presence of water is a necessary condition for drug dissolution from solid dispersions, its penetration rate into the tablet does not seem to have the main influence on drug release in this case.

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While ATR-FTIR spectroscopic imaging enables the identification of individual chemical species and also the distinction between amorphous and crystalline form of the drug at a local level (boundary layer between the tablet and the dissolution medium), MRI analysis makes it possible to observe phenomena at the length-scale of the whole tablet. Since it was seen in the pure polymers that the wetting front velocities evaluated from ATR-FITR imaging were underestimated, quantitative evaluation of water penetration rates into the tablets containing the API was performed using MRI. The same tablets whose dissolution was previously measured by the classical dissolution test (Section 3.1) were imaged by MRI in the flow cell described in Section 2.6. The image sequences obtained during the dissolution of four types of tablets (aprepitant:PVP and aprepitant:soluplus with and without disintegrant (27.5% w/w)) are shown in Fig. 13 and the wetting front velocities evaluated from the images are summarized in Fig. 14. Interestingly, the water penetration rate into the aprepitant: PVP and aprepitant:soluplus formulations without distintegrant are almost identical, which was not the case when these systems were imaged my means of the ATR-FTIR spectroscopic imaging approach. Also, the formulation with PVP does actually form a gel layer, which was also not obvious from the ATR-FTIR images. The enhancement of water penetration and polymer swelling caused by the addition of the disintegrant, croscarmellose, is significant (Fig. 13). The water penetration rate more than doubles, as can be seen by comparing the gradients of the curves in Fig. 14a and b.

By utilizing the different principles involved with the two different imaging approaches, consistent dissolution mechanisms of aprepitant from solid dispersions in both powder and tablet form were confirmed. The effect of the polymers on drug release was determined using classical dissolution tests where phenomena observed in the release profiles were further explained by the imaging data. Images of pure polymers showed that the mechanism of dissolution and the rate of water penetration were different, which could be used for effective selection of the polymer matrix based on the desired properties of the tablet sample. PVP had a fast dissolution rate, similar to the rate of water penetration. Soluplus had a more gradual, controlled dissolution with a wide gel layer but no swelling. However, the dissolution of PVP significantly slowed down when combined with a poorly water-soluble drug. Also, the dissolution of soluplus was significantly slower when combined with the poorly soluble drug. This could be caused by a decrease the wettability of the composite matrix due to the presence of non-polar groups in the API. The API-polymer interactions in solid dispersion, which are due to hydrogen donor and acceptor groups present in the API molecule and polymer, can decrease the dissolution rate of the polymer, while simultaneously enhancing the dissolution rate of the API. The concentration gradient of the polymer, which was determined in the gel layer and caused by water penetration and polymer swelling, improved the release of the poorly watersoluble drug by inhibiting its precipitation and allowing it to exist at locally elevated, potentially supersaturated, concentrations. The

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imaging approaches, specifically ATR-FTIR spectroscopic imaging, were shown to be a useful tool for the selection of suitable polymers in terms of detecting precipitation during dissolution. The precipitation of the API was recognized by ATR-FTIR imaging and can be explained by fast dissolution of PVP resulting in a high concentration of water and local supersaturation of API. MRI was used to determine the propagation rates of different fronts such as the wetting and erosion fronts during dissolution in quantitative manner. The comparison of dissolution results and imaging results shows that the release of the API was controlled by the rate of water ingress into the tablet in the early stages of dissolution, and by drug diffusion through the gel layer in the later stages. However, when a disintegrant was added into the formulation, which increased the initial rate of water penetration and gel layer formation, the API release became diffusion-limited from the very onset of tablet dissolution. The combination of two principally different imaging approaches with classical dissolution tests proved to be a powerful approach for the analysis and mechanistic understanding of dissolution processes from solid dispersion, which enabled not only qualitative but also quantitative description of the processes involved in drug release. Further research shall focus on investigating the ability of different polymer grades (i.e., different molecular weight of the polymer) to enhance the dissolution rate of the API and suppress its recrystallization. Also, a mathematical model that considers the elementary processes of water diffusion, polymer swelling and erosion, API diffusion and recrystallization kinetics will be developed and used for improved parameter evaluation from the ATR-FTIR and MRI images, and eventually for the prediction of release profiles and in silico formulation design.

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Acknowledgment

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K.P., N.S. and M.G. would like to acknowledge financial support from Specific University Research (project no. 20/2014).

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Appendix A. Supplementary data

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Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ijpharm.2015.02.035.

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Stability of indomethacin with relevance to the release from amorphous solid dispersions studied with ATR-FTIR spectroscopic imaging.

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