The influence of different mechanical stress on the release properties of HPMC matrix tablets in sucrose-NaCl media

Journal of Drug Delivery Science and Technology 54 (2019) 101246

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The influence of different mechanical stress on the release properties of HPMC matrix tablets in sucrose-NaCl media

T

Helena Vrbanaca,∗, Ana Kreseb a b

Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia Lek Pharmaceutics d.d, a Sandoz Company, Verovškova 57, 1562, Ljubljana, Slovenia

A R T I C LE I N FO

A B S T R A C T

Keywords: HPMC matrix tablets Biorelevant dissolution testing Sucrose NaCl Erosion Glass bead device

Four types of HPMC matrix tablets were studied to investigate the influence of mechanical stress on matrix behaviour using biorelevant in vitro dissolution model, the glass bead device (GBD) and paddle apparatus (USP2), in media with various concentrations of sucrose and NaCl. High or low viscosity grade HPMC was incorporated in the matrix with soluble (lactose) and insoluble (microcrystalline cellulose) diluent. The composition of the tablets and dissolution media were selected based on available literature data, with the intention of providing a sensitive system to reflect differences in hydrodynamics and mechanical stress generated by dissolution apparatuses. Between the GBD and USP2 no substantial differences were demonstrated in low concentration media. The differences were induced in high concentration media; compared to USP2 a higher drug release was observed in GBD for each matrix type. Due to solutes in the media an incoherent gel layer is formed and therefore the matrices are more prone towards the hydrodynamic and mechanical stress of dissolution method, suggesting that motion on the surface of glass beads is an important parameter that affects the removal of the gel layer. In critical media where formation of the functional gel barrier might be compromised, the use of GBD could provide additional insight into the drug release behaviour of the matrix tablet.

1. Introduction The influence of various solutes in the aqueous dissolution media on drug release from HPMC (hydroxypropylmethylcellulose) matrix tablets has been widely researched. When tablets are in contact with aqueous solutions water uptake occurs. By further water uptake into the matrix, the polymer hydrates and due to additional hydrogen bonding with water molecules massive entanglement is achieved. The gel layer is formed preventing further water uptake [1,2]. The processes of water penetration, polymer swelling, drug dissolution, drug diffusion and matrix erosion are continuously represented and balanced in the gel layer. These characteristics enable extended release from dosage form during gastrointestinal (GI) transit. Drug release from HPMC matrix tablet is controlled by matrix erosion and diffusion through the gel layer. Which of these mechanisms is dominant depends on the characteristics of the matrix tablet. Common formulation-related parameters influencing drug release are, for example, substitution type and viscosity grade of HPMC, drug/HPMC ratio, particle size and solubility of the drug and matrix fillers [3–7]. Usually, erosion of the polymer matrix is the primary release mechanism when low-soluble drugs are incorporated into the matrix. Moreover, erosion is enhanced when the

∗

matrix is comprised of low polymer viscosity (low molecular weight) grades [8–12]. Sucrose is one of the most commonly present dietary sugars, mainly in refined food products, such as soft and sports drinks, fruit juices, sweet spreads, cereals, yogurts and preserved fruit products. Similarly, sodium chloride is present in high quantities in convenience foods, dairy products, sauces and spreads, non-alcoholic beverages, processed vegetables etc. The classic western diet is high in both sugar (77 g/day [13]) and sodium chloride (7–13 g/day [14]) consumption. Due to high solubility of both entities, the consumption could create high-localized sucrose and/or sodium chloride concentrations in the fed stomach, potentially influencing the hydration process of the co-administered HPMC matrix tablet. When in contact with complex dissolution media that mimics the fed state environment, the formation of the gel layer and extended release properties of the matrix tablet could be affected. With low concentration of solutes added in the dissolution media, no apparent effect on the dissolution profile or minor decrease in release rates was demonstrated. With further increase in concentration of solutes the acceleration in drug release, known as burst release, from the tablet matrix can be observed [15–17,35]. The slower drug release was attributed to a salting-out of polymer with disintegration of the matrix

Corresponding author. E-mail addresses: Helena.Vrbanac@ffa.uni-lj.si (H. Vrbanac), [email protected] (A. Krese).

https://doi.org/10.1016/j.jddst.2019.101246 Received 10 June 2019; Received in revised form 13 August 2019; Accepted 27 August 2019 Available online 29 August 2019 1773-2247/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

Journal of Drug Delivery Science and Technology 54 (2019) 101246

H. Vrbanac and A. Krese

before a functional gel barrier was formed [15–20,35]. The inefficient gel layer presents an incoherent diffusion barrier and enhanced water penetration is enabled. The higher erosion of the matrix can be expected when a low integrity gel layer is present. The surrounding medium of the matrix tablet is therefore one of the factors affecting drug release. Different hydrodynamic and mechanical (shear stress, frictional forces) events that occur in the GI tract may also play a significant role in the behaviour of the matrix tablet [10,21–24]. In the fasted state, especially during the phase III of the migrating myoelectric complex (MMC) the stomach content is exposed to intense contractions and hydrodynamic. After food intake, the gastric motility is elevated and prolonged stress on the stomach content is expected. Conventional dissolution methods are well established in most laboratories due to their simplicity and robustness. However, due to increased growth of complex dosage forms and poorly soluble drugs, there is also a need for biorelevant methods that can recreate crucial physiological conditions of the GI tract. With the aim of better simulating the motility, hydrodynamic and mechanical stress in the GI tract, Bogataj and co-workers developed a glass bead device that enables the physical contact and movement of tablets on the surface of the glass bead layer [25]. Therefore, we can assume that a different hydrodynamic and mechanical stress is generated by the glass bead device with respect to the conventional USP dissolution apparatuses. Furthermore, the rotating beaker dissolution apparatus that enabled the shear-stress on the surface of the matrix tablet was designed by Abrahamsson et al. [26]. Aoki et al. proposed the paddle-bead method by introducing polystyrene beads in the USP2 apparatus and achieved good correlation with in vivo results in beagle dogs [27]. The development of an additional compartment for the dosage form, connected with the USP2 apparatus vessel, where different hydrodynamic and mechanical stress can be applied, are demonstrated in the work of Garbacz et al. [23] and Koziolek et al. [28]. Klančar et al. modified USP3 apparatus by inserting plastic beads into the reciprocating cylinder and achieved level A of in vitro/in vivo correlation (IVIVC) [29]. In addition to simple modifications of existing conventional dissolution methods and development of static apparatuses, more complex, dynamic devices were also developed. Legen et al. [30] developed an innovative, biorelevant, advanced gastric simulator (AGS) and intestinal model for simulating peristaltic action (IMPSA). Both of the methods were found to be mechanically biorelevant, enabling the establishment of a better IVIVC compared to the conventional methods for formulations with release properties susceptible to strong mechanical effects in the GI tract [31,32]. This study investigates the applicability of the glass bead device to enable mechanical stress that induces different HPMC matrix tablet behaviour, with respect to conventional USP2 apparatus for dissolution testing. Also, the additional insight on drug release behaviour in the critical media composition for the prepared matrix tablets with the GBD was investigated. The composition of the matrix tablets and dissolution media were chosen with the intention of providing sensitive systems to reflect the differences between the devices in terms of the various responses to drug release, matrix erosion and morphology of the hydrated matrices. Investigated matrices contained low or high HPMC viscosity grade as well as soluble or insoluble diluent. Moreover, tests were performed in media containing various concentrations of sodium chloride and sucrose.

Table 1 Composition of the tablet formulation (w/w). High HPMC/ MCC

Low HPMC/ MCC

High HPMC/ lactose

Low HPMC/ lactose

Paracetamol HPMC (90SH100.000SR)

0.25 0.35

0.25 –

0.25 0.35

0.25 –

HPMC (90SH-100SR) MCC Lactose ·H2O Mg stearate

–

0.35

–

0.35

0.395 – 0.005

0.395 – 0.005

– 0.395 0.005

– 0.395 0.005

cellulose (MCC), Avicel PH = 200 (FMC BioPolymer) was kindly donated by Lek, Sandoz company, Slovenija. Magnesium stearate was purchased by Lex, Slovenia. Hydrochloric acid, Titrisol for the preparation of 1.0 M HCl solution, and sodium chloride were of analytical grade (Merck, Darmstadt, Germany). Sucrose of Ph Eur grade was obtained from Lex (Slovenia).

2.2. Manufacture of tablets The matrix compositions used in this study are shown in Table 1. The ingredients were mixed in a polyethylene bag and then compressed using an instrumented single-punch tablet press (Kilian SP300, IMA Kilian, Germany) with 12 mm flat-faced punches and an applied pressure necessary to obtain tablets with a breaking force of 100–120 N (Vanderkamp VK200, Varian, USA) and a target mass of 400 mg.

2.3. Dissolution testing Dissolution testing using USP2 apparatus (paddle method) was undertaken at rotational speeds of 50 and 100 rpm and 900 mL of dissolution media. The dissolution tests were performed using a dissolution system (Vankel 7000, Vankel Technology Group, USA) coupled with an automatic sampler (VK 8000, Varian Cary, USA). The tablets were placed in dissolution sinkers made of stainless-steel wire. The flow through dissolution system with glass beads (GBD) [15] is composed of a glass vessel in a thermostat-controlled water bath with a magnetic stirrer (constructed by Merel, Slovenija) and a peristaltic pump (Masterflex L/S, Cole-Parmer, USA). The media volume of 40 mL was used in the working vessel with a flow rate of 2 mL min−1. The amount of glass beads was 25 g and stirring rates were 50 or 100 rpm. Time interval for sample collection was set to 20 min. The scheme of the working vessel of the GBD is presented in Fig. 1. The media compositions are presented in Table 2. Fasting conditions were represented by 0.001 M HCl, while dissolution media with added solutes simulated fed stomach conditions. The media temperature was set to 37 ± 0.5 °C. Drug release was tested at least in triplicate for all experimental conditions. The samples were filtered through 0.45 μm filters (Minisart RC, Sartorius Sledim Biotech GmbH, Germany). Drug concentration was measured by UV spectrometry (Agilent 8453, Agilent Technologies, Germany) in 10 mm quartz cells at λ = 244 nm.

2. Materials and methods 2.4. Measurement of tablet erosion 2.1. Materials Tablet erosion studies were performed by weighing the tablet (W0) before the dissolution study and at the end of the experiment after the wet matrix tablet mass had been dried in a vacuum dryer (VS–50S, Kambič, Slovenija) at 60 °C for a time period of 24 h, until constant weight was achieved (dry weight, Wd). The tablet erosion (E) was calculated from the following equation:

Hydroxypropylmethylcellulose (Hypromellose USP 2208) 90SH – 100000SR and 90SH – 100SR were produced by Shin Etsu Chemical Co. and kindly donated by Harke Pharma. Lactose monohydrate was supplied by Caelo (Caesar&Loretz GmbH, Germany). Paracetamol (≥99.0%) was obtained from Sigma–Aldrich, USA. Microcrystalline 2

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Fig. 1. Schematic presentation of the vessel and tablet translocation on the glass bead surface in the glass bead device (GBD).

W 0 − Wd ⎞ Erosion (%) = ⎛ ∗ 100 W0 ⎝ ⎠

was high in the media with higher concentration of solutes. In this media, either the dissolution rate was already high in the beginning of the test or extended release with a sharp increase at a certain time point was observed. Interestingly, the release behaviour of Low HPMC/MCC matrices remained unaffected by the highest concentration of combined solutes in the media (sucrose/0.26 M NaCl, sucrose/0.34 M NaCl) with regard to the HCl medium.

(1)

2.5. Morphology of swollen tablets Morphological observation of the swollen tablets was carried out using a stereo microscope (Olympus S7X12, Olympus, Japan) equipped with a digital camera (XC50, 3CCD Color Video Camera, Power HAD, Sony, Japan). All matrix tablets were photographed under the same optical conditions with Olympus DF PLAPO 1x PF Japan objective. Photo imaging was performed on each tablet formulation after hydrating for a specific time (5, 20 or 60 min) in the glass bead device and USP2 apparatus, with different media, at 50 rpm. The tablets were taken out of the dissolution vessel and carefully placed in a vertical position on the microscope slide. Images were captured using cellSens Dimension software by Olympus and processed by Quick Photo Camera 3.1 software by PROMICRA.

3.2. Comparing drug release using GBD and USP2 apparatus In Fig. 3 the extended drug release profiles for tested media in a lower concentration range are depicted: HCl, sucrose, NaCl, sucrose/ 0.17 M NaCl media, are presented. In the case of Low HPMC/lactose matrix tablets the higher release rates were generated by GBD with respect to USP2 apparatus in HCl, NaCl and sucrose media (p < 0.05 independent samples t-test). However, for other tested matrices no significant differences in drug release profiles were observed between both dissolution apparatuses in these media. Nevertheless, in the media containing sucrose and increased concentration of NaCl (sucrose/0.17 M NaCl, sucrose/0.26 M NaCl, sucrose/0.34 M NaCl) a trend of higher drug release rate was observed in GBD, where a loss of extended release characteristic, i.e. burst release, can be seen at earlier time points with respect to USP2 apparatus (Figs. 3 and 4). However, due to high standard deviations in this media, no statistical differences can be confirmed. In the case of Low HPMC/ MCC matrices extended release characteristics were obtained in these media (Figs. 3 and 4). However, a trend of higher release rates are indicated when GBD is used with respect to USP2 apparatus. Additionally, higher stirring rates (100 rpm) were applied in the media containing sucrose and increased concentration of NaCl. However, no significant impact on drug release profiles regarding to profiles at 50 rpm (Fig. 5) was observed.

3. Results 3.1. The effect of increased NaCl and sucrose concentration on drug release using GBD Four types of HPMC matrix tablets were studied, with the differences between them being the incorporated matrix diluent (MCC/lactose) and viscosity grade of 2208 HPMC (100.000SR/100SR). In the HCl medium with no added NaCl or sucrose, lower drug release was observed from the matrices of higher viscosity grade HPMC (Fig. 2). Additionally, higher drug release was indicated from lactose – matrices at the same viscosity grade with respect to MCC – matrices (p < 0.05 independent samples t-test). Furthermore, decrease in drug release from all tested matrices was demonstrated when medium with added NaCl, sucrose medium, or sucrose/0.17 M NaCl were used, except in the case of Low HPMC/lactose matrices in media with added NaCl, where no statistical differences were observed (p ≤ 0.05, one-way ANOVA, Bonferroni post hoc test). In the media with higher concentration of combined solutes (sucrose/0.26 M NaCl and sucrose/0.34 M NaCl) higher drug release was observed as the concentration of NaCl increased, whereas the concentration of sucrose remained constant (p ≤ 0.05, one-way ANOVA). Standard deviation in drug release profile

3.3. Erosion of the matrices The erosion of the matrix tablets was monitored at the end of the dissolution test in tested media and is presented in Fig. 6. In media containing sucrose, negative values of tablet erosion could be observed in experiments performed in the USP2 apparatus, for matrices with higher viscosity grade HPMC. The increase in the dried matrix tablet weight could be a result of a combination of smaller mechanical stress

Table 2 Composition of the tested dissolution media. HCl

NaCl

Sucrose

Sucrose/0.17 M NaCl

Sucrose/0.26 M NaCl

Sucrose/0.34 M NaCl

HCl

1 mmol

1 mmol

1 mmol

1 mmol

1 mmol

1 mmol

NaCl Sucrose Deionized water

– – ad 1 L

342,2 mmol (20 g) – ad 1 L

– 438.2 mmol (150 g) ad 1 L

171.1 mmol (10 g) 438.2 mmol (150 g) ad 1 L

256.7 mmol (15 g) 438.2 mmol (150 g) ad 1 L

342.2 mmol (20 g) 438.2 mmol (150 g) ad 1 L

3

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Fig. 2. Drug release from tested matrices in different dissolution media using glass bead device at stirring rate 50 rpm.

indicated. The lowest swelling is observed in Low HPMC/MCC tablet. In the HCl medium no significant difference were observed between morphology of hydrated matrices from both tested dissolution devices after 60 min. In media, containing sucrose and NaCl higher degree of matrix swelling was initiated at an earlier time point with regard to HCl medium. For High HPMC/MCC and Low HPMC/MCC matrix tablets there is a higher degree of swelling in the USP2 apparatus with regard to GBD in sucrose/0.26 M NaCl medium at 5 min. Due to the vertical position of a tablet during observation of the gel layer with the stereo microscope, some of the gel layer from the matrix surface slipped around the stationed matrix tablet. This is expressed on the images as a misty area

generated by USP2 apparatus compared to GBD and diffusion of the solutes from dissolution media in the matrix gel layer, where they stayed captured after the matrix has dried. Significant differences (p < 0.05 independent samples t-test) in the amount of eroded gel layer were observed in both devices (Fig. 6, marked with stars), which correlates with higher drug release indicated by the GBD (Fig. 4). 3.4. Morphology of hydrated matrices In Fig. 7 images of hydrated matrices are presented. In general, a greater extent of swelling from higher viscosity grade matrices is

Fig. 3. Drug release from 4 types of matrices using glass bead device (GBD) and USP2 apparatus at 50 rpm in tested media of lower concentration range. 4

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Fig. 4. Drug release from 4 types of matrices using glass bead device (GBD) and USP2 apparatus at 50 rpm in tested media of higher concentration range.

4.1. The effect of increased NaCl and sucrose concentration on drug release using GBD

around the hydrated matrices (Fig. 7, marked with red arrow). The effect can be observed for High HPMC/MCC in sucrose/0.17 M NaCl medium as well as in sucrose/0.26 M NaCl medium for High HPMC/ MCC and Low HPMC/MCC tablets using USP2 apparatus. The slipped layer is less expressed around matrices from the GBD.

Four types of investigated matrix tablet were studied, defined by diluent solubility (MCC or lactose) and polymer viscosity (HPMC 100.000SR or 100SR). In the HCl medium lower drug release was observed from matrices of higher viscosity grade HPMC (Fig. 2). The effect is in accordance with other studies where the tendency for lower drug release from the highest viscosity grade matrices was demonstrated [4–7]. The rationale behind this lies in the greater viscosity of the gel layer and higher resistance to diffusion [7]. Additionally, higher drug release was indicated from lactose - matrices at the same viscosity grade with respect to MCC - matrices. It was proposed that soluble diluent in the matrix decreases the tortuosity and increases the porosity of the dissolution path [2,6]. Furthermore, decrease in drug release from the matrices with lower viscosity grade of HPMC was demonstrated when media with salt or sucrose in the lower tested concentration range were used: NaCl, Sucrose, Sucrose/0.17 M NaCl media (Fig. 1). The mechanism behind this is probably formation of the more compacted gel layer due to decreased hydration of the polymer and increased extent of hydrophobic interaction primarily between the methoxy substituent of HPMC [15]. In media with higher solute concentrations (Sucrose/0.26 M NaCl, Sucrose/0.34 M NaCl) higher drug release was observed as the concentration of NaCl increased, whereas the concentration of sucrose remained constant (Fig. 1). The salting-out of the polymer and incoherent

4. Discussion HPMC matrices are generally known as robust hydrophilic matrix tablets to provide extended release characteristics. However, in the presence of high concentration of solutes in the dissolution media, release from HPMC matrices can be accelerated [15–18,35]. The consequence of not detecting the potential for in vivo dose dumping with the available in vitro methods can pose a serious safety concern due to a potential rapid increase in the plasma drug concentration. The influences of matrix diluent solubility and polymer viscosity have been already investigated and a more robust HPMC matrix formulation was proposed to obtain extended release in media with high concentration of solutes [33]. In our study the composition of the matrix tablets and dissolution media was selected, based on literature data [11,16,17,34,35], in order to provide a sensitive system that reflects the differences in the hydrodynamics and mechanical stress generated by the dissolution apparatus.

Fig. 5. Drug release from Low HPMC/MCC matrices at 50 rpm and 100 rpm using GBD and USP2 apparatus in tested media. 5

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Fig. 6. Percentage of matrix erosion at the end of the dissolution test for the tested matrices at stirring rate 50 rpm in tested media using glass bead device (GBD) and USP2 apparatus.

Volume of dissolution medium in the GBD vessel is small and comparable to the physiological one. The flow through setup of the GBD enables continuous change of the dissolution media, allowing for the simulation of the media pH and composition change as the drug delivery system transits from the stomach to the small intestine. However, the apparatus is not capable of recreating strong peristaltic contractions that occur in vivo and can potentially affect drug release kinetics. On the other hand, the main parameter to induce mechanical stress on the tablet in the case of USP2 apparatus is the hydrodynamics of the media, resulting from the paddle rotation. Tablet motion is one of the factors that may affect the matrix surface and consequently the drug release behaviour. The erosion of the matrix tablets was monitored at the end of each dissolution test. The results of matrix erosion reflect the amount of drug polymer dissolved as well as the erosion of the matrix during the dissolution process. Finally, the hydrated matrices were observed to gain additional information on the nature of the matrix in both of the tested devices. The extended drug release profiles from the matrices in the dissolution media in the lower tested concentration range are presented in Fig. 3. In these media no significant differences in drug release were observed between tested devices for high HPMC viscosity grade matrices and matrices with MCC. This indicates that the dissolution process and matrix performance is affected to a similar extent by generated conditions within the dissolution vessel of GBD and USP2 apparatus. A trend for higher erosion of the tested matrices in GBD is presumably due to the removal of the outer layer of the matrix gel layer with hydrated and uncoiled polymer chains that do not represent the diffusion barrier. Moreover, higher drug release rates and higher extent of final erosion were observed in GBD for Low HPMC/lactose matrix tablets rather than in the USP2 apparatus (Figs. 3 and 6). The rationale for observed effect could be in the susceptibility of the matrix to hydrodynamic and mechanical events generated by GBD, due to the formation of pores within the matrix as lactose dissolves resulting in increased porosity of the matrix and thus enhanced penetration of the dissolution medium [11]. Furthermore, owing to the lower HPMC viscosity grade lower polymer chain entanglement is also assumed [8,41] and consequently, quicker water uptake, drug diffusion and faster disentanglement of the polymer chain can be expected. The observations of hydrated matrix morphology revealed a greater extent of swelling from higher viscosity grade (Fig. 7). The reason for the effect could be in the higher intrinsic water holding capacity provided by longer polymer chains. Furthermore, due to the vertical position of a tablet during observation of the gel layer with the stereo microscope, some of the gel layer from the matrix surface slipped around the stationed matrix tablet. This is expressed in the images as a misty area around the hydrated matrices. The reason for the observed slipped gel layer could be the low integrity of the gel and higher tendency for translocation of hydrated polymer

gel barrier formation was proposed, thus water uptake into the matrix and drug diffusion are enhanced [15,16,18]. Interestingly, in the release behaviour of Low HPMC/MCC matrices no acceleration in drug release was observed for the tested media. The trend for enhanced resistance of lower viscosity grade HPMC with respect to higher grades in media with high concentration of solutes was indicated in our previous study [35]. On the contrary, the study by Asare-Addo et al. [36] showed the trend for higher release rates from matrices of lower viscosity grade in high ionic strength media (0.4 M), with regard to higher viscosity grades. In the present study this trend was observed between lactose matrices: High HPMC/lactose and Low HPMC/lactose. However, when lower concentrations of solutes are present in the dissolution media (HCl, NaCl, Sucrose, Sucrose/0.17 M NaCl) this trend is indicated also between MMC matrices: High HPMC/MCC and Low HPMC/MCC. The variation in matrix diluent type or HPMC viscosity grade can provoke substantial differences in drug release behaviour at specific dissolution conditions. Moreover, Williams et al. [33] demonstrated that HPMC matrices with the highest tested viscosity grades and MCC as diluent expressed improved resistance to dissolved sugars in comparison to matrices with lactose as diluent. The possible influence of lactose and MCC on gel layer characteristics was proposed [33,37,38]. When lactose dissolves within the matrix the porosity of the gel layer increases, facilitating drug transport through the gel layer. Also lactose can contribute to suppression of the polymer hydration, which is reflected in a formation of non-coherent gel barrier and that could result in higher water intake into the matrix. In the case of MCC, the soluble content of the matrix is reduced, thus the porosity of gel and osmotic pressure within the matrix decreases and lower water intake into the matrix is expected [33]. Furthermore, it is difficult to identify the reason for differences in drug release between matrices of lower (Low HPMC/MCC) and higher (High HPMC/MCC) viscosity grade in media of high solute concentrations. The combination of lower HMPC viscosity grade and insoluble filler (MCC) maintained the extended release characteristic in high concentration media. 4.2. Drug release, erosion and matrix morphology using GBD and USP2 apparatus After ingestion, a dosage form is presumably, frequently in direct contact with the GIT mucosa, exposed to relatively small volumes of physiological media [39,40]. GBD is a static dissolution apparatus, enabling gentle physical contact of a dosage form with the surface of the glass beads and motion due to movement of the beads at the bottom of the vessel (Fig. 1) [25]. We believe this reflects the in vivo transition of the dosage form along the GI tract, where the dosage form is, for most of the time, in direct contact with the digestive tract mucosa. 6

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Fig. 7. Images of hydrated matrices after dissolution testing at determined time in GBD and USP2 apparatus. Red arrow marks the misty area of the slipped gel layer. Scale bar 2000 μm. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

observed when GBD was used with respect to USP2 apparatus. Also, the slipped gel layer was more noticeable in the morphology of the hydrated matrices after 5 min exposure to sucrose/0.26 M NaCl medium in the case of USP2 apparatus (Fig. 7). Mechanical contact of the gel layer with beads could presumably be an important parameter influencing release from the matrices. It was proposed that removal of fully hydrated polymer chains is facilitated by translocation of matrix tablets on the glass bead surface. Presumably, low integrity of the gel layer induced by media with high solutes concentration makes the matrix susceptible to changes in the hydrodynamic and mechanical stress between the two dissolution apparatus. As the gel layer is partially removed by the glass beads, the drug diffusion and dissolution from the matrix increases. Furthermore, in the case of Low HPMC/MCC matrices the extended release characteristics were obtained in sucrose/0.26 M NaCl and

chains. The lower degree of the slipped gel layer is demonstrated on the matrix images from GBD (Fig. 7, sucrose/0.17 M NaCl medium, 20 min). A higher degree of erosion of the weak gel structure on the matrix surface is assumed by the glass beads. The matrices from the glass bead device might be structured with gel strength that have a lower tendency for slipping from the matrix since the fragile outside gel layer of hydrated and disentangled polymer has been removed due to translocation on the glass bead surface. The association between lower erosion and higher amount of slipped gel layer for the USP2 apparatus is noticed in sucrose/0.17 M NaCl medium (Figs. 6 and 7). In media containing sucrose and increased concentration of NaCl (sucrose/0.26 M NaCl, sucrose/0.34 M NaCl), the noteworthy differences in drug release rate and matrix erosion were induced between the two dissolution apparatus (Figs. 4 and 6). Higher drug release profiles or quicker acceleration in release rate as well as higher erosion were 7

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sucrose/0.34 M NaCl media and therefore we assume that the gel layer integrity was not affected to the extent that a burst release would be induced. However, higher release rates from these matrices and a greater extent of matric erosion were also clearly indicated when GBD was used with respect to USP2 apparatus (Figs. 4 and 6). Therefore, it is supposed that the gel integrity of Low HPMC/MCC matrices is weakened in these media which leads to a higher susceptibility to mechanical stress resulting in higher erosion. This is in accordance with the results of the matrix morphology in sucrose/0.26 M NaCl medium, with a larger extent of slipped gel observed in the case of USP2 apparatus. No significant influence of higher stirring rates on drug release profile was demonstrated. Thus, a greater importance of mechanical contact in the GBD and subsequent removal of the gel layer with regards to higher hydrodynamic within USP2 apparatus was proposed (Fig. 5).

[8] N. Kavanagh, O.I. Corrigan, Swelling and erosion properties of hydroxypropylmethylcellulose (Hypromellose) matrices–influence of agitation rate and dissolution medium composition, Int. J. Pharm. 279 (1–2) (2004) 141–152 https:// doi.org/10.1016/j.ijpharm.2004.04.016. [9] B. Abrahamsson, et al., In vitro and in vivo erosion of two different hydrophilic gel matrix tablets, Eur. J. Pharm. Biopharm. 46 (1) (1998) 69–75 https://doi.org/10. 1007/s11095-017-2113-7. [10] M. Ghimire, et al., In-vitro and in-vivo erosion profiles of hydroxypropylmethylcellulose (HPMC) matrix tablets, J. Control. Release 147 (1) (2010) 70–75 https://doi.org/10.1016/j.jconrel.2010.06.015. [11] B.N. Tukaram, I.V. Rajagopalan, P.S.I. Shartchandra, The effects of lactose, microcrystalline cellulose and dicalcium phosphate on swelling and erosion of compressed HPMC matrix tablets: texture analyzer, Iran. J. Pharm. Res. (IJPR) 9 (4) (2010) 349–358. [12] K. Sako, et al., Influence of water soluble fillers in hydroxypropylmethylcellulose matrices on in vitro and in vivo drug release, J. Control. Release 81 (1–2) (2002) 165–172 https://doi.org/10.1016/S0168-3659(02)00067-6. [13] S.E. Powell, et al., Added sugars intake across the distribution of US children and adult consumers: 1977-2019, J. Acad. Nutr. Diet. 116 (10) (2016) 1543–1550 https://doi.org/10.1016/j.jand.2016.06.003. [14] L. Kloss, et al., Sodium intake and its reduction by food reformulation in the European Union – a review, NFS J. 1 (2015) 9–19 https://doi.org/10.1016/j.nfs. 2015.03.001. [15] K. Mitchell, et al., The influence of additives on the cloud point, disintegration and dissolution of hydroxypropylmethylcellulose gels and matrix tablets, Int. J. Pharm. 66 (1–3) (1990) 233–242 https://doi.org/10.1016/0378-5173(90)90404-R. [16] H.D. Williams, et al., The extended release properties of HPMC matrices in the presence of dietary sugars, J. Control. Release 138 (3) (2009) 251–259 https://doi. org/10.1016/j.jconrel.2009.05.017. [17] H.D. Williams, et al., The effect of sucrose and salts in combination on the drug release behaviour of an HPMC matrix, Eur. J. Pharm. Biopharm. 76 (3) (2010) 433–436 https://doi.org/10.1016/j.ejpb.2010.09.001. [18] J.L. Johnson, J. Holinej, M.D. Williams, Influence of ionic-strength on matrix integrity and drug release from hydroxypropyl cellulose compacts, Int. J. Pharm. 90 (2) (1993) 151–159 https://doi.org/10.1016/0378-5173(93)90151-5. [19] S.C. Joshi, Sol-Gel Behavior of hydroxypropyl methylcellulose (HPMC) in ionic media including drug release, Materials 4 (10) (2011) 1861–1905 https://doi.org/ 10.3390/ma4101861. [20] G.S. Bajwa, et al., Microstructural imaging of early gel layer formation in HPMC matrices, J. Pharm. Sci. 95 (10) (2006) 2145–2157 https://doi.org/10.1002/jps. 20656. [21] B. Abrahamsson, K. Roos, J. Sjogren, Investigation of prandial effects on hydrophilic matrix tablets, Drug Dev. Ind. Pharm. 25 (6) (1999) 765–771 https://doi.org/10. 1081/DDC-100102236. [22] M. Takieddin, et al., A novel approach in distinguishing between role of hydrodynamics and mechanical stresses similar to contraction forces of GI tract on drug release from modified release dosage forms, AAPS PharmSciTech 16 (2) (2015) 278–283 https://doi.org/10.1208/s12249-014-0225-5. [23] G. Garbacz, et al., Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses, Eur. J. Pharm. Biopharm. 70 (2) (2008) 421–428 https://doi. org/10.1016/j.ejpb.2008.05.029. [24] W. Weitchies, et al., In vitro simulation of realistic gastric pressure profiles, Eur. J. Pharm. Sci. 107 (2017) 71–77 https://doi.org/10.1016/j.ejps.2017.06.037. [25] M. Bogataj, G. Cof, A. Mrhar, Development of a glass bead device for dissolution testing, Dissolution Technol. 22 (3) (2015) 18–24 https://doi.org/10.14227/ DT220315P18. [26] B. Abrahamsson, et al., A novel in vitro and numerical analysis of shear-induced drug release from extended-release tablets in the fed stomach, Pharm. Res. 22 (8) (2005) 1215–1226 https://doi.org/10.1007/s11095-005-5272-x. [27] S. Aoki, et al., Determination of the mechanical impact force in the in-vitro dissolution test and evaluation of the correlation between in-vivo and in-vitro release, Int. J. Pharm. 95 (1–3) (1993) 67–75 https://doi.org/10.1016/0378-5173(93) 90391-R. [28] M. Koziolek, et al., Development of a bio-relevant dissolution test device simulating mechanical aspects present in the fed stomach, Eur. J. Pharm. Sci. 57 (2014) 250–256 https://doi.org/10.1016/j.ejps.2013.09.004. [29] U. Klancar, et al., A novel beads-based dissolution method for the in vitro evaluation of extended release HPMC matrix tablets and the correlation with the in vivo data, AAPS J. 15 (1) (2013) 267–277 https://doi.org/10.1208/s12248-012-9422-x. [30] Legen I. et al. Apparatus for Simulating the Function of Human Stomach And/or Human Intestine. U.S. Patent 20160351079. Nov, 2018. Accessed Mar 2019. [31] M. Hribar, et al., Determining the pressure-generating capacity of the classical and alternative in vitro dissolution methods using a wireless motility capsule, J. Pharm. Innov. 13 (3) (2018) 226–236 https://doi.org/10.1007/s12247-018-9317-1. [32] M. Hribar, et al., I. A novel intestine model apparatus for drug dissolution capable of simulating the peristaltic action, AAPS PharmSciTech 18 (5) (2017) 1646–1656 https://doi.org/10.1208/s12249-016-0629-5. [33] H.D. Williams, et al., Designing HPMC matrices with improved resistance to dissolved sugar, Int. J. Pharm. 401 (1–2) (2010) 51–59 https://doi.org/10.1016/j. ijpharm.2010.09.009. [34] M. Levina, A.R. Rajabi-Siahboomi, The influence of excipients on drug release from hydroxypropyl methylcellulose matrices, J. Pharm. Sci. 93 (11) (2004) 2746–2754 https://doi.org/10.1002/jps.20181. [35] A. Krese, et al., Influence of ionic strength and HPMC viscosity grade on drug release and swelling behavior of HPMC matrix tablets, J. Appl. Polym. Sci. 133 (26)

5. Conclusions The use of glass bead device can provide additional insight into the behaviour of HPMC matrix tablets when dissolution is performed in media with high concentration of solutes (sucrose, NaCl). The drug release, measurement of matrix erosion and in some cases the observed morphology of hydrated matrices, demonstrate an important influence of matrix tablet motion on the glass beads surface due to facilitated removal of the gel layer. When the integrity of the gel layer of the matrix is compromised, the role of mechanical contact is emphasised more. In this study, the amount of incorporated HPMC polymer was within the generally recommended level (30–35%) for all tested matrices [10]. Nevertheless, burst release was observed in media with high concentration of solutes in GBD for all matrices except for Low HPMC/ MCC. In the light of these findings, GBD could be a very useful tool in the design of more robust formulations, which would be of great advantage primarily for patient safety. Conflicts of interest statement None. Acknowledgments The authors would like to acknowledge Prof. Marija Bogataj for her valuable and constructive consultations during the planning and development of this research work and Ms. Greta Cof from the Faculty of Pharmacy, University of Ljubljana, for valuable technical support in conducting the experiments. References [1] P. Colombo, et al., Analysis of the swelling and release mechanisms from drug delivery systems with emphasis on drug solubility and water transport, J. Control. Release 39 (2–3) (1996) 231–237 https://doi.org/10.1016/0168-3659(95) 00158-1. [2] L.J. Ford, Design and evaluation of hydropropyl methylcellulose matrix tablets for oral controlled release: a historical perspective, in: P.T, et al. (Ed.), Hydrophilic Matrix Tablets for Oral Controlled Release, AAPS Advances in the Pharmaceutical Sciences Series, 2014, pp. 17–51. [3] C.L. Li, et al., The use of hypromellose in oral drug delivery, J. Pharm. Pharmacol. 57 (5) (2005) 533–546 https://doi.org/10.1211/0022357055957. [4] P. Gao, et al., Swelling of hydroxypropyl methylcellulose matrix tablets. 2. Mechanistic study of the influence of formulation variables on matrix performance and drug release, J. Pharm. Sci. 85 (7) (1996) 732–740 https://doi.org/10.1021/ js9504595. [5] B.J. Lee, S.G. Ryu, J.H. Cui, Formulation and release characteristics of hydroxypropyl methylcellulose matrix tablet containing melatonin, Drug Dev. Ind. Pharm. 25 (4) (1999) 493–501 https://doi.org/10.1081/DDC-100102199. [6] K.C. Sung, et al., Effect of formulation variables on drug and polymer release from HPMC-based matrix tablets, Int. J. Pharm. 142 (1) (1996) 53–60 https://doi.org/ 10.1016/0378-5173(96)04644-3. [7] L.W. Cheong, P.W. Heng, L.F. Wong, Relationship between polymer viscosity and drug release from a matrix system, Pharm. Res. 9 (11) (1992) 1510–1514 https:// doi.org/10.1163/156855598X00215.

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Pharm. Sci. 37 (2) (2009) 89–97 https://doi.org/10.1016/j.ejps.2009.01.008. [39] C. Schiller, et al., Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging, Aliment. Pharmacol. Ther. 22 (10) (2005) 971–979 https://doi.org/10.1111/j.1365-2036.2005.02683.x. [40] M.D. Mudie, et al., Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state, Mol. Pharm. 11 (9) (2014) 3039–3047 https://doi.org/10.1021/mp500210c. [41] L.S.C. Wan, P.W.S. Heng, L.F. Wong, The effect of hydroxypropylmethylcellulose on water penetration into a matrix system, Int. J. Pharm. 73 (2) (1991) 111–116 https://doi.org/10.1016/0378-5173(91)90033-K.

(2016), https://doi.org/10.1002/app.43604. [36] K. Asare-Addo, et al., Effect of ionic strength and pH of dissolution media on theophylline release from hypromellose matrix tablets-Apparatus USP III, simulated fasted and fed conditions, Carbohydr. Polym. 86 (1) (2011) 85–93 https://doi.org/ 10.1016/j.carbpol.2011.04.014. [37] S.R. Pygall, et al., Mechanisms of drug release in citrate buffered HPMC matrices, Int. J. Pharm. 370 (1–2) (2009) 110–120 https://doi.org/10.1016/j.ijpharm.2008. 11.022. [38] F. Tajarobi, et al., Simultaneous probing of swelling, erosion and dissolution by NMR-microimaging–effect of solubility of additives on HPMC matrix tablets, Eur. J.

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