Simultaneous probing of swelling, erosion and dissolution by NMR-microimaging—Effect of solubility of additives on HPMC matrix tablets

European Journal of Pharmaceutical Sciences 37 (2009) 89–97

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European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps

Simultaneous probing of swelling, erosion and dissolution by NMR-microimaging—Effect of solubility of additives on HPMC matrix tablets Farhad Tajarobi a,c,∗ , Susanna Abrahmsén-Alami b , Anders S. Carlsson a , Anette Larsson c a

AstraZeneca R&D, SE-431 83 Mölndal, Sweden AstraZeneca R&D, SE-221 87 Lund, Sweden c Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden b

a r t i c l e

i n f o

Article history: Received 31 October 2008 Received in revised form 9 January 2009 Accepted 13 January 2009 Available online 31 January 2009 Keywords: MRI HPMC Swellable matrices Front movement Diffusion Osmotic pressure

a b s t r a c t Extensive studies of extended release tablets based on hydrophilic polymers have illuminated several aspects linked to their functionality. However, in some respects key factors affecting the mechanisms of release are yet unexplored. In the present study, a novel NMR-microimaging method has been used to study the influence of the solubility of additives in extended release hydroxypropyl methylcellulose (HPMC) matrix tablets. During the course of the tablet dissolution the movement of the swelling and erosion fronts were studied simultaneously to the release of both polymer and additives. Moreover, the focused beam reflectance measurement (FBRM) technology was for the first time assessed for both release and dissolution rate studies of poorly soluble particles. The studied formulations comprised solely HPMC, 40% HPMC and 60% mannitol (Cs = 240 mg/ml) and 40% HPMC and 60% dicalcium phosphate (DCP) (Cs = 0.05 mg/ml). The dissolution rate of the tablets was highest for the HPMC/mannitol formulation, followed by HPMC/DCP and plain HPMC tablet. A contrasting order was found regarding the degree and kinetics of swelling. The results were interpreted in light of how the mass transport in the gel layer is influenced by the solubility of additives. A mechanistic model, considering osmotic pressure gradient and the effective diffusion of the dissolution medium in the gel is proposed. © 2009 Elsevier B.V. All rights reserved.

1. Introduction High drug loading, regulatory and manufacturing advantages and potential to provide time independent release have made the swellable matrices an object for extensive study in the past decades. In particular, the fast gel formation and viscosity inducing properties of hydroxypropyl methylcellulose (HPMC) have lead to frequent use of this polymer as a matrix former in extended release formulations (Lapidus and Lordi, 1968; Alderman, 1984; Colombo et al., 2000). As drug candidates from the discovery pipelines in the industry can feature different solubilities, the influence of this parameter on the release behavior of the additives is of interest. Many studies have shed light on this topic. However, the mechanistic explanations have at times been contradictory. For example, in some studies it is suggested that the presence of poorly soluble additives render

∗ Corresponding author at: Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden. Tel.: +46317723411. E-mail addresses: [email protected], [email protected] (F. Tajarobi). 0928-0987/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2009.01.008

the matrix more erodible by jeopardizing the integrity of the gel. Release plots featuring dual phases have been presented, where a considerably faster release has been observed after a total hydration of the glassy tablet core (Alderman, 1984; Bettini et al., 2001). Other groups have suggested that the presence of additives in particulate form in the gel may in fact contribute to stabilize the gel and the release from swellable matrices (Jamzad et al., 2005). Moreover, the release of additives has in the literature been attributed to many parameters such as gel thickness (front synchronization) (Conte et al., 1988), rate of polymer swelling linked with additive dissolution in the gel (Colombo et al., 1999) and drug diffusivity (Gao and Fagerness, 1995). However, the emphasis of these parameters on the overall release and dissolution of the tablet is yet not fully understood. One of the important factors for understanding the functionality of swellable matrices lies in the swelling and erosion of the polymer chains in addition to the diffusivity of the additives, which in turn can be linked to their solubility. An important element governing the rate of gel formation and additive dissolution is the rate of water ingress into the tablet (Gao and Fagerness, 1995; Colombo et al., 2000). A model describing the swelling, erosion and ultimately gel formation of a hydrophilic matrix was presented by Peppas et al. (1980) nearly 3 decades ago. In this model, a mechanism for matrix

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dissolution was described by the movements of the boundaries between the rubbery gel and the glassy tablet core (swelling front) and the gel and the dissolution medium (erosion front). In addition, a front corresponding to the dissolution of the additives in the gel has also been identified (diffusion front). Numerous methods, ranging from various imaging techniques such as magnetic resonance imaging (MRI) (Richardson et al., 2005) and fluorescence microscopy (Bajwa et al., 2006), ultrasound (Konrad et al., 1998), texture analyzer (Jamzad et al., 2005) and FTIR spectroscopy imaging (Kazarian and Van der Weerd, 2008) have been used to describe the dynamic process of these front progressions. However, few have combined non-invasive imaging studies to probe front movements with simultaneous determinations of polymer and additive release under non-static hydrodynamic conditions. The aim of the presented study was to attain mechanistic insight on the influence of the solubility of additives on the gel formation and erosion of extended release tablets containing HPMC. For this purpose a non-invasive method and suitable experimental setup for creating a dynamic flow condition was required. This was achieved through the use of a recently developed experimental setup for MRI studies (Abrahmsén-Alami et al., 2007). This setup provided spatial information under dynamic conditions combined with possibility for sample out takes during the course of dissolution. A new chromatography method using mass spectrometry detection was developed for quantifying the release of mannitol, the highly soluble additive. HPMC release was determined using size exclusion chromatography. In addition, as a new application, focused beam reflectance measurement (FBRM) was used to qualitatively determine the release of calcium phosphate, which was used as a poorly soluble additive from the tablets.

2. Materials and methods 2.1. Materials Binary tablet compositions were prepared. The formulations comprised 40% hypromellose of grade 90SH-100 SR (Shin-Etsu Chemical Co., Ltd., Tokyo, Japan) and 60% mannitol (Pearlitol 50, Roquette, France) or dicalcium phosphate (DCP; Merck, Germany). A third composition containing solely HPMC of the same grade was also studied. The loss on drying of the components in the compositions was measured (Mettler Toledo HR 73 Halogen moisture analyser (USA), drying time 15 min, drying temperature 110 ◦ C, standard program) and the moisture content in the tablet (approximately 1%) was not assumed to affect the targeted content of the tablets.

2.2. Tablet preparation Prior to compaction, the powder blend for each composition was mixed in a small diffusion mixer (Turbula, Willy A. Bachhofen AG Maschinenfabrik, Switzerland) at 42 rpm for 2 min. Tablets were produced by direct compression using 8 mm flat faced punches. The weight and the height of the tablets were 200 ± 2 mg and 3.0 ± 0.3 mm, respectively. Tablet tensile strength by diametral compression () was derived from the force (F) needed to fracture the tablets (C50 Holland Tablet Hardness Tester Engineering Systems, England) and was calculated according to Eq. (1) (Fell and Newton, 1970): =

2F Dh

where D is the tablet diameter and h is the tablet height.

(1)

The theoretical porosity E (%) of the tablets was calculated according to: E=

r 2 h − (0.4 · mtot /HPMC ) + (0.6 · mtot /additive ) × 100 r 2 h

(2)

where r is the radius of the tablet (cm);  is the apparent density (g/cm3 ) and mtot is the total weight of the tablet (g). 2.3. Characterisation of the starting materials The solubility of mannitol and DCP was determined in the dissolution media at 37 ◦ C. The concentration of a saturated solution of mannitol was determined by chromatography according to the method described in Section 2.5.1. The solubility of DCP was estimated by mixing 120 mg of the model substance in 500 ml dissolution media for approximately 1 h (three replicates), followed by centrifuging the suspension and carefully withdrawing the supernatant. The remaining media containing the DCP sediments were dried in an oven until no more water was evaporated. The weights of the sediments were measured and the mass of the dissolved DCP was calculated. All starting materials were sieved and a limited particle size fraction (60–100 ␮m) was used in the tablet compositions. The apparent density of the starting materials was determined by Hepycnometry (Micromeritics, Accupyc 1330, USA), using 1.5 bar gas pressure and 10 consecutive runs and purges. 2.4. MRI-setup and methodology MRI studies were performed on all compositions (two replicates). A detailed description of the hardware and experimental setup during the MRI studies is provided by Abrahmsén-Alami et al. (2007). In brief, the tablets were glued to the centre of a rotating disc, which was positioned in an MRI release cell and inserted into the MRI probe for imaging. The release cell was connected to a 37 ◦ C tempered beaker, containing the dissolution medium. The solvent was pumped through the release cell by a peristaltic pump via plastic tubes. The dissolution media consisted of 500 ml phosphate buffer at 37 ◦ C (100 mM, pH 6.8, I = 0.1). The speed of the rotating disc was set by a digital stirrer at 100 rpm (Eurostar, IKAWerke GmbH&Co. KG, Germany). The rotation of the disc was switched off 2 min before the start of imaging sequences, at which time samples from the dissolution media were collected. Images were obtained from both radial and axial scans of the tablets. The scanning direction altered after each imaging sequence. The scans were centred at a position 2 mm below the rotating disc in the radial direction and in the middle of the tablet in the axial direction. A slice thickness of 2 mm was used. The duration of each measurement was 21.2 min. The stirring intervals before the sample/imaging sequences were 20 min until the thirteenth sequence, after which the length of the stirring sequences increased to 130 min. The studies were performed using the Bruker Para Vision 3.0 software and a wb400 Bruker spectrometer with a 2.5 1 H resonator. Diffusion of the dissolution media into the tablet was studied by using the original multi-spin pulse sequence (m msme), supplied by Bruker. Using this method, the signal intensity is weighted according to the proton spin–spin (T2 ) and spin–lattice (T1 ) relaxation times. Due to the very short T2 -relaxation times of the solid material protons, differences in the image intensity will predominantly depend on the properties of the dissolution media. Under the condition that the repetition time (TR = 10 s) was 3–5 times longer than the T1 , the intensity of the image signal is given by Eq. (3): I(TE ) = I(0) exp

 −T  E

T2

(3)

F. Tajarobi et al. / European Journal of Pharmaceutical Sciences 37 (2009) 89–97

where T2 and TE are the “effective” spin–spin relaxation of proton time and the echo-time, respectively. I(0) is the total intensity, and I(TE ) is the intensity of the signal TE . The T1 -relaxation time of water in 0.1 M phosphate buffer at pH 6.8 was determined to 3.9 s at 37 ◦ C. With increasing HPMC concentration, the relaxation time decreases and therefore, a TR of 10 s was sufficient to obtain a measure of the T2 in the polymer gel. Except for some initial tests using a shorter TR , a TR of 10 s was used in all studies. Images were probed at 20 different echo times (10–200 ms) and were used to create images weighted mainly with the T2 of water protons in the sample. The acquisition parameters were; a field of view (FOV) of 2.5 cm × 2.5 cm digitized into 128 × 128 pixels, giving a resolution down to 0.2 mm. 2.5. Release and assay of the tablet content 2.5.1. HPMC/mannitol tablets The release of mannitol and HPMC from all formulations was measured in the beginning of each imaging sequence. The withdrawn sample volume was 1.5 ml. In order to obtain three replicates of the release studies a third dissolution experiment, in addition to the two obtained during the MRI measurements was performed for all formulations. The additional tablet release measurements were performed under similar conditions and setup as in the MRI studies. This was done by using a similar release cell, placed in the position of the paddle in a USP dissolution bath. Moreover, the same release conditions as used in the MRI-setup were applied. The polymer concentration in the release medium was determined by size exclusion chromatography with refractive index detector (SEC-RI). The mobile phase consisted of 0.1 M phosphate buffer (I = 0.1, pH 6.8) with 0.02% (w/w) NaN3 . The analyses were performed at a flow rate of 0.8 ml/min, injecting 100 ␮l samples into the SEC column. The column, a TSK gel GMPWXL , 7.8 mm ID × 30.0 cm L with a pore size 13 ␮m (TOSOH corporation, Japan) was placed in a column oven at 30 ◦ C. The temperature of the RIdetector (Varian, RI-4, Japan) was fixed at 35 ◦ C and the range at 1/8. The software CSW32 Chromatography Station was used to evaluate the raw data. Mannitol assays were analysed using liquid chromatography equipped with a mass spectrometry (MS) detector (Waters, Micromass ZQ 2000, USA). The mobile phase consisted of acetonitrile:water in 45:55 volume proportions and 0.2 vol% formic acid. The analyses were performed at a flow rate of 0.15 ml/min. 5 ␮l sample was injected into the column (Genesis NH2 , 250 mm × 2.1 mm, with pore size 3 ␮m and 120 Å (USA)). The MS detector used a cone voltage of 15 kV with the mass number (m/z) set at 183. The source and desolvation temperatures used were 120 and 350 ◦ C, respectively. 2.5.2. HPMC/DCP tablets The release of HPMC from HPMC/DCP tablets was studied during the MRI experiments as described previously. However, owing to the low solubility and subsequent difficulties in using the MRIsetup, a new methodology, FBRM® was used to determine the release of DCP (three replicates). FBRM has previously been used to study a vast range of kinetic processes such as particle growth and morphological changes of biological material (Jeffers et al., 2004) and during crystallisation (Kougoulos et al., 2005), granular growth in process technology (Xinhui et al., 2007) and flocculation kinetics (Heath et al., 2006). The use of this technique for in-line monitoring of release from tablets has been discussed by Johansson et al. (2006). In brief, a continuous beam of monochromatic laser light is launched down a probe (Lasentec® , model S400Q, Mettler Toledo, USA) with the

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focal point positioned at the interface between the probe window and the actual process. The laser beam rotates in a continuous and very rapid circular motion at a constant speed to avoid interference from particle movements. As the scanning beam sweeps across the face of the probe window, individual particles or aggregates of particles backscatter the laser light back into the probe. These pulses of backscattered light are translated into chord lengths (CL) according to Eq. (4). In this way a measure of particle count and size can be attained. CL = Vscan × tb

(4)

where Vscan is the velocity of the laser beam and tb is the time of the pulse width. The FBRM measurements were performed by placing the probe in the dissolution medium. As the probe could not be incorporated in the MRI-setting, the release of DCP was studied using new set of tablets, a similar release cell and USP dissolution bath as described in Section 2.5.1. The tablet was glued to the centre of the rotating disc and was positioned in the release cell in place of the paddle. The release conditions and intervals for particle count were the same as used in MRI-experiments. Prior to the start of each release study the FBRM probe was checked for background signals, which were eliminated by thoroughly cleaning the Sapphire glass of the probe. It was found that the most optimal performance of the FBRM probe was obtained when sufficient particle flow was present in the medium. Therefore, at the time of the measurements, the rotating disc was carefully replaced with a paddle and the rotation speed was increased from 100 to 125 rpm. After the end of each measurement the tablet was placed back in the paddle position. Each particle count measurement lasted for 5 min with 5 s scanning duration. The registered particle size range was 1–100 ␮m. The results were scaled to the last measurement (carried out 1 h after the tablet had visually dissolved) of the respective trial. By this mean, FBRM provided a qualitative measure of the release of particulate DCP. The FBRM technique was also used as a method to confirm the measured solubility of DCP as described in Section 2.3. An incremental increased amount of DCP (approximately 5–300 mg) was added to 500 ml dissolution media. The particle count was measured for 1 h after each addition. The scanning duration was 5 s and the studied size interval was 1–100 ␮m. The added DCP was under agitation at 125 rpm for 1 h. Each particle count measurement lasted for 5 min.

Fig. 1. Particle count of incremental addition of calcium phosphate to phosphate buffer as registered by focused beam reflectance measurement probe.

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Fig. 2. The fraction of polymer and additive released for the tablets comprised of 40% HPMC, 60% additive and solely HPMC. Mannitol is denoted as (䊉), HPMC (HPMC/mannitol tablets) (), DCP (), HPMC (HPMC/DCP tablets) () and HPMC (plain HPMC tablets) ().

3. Results 3.1. Characterisation of starting materials and tablets Mannitol and DCP showed a significant difference in regards to solubility in phosphate buffer. The solubility of mannitol in the used dissolution medium was determined to 240 g/l and was thus considered as highly soluble. The solubility of DCP as measured by weighing the sediments according to the method described in Section 2.3 was determined to 0.05 ± 0.005 g/l. This result was confirmed by the measurements performed on FBRM according to Section 2.5.2. Fig. 1 shows particle count of incrementally added DCP to phosphate buffer as measured by FBRM. Additions of DCP gave initially a slight increase in particle count, indicating a slow, nonetheless simultaneous dissolution of DCP. However,

further additions of DCP, corresponding to >0.049 g/l led to a distinguishable increase in particle count, implying that at this point a saturated solution of DCP was obtained and all further additions of DCP to the solution were maintained in particulate form. The results indicate that DCP was practically insoluble in the used dissolution medium. Apparent densities of HPMC, mannitol and DCP were 1.34, 1.49 and 2.14 g/cm3 , respectively (standard deviations less than 0.01 g/cm3 ). Attaining the same relative surface area exposed to the dissolution medium for all tablet compositions implied some variations in tablet porosities. This was a consequence of the differences in the apparent densities of the starting materials. The theoretical tablet porosities were 10, 12 and 20%. Measured in triplicates, the radial tensile strengths of the tablets were 3.6 and 3.5 MPa (±0.42 MPa) for the HPMC and HPMC/mannitol tablets and 1.7 MPa (±0.24 MPa) for the HPMC/DCP tablets. Visual inspection of all tablets was conducted during the release. All tablets maintained their mechanical integrity throughout the release process. 3.2. Release profiles of HPMC and additives The release of the relative amount of HPMC and additives is presented in Fig. 2. The release of HPMC increased linearly with time through most of the release process for all formulations. However, the presence of additives accelerated the rate of matrix erosion. The HPMC/mannitol tablets showed highest fraction HPMC released at the time which 50% (T50) polymer was released (6 h). The HPMC/DCP tablets showed slower release rates with T50 at approximately 9 h. The lowest fraction HPMC release rate was observed for the plain HPMC tablets with T50 of approximately 15 h. In addition, a lag time of 1 h was observed in the initial part of the release for the HPMC/DCP and HPMC tablets. The release profiles of the additives in relation to HPMC differed significantly. Approximately 20% of mannitol was released after the initial 45 min of the release process for the HPMC/mannitol tablets. Moreover, the release of mannitol was considerably faster than that

Fig. 3. T2 -weighted radial (a) and axial (b) images and their corresponding T2 -profiles (c and d) of a tablet containing 40% HPMC and 60% mannitol after approximately 2 h (radial) and 1.5 h (axial) release. rSF and rEF are the T2 -times and the corresponding swelling and erosion fronts for the radial image, respectively. aSF and aEF are the T2 -times and the corresponding swelling and erosion fronts for the axial image, respectively.

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Fig. 4. Front movements in radial (left) and axial (right) direction including polymer and additive release for the HPMC/mannitol (a and b) and HPMC/DCP (c and d) and plain HPMC (e and f) tablets. The figures include the position of the erosion front (), the swelling front (䊉), the release of HPMC () and the release of additives (). The shaded area in between the fronts resembles the gel layer thickness.

of HPMC, with a T50 value which was approximately 3 h lower than the corresponding T50 for the polymer release. In contrast to mannitol, the release of DCP occurred at a significantly lower rate and almost simultaneously to HPMC release.

(aSF, aEF) (Fig. 3c and d). This observation indicated that the concentration of water in the gel increased closer to the fringe of the tablet. The fronts in the radial direction were defined as the tablet and core radius (Fig. 3a), whereas the distance from the rotating disc to the respective front defined these boundaries in the axial direction (Fig. 3d). In this manner, images recorded at different time points during the dissolution process constituted the basis for the determination of the front positions.

3.3. MRI—defining the erosion and core fronts The positions of the erosion front (EF) and swelling front (SF) were assessed by identifying changes in the T2 -profiles at these boundaries of the tablet. The determination process of the SF and EF for the radial and axial scans of a tablet comprised of 40% HPMC and 60% mannitol is shown in Fig. 3. The T2 -time of the water protons increased slowly from the SF of the tablet towards the EF in radial (rSF, rEF) and axial directions

3.4. Front movements—radial view The front movements presented in this paper constitute the results from one of the studied replicates along with release data from three replicates. The trends of the front movements were how-

Table 1 Parameters related to the front movements studied from radial scans for HPMC, HPMC/mannitol and HPMC/DCP tablets.

Mannitol DCP HPMC a b

Tablet radius max. (mm)

Time max. radius (h)

T50a (h)

T50 EF (mm)

T50 SF (mm)

T50 gel thicknessb (mm)

5.1 4.8 5.6

0.5 0.8 2.1

6.2 9.4 14.1

3.8 4.0 4.3

0.8 2.1 1.5

3.0 1.9 2.8

Positions when the time is equal to T50. Calculated as the difference between EF and SF at T50.

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Fig. 5. Images illustrating the progression of the front boundaries in the axial plane for a tablet comprised of solely HPMC after approximately (a) 2 h, (b) 6 h, (c) 12 h and (d) 15 h.

ever similar for both imaging experiments within each formulation series. Fig. 4a–c illustrates the movement of the SF and EF viewed from the radial direction along with the release of HPMC and additives. The term progression is used in this context to describe the expansion and movements of the fronts away from the centre of the tablet. Similarly, the term regression is used to describe the diminishing and movements of the fronts towards the centre of the tablet. A rapid progression of the EF at the initial phase of the release was seen for all formulations, implying a fast hydration of the polymer chains and a rapid formation of a gel layer around the tablets. In addition, the maximum tablet size obtained upon swelling varied between the formulations. In this respect, the tablets comprised solely of HPMC and HPMC/mannitol showed higher degree of swelling compared to the HPMC/DCP tablets (Table 1). Clear differences were seen in regards to the time at which maximum tablet radius was reached. The HPMC/mannitol formulation reached maximum swelling after merely 0.5 h, whereas the HPMC/DCP and plain HPMC tablets reached this parameter after 0.8 and 2.1 h, respectively. The release of HPMC at this initial phase was notably higher for HPMC/mannitol composition, compared to the HPMC and HPMC/DCP tablets, which both showed a lag time in the initial part of the release. Moreover, a constant maximum swelling was seen for the HPMC/DCP and plain HPMC tablets (approximately at 4 and 5 h, respectively). In contrast, the HPMC/mannitol composition showed a rapid regression of the EF after reaching maximum swelling. The overall swelling and erosion behavior of the tablets can further be compared by determining the positions of the fronts at T50 for HPMC release. The EF for the HPMC tablet (4.3 mm) was more progressed compared to the HPMC/mannitol composition (3.8 mm). Concomitantly, a somewhat thicker gel

was observed for the HPMC/mannitol composition (3.1 mm) compared to the HPMC tablet (2.8 mm). The higher polymer release rate and faster regression of the EF boundary of the HPMC/mannitol tablet indicated faster rate of matrix erosion. The position of the SF at T50 was considerably more regressed for the HPMC/mannitol composition (0.8 mm) compared to the HPMC tablet (1.6 mm). Comparing the EF between HPMC/DCP and plain HPMC tablets at T50 revealed nearly the same tablet radius. Interestingly, a notable difference can be observed in the position of the SF for the two formulations. Positioned at 2.1 mm the SF of the HPMC/DCP tablet was least regressed compared to the other two formulations, hence this composition featured thinnest gel layer (1.9 mm). 3.5. Front movements—axial view Axial front movements and polymer release are shown in Fig. 5. None of the formulations showed a regression of the EF during the course of the release. In fact, considerably higher degree of EF progression was seen for the HPMC/mannitol and HPMC tablets as they expanded nearly 2- and 3-fold the original tablet heights, respectively. The height of the HPMC/DCP tablet was recorded roughly at the same position throughout the release process. A progression of not only the EF but also the SF can be noted for the plain HPMC tablet in the axial direction (Fig. 4). As depicted in Fig. 4, both the core and the tablet acquire a drop shaped configuration for this composition. Although not as pronounced as the HPMC tablet, the HPMC/mannitol tablet also showed drop shaped tablet and core in the axial plane (pictures not shown). The constant increase of the EF, in addition to the lack of regression of the SF yielded a thicker gel layer on the axial than the radial axis of the tablets.

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4. Discussion 4.1. Differences in the front boundaries in the radial and axial planes Anisotropic swelling of HPMC tablets have previously been reported in literature (Gao and Meury, 1996; Rajabi-Siahboomi et al., 1994). In most cases this finding was attributed to the uni-axial stress relaxation in the axial direction, in which the tablet was compressed. Higher shear forces exerted on the tablets from the radial direction during the dissolution has also been mentioned as a contributing factor to the more expanded position of the tablet vertically (Abrahmsén-Alami et al., 2007). In addition, the observed overall more durable gel layer of the plain HPMC tablet (Fig. 4e and f), which in turn implied higher water content in the gel could render the tablet more heavy and lead to higher impact of gravity in the axial direction. The position of the SF in the axial direction may also to some extent be affected by gravity. This is plausible as the swelled tablet contains a considerable amount of water at the position defined as the SF in the presented study. By performing T2 -relaxation weighted MRI on polymer solutions of known concentrations, the amount of water at the SF was estimated to 60% (w/w) (data not shown). Literature data suggests that the transition of HPMC from the glassy to the rubbery state close to room temperature occurs at a water content of approximately 20% (w/w) (Ford, 1999; Hancock et al., 1995; Trotzig, 2006). As release conditions in our study were performed at 37 ◦ C, this implies that the front determined as SF occurs at a water content significantly higher than that of the glass to rubber transition. As a consequence of the high content of water at the SF it may be concluded that gravity not only affects the position of the EF, but also the position of the SF in the axial direction. 4.2. Release mechanism of additives The release of the highly soluble mannitol was governed by diffusion, whereas DCP was released at the same rate or at some points even slower than HPMC. The small lag time of DCP in the beginning of the release process (Fig. 2) requires some attention. On one hand, as previously shown, the solubility of DCP in the current release conditions was 0.05 mg/ml. Given the volume of the release medium (0.5 l) the measured solubility implied that 25 mg DCP of the total dose (125 mg) was dissolved and gradually contributed to saturate the solution. However, as the FBRM technique only can account for the release of DCP in particulate form, the dissolved fraction of DCP was not seen in the release profile. By assuming that the first 25 mg of the released DCP dissolved before a steady increase of particulate DCP appeared, the release plots were recalculated as particle counts per mass unit as a function of elapsed time (Fig. 6). This result indicates that the particle count increase is of the same rate as the release of HPMC from the tablets. Nevertheless, it cannot be excluded that in the initial part of the release, HPMC hydration and swelling may occur at a faster rate than the DCP particles were translocated through the gel. This is suggested since longer time is required for the polymer chains to generate sufficient pushing force on the additive particles towards the EF (Bettini et al., 2001). 4.3. Release coupled with front movements The position and progression of the diffusion front have been contrarily debated in the literature. In some studies (Colombo et al., 1996; Bettini et al., 2001), a distinct boundary indicative of the dissolution of the additives in the gel has been assigned to this front. In

Fig. 6. Particle count per milligram DCP as the function of time as measured by FBRM. The release as HPMC is denoted as () and the release of DCP as ().

other studies such as that conducted by Gao (Gao and Meury, 1996), this process has not been accounted as visible. Although the diffusion front is not visualized in the presented study, the higher rate of core elimination indicates a more rapid diffusion of water into the HPMC/mannitol tablets. As seen in Fig. 4a, nearly all mannitol was released at the time the core of the HPMC/mannitol tablet had disappeared. This result suggests that the diffusion front of mannitol was practically adjacent to the SF throughout the release process, hence quick dissolution and release of this additive was obtained. The high solubility of mannitol may likely increase the wetting of the dry tablet core, which in turn can promote faster hydration and swelling of the polymer. In this respect, similar result was seen by Kazarian and Van der Weerd (2008), where the “true penetration front” (defined in this study much below 30% water content) was accompanied by a fast dissolution of a highly soluble additive. The influence of mannitol on the increased rate of water transport into the tablet can be expressed in terms of chemical potential or osmotic pressure. As long as the equilibrium of chemical potential in all parts of the system is not reached, an increased rate of solvent transport into the tablet may occur. This can be expressed as: J(z) ∝ −Deff c(z)



d   dz z

(5)

where J(z) is the flux  of water at position z, c(z) the concentration at position z, d/dz  the gradient in chemical potential  taken at z position z and Deff the effective diffusion coefficient. A definition of osmotic pressure, ˘, is provided in Eq. (6): 1 ˘(z) = − ((z) − ◦ )

v

(6)

where  is the molar volume of the solvent,  is the chemical potential of water at position z and ◦ is the chemical potential of pure solvent. By inserting the definition of ˘ into Eq. (5) an expression for the water flux as a function of osmotic pressure gradient is obtained: JH2 O ∝ Deff ×

d˘ dz

(7)

This expression has been used to describe the flux of water into the matrix tablets (Körner, 2006). Furthermore, the dissolution of additives can increase the osmotic pressure in the gel layer. In the case of plain HPMC and HPMC/DCP tablets only HPMC is the solute, whereas in the case of HPMC/mannitol tablets both HPMC and the highly soluble mannitol constitute the solute phase. Keeping in mind that osmotic pressure is a colligative property; a gradient in the gel is built up as the concentration of the dissolved additives is

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5. Conclusion

Fig. 7. The release of HPMC (mg) from HPMC/mannitol (䊉), HPMC/DCP () and plain HPMC tablets ().

higher closer to the SF. This will result in an effective mass transport of water into the matrix containing mannitol. Due to low solubility, DCP can contribute less than mannitol to the osmotic pressure, and thus less water transport into the gel. In addition, due to the high concentration of particulate DCP in the gel, it is likely that the effective diffusion of the dissolution medium (Deff ) is lower in the HPMC/DCP than HPMC/mannitol tablet. This is a conceivable scenario as DCP theoretically renders 60% excluded volume for water transport in the gel. In contrast, as the readily soluble mannitol exhibit fast dissolution upon contact with water, a large volume will be directly accessible for the dissolution medium in the gel. In summary, the dissolution media is more readily conveyed into the matrix containing mannitol and slowest in the matrix containing DCP. The different transport of water in the tablet formulations can affect polymer dissociation from the matrix in different ways. The dissociation and release of polymers from a gelling matrix has been found to be inversely proportional to the intrinsic viscosity, which in turn is linked to the critical disentanglement concentration (Ju et al., 1995; Körner et al., 2005). At this concentration the polymer chains at the EF are diluted to the point, where the shear forces in the dissolution medium can disjoint aggregates or individual polymer chains from the matrix. Fig. 7 exhibits the release of HPMC for all studied formulations expressed as mass unit per time. Noteworthy, the polymer release rates from the plain HPMC and HPMC/mannitol tablets are similar. This implies the same critical disentanglement concentration for both formulations. Although mannitol increases the rate of hydration of the glassy tablet core it does not seem to affect the rate of polymer disentanglement from the matrix. Therefore, the faster erosion rate of the HPMC/mannitol tablets can in fact be a consequence of the lower amount of HPMC in the HPMC/mannitol formulation. It should be noted that the results shown in Fig. 6 do not give any information in regards to the rate at which the disentanglement concentration is reached for the two formulations. A parameter that further can contribute to understanding this mechanism is the concentration gradient of solvent/polymer in the gel systems. Fig. 7 also reveals that the amount of HPMC released from DCP tablets is slightly lower than that of the two other formulations. This implies that the gel layer may need to dilute more to reach the disentanglement concentration in the presence of the low soluble additive. This effect in turn decelerates the release of the polymers from the tablet. In addition, the lower rate of water transport into the tablet may also contribute to the slower erosion of the HPMC/DCP formulation.

The objective of the presented work was to investigate the impact of the solubility of additives (excipients or active substances) on the progression of the swelling and erosion fronts of extended release HPMC matrix tablets. These front movements were determined by MRI and were related to the overall functionality of the tablets as expressed by the release of polymer and additives. The release of the highly soluble mannitol was governed by diffusion, whereas the poorly soluble DCP was released at the same rate as the matrix erosion. The rate of matrix erosion appeared to be dependent not only on the fraction of polymer used in the formulation, but also the solubility of the used additive. The formulation which did not comprise additives exhibited slowest rate of erosion. An important factor distinguishing the formulations containing mannitol and DCP was the rate of solvent transport into the tablets. Mannitol increased the rate of solvent ingress into the tablet. This was likely an effect of a created osmotic gradient, which in turn increased the rate of the solvent flux into the tablet. However, although mannitol increased the rate of hydration of the glassy tablet core it did not seem to affect the rate of polymer disentanglement from the matrix. The rate of water transport into the tablets containing the low soluble DCP was considerably lower than HPMC/mannitol tablet. This was attributed to the lower impact of osmotic pressure and slower diffusion of the solvent into the gel containing particulate DCP. Acknowledgments AstraZeneca and Swedish Knowledge Foundation (particularly the YPK-project) are acknowledged for funding this work. Sincere thanks to Jonas Johansson (FBRM) and Frida Iselau (SEC-RI chromatography) for their technical expertise and assistance with the analytical methods. AL was financed by the Swedish Research Council and by Chalmers Bioscience Program. References Abrahmsén-Alami, S., Körner, A., Nilsson, I., Larsson, A., 2007. New release cell for NMR microimaging of tablets. Swelling and erosion of poly(ethylene oxide). Int. J. Pharm. 342, 105–114. Alderman, D.A., 1984. A review of cellulose ethers in hydrophilic matrices for oral controlled-release dosage forms. Int. J. Pharm. Tech. Prod. 5, 1–9. Bajwa, S.G., Hoebler, K., Sammon, C., Timmins, P., Melia, C., 2006. Microstructural imaging of early gel layer formation in HPMC matrices. J. Pharm. Sci. 95, 2145–2157. Bettini, R., Catellani, P.L., Santi, P., Massimo, G., Peppas, A.N., Colombo, P., 2001. Translocation of drug particles in HPMC matrix gel layer: effect of drug solubility and influence on release rate. J. Control. Release 70, 383–391. Colombo, P., Bettini, R., Catellani, P.L., Santi, P., Peppas, A.N., 1999. Drug volume fraction profile in the gel phase and drug release kinetics in hydroxypropylmethyl cellulose matrices containing a soluble drug. Eur. J. Pharm. Sci. 9, 33–40. Colombo, P., Bettini, R., De Ascentiis, A., Peppas, N. A., 1996. Analysis of the swelling and release mechanisms from drug delivery systems with emphasis on drug solubility and water transport. J. Control. Release 39, 231–237. Colombo, P., Bettini, R., Santi, P., Peppas, A.N., 2000. Swellable matrices for controlled drug delivery: gel-layer behaviour, mechanisms and optimal performance. Pharm. Sci. Technol. Today 3, 198–204. Conte, U., Colombo, P., Gazzaniga, A., Sangalli, M.E., La Manna, A., 1988. Swellingactivated drug delivery systems. Biomaterials 9, 489–493. Fell, J.T., Newton, J.M., 1970. Determination of tablet strength by diametral compression test. J. Pharm. Sci. 59, 688–691. Ford, J.L., 1999. Thermal analysis of hydroxypropylmethylcellulose and methylcellulose: powders, gels and matrix tablets. Int. J. Pharm. 179, 209–228. Gao, P., Fagerness, P.E., 1995. Diffusion in HPMC gels. I. Determination of drug and water diffusivity by pulsed-field-gradient spin-echo NMR. Pharm. Res. 12, 955–964. Gao, P., Meury, R.H., 1996. Swelling of hydroxypropyl methylcellulose matrix tablets. 1. Characterization of swelling using a novel optical imaging method. J. Pharm. Sci. 85, 725–731. Hancock, C.B., Shamblin, S.L., Zografi, G., 1995. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperature. Pharm. Res. 12, 799–806.

F. Tajarobi et al. / European Journal of Pharmaceutical Sciences 37 (2009) 89–97 Heath, A.R., Bahri, P.A., Fawell, P.D., Farrow, J.B., 2006. Fluid mechanics and transport phenomena; polymer flocculation of calcite: relating the aggregate size to the settling rate. AIChE J. 52, 1987–1994. Jamzad, S., Tutunji, L., Fassihi, R., 2005. Analysis of macromolecular changes and drug release from hydrophilic matrix systems. Int. J. Pharm. 292, 75–85. Jeffers, P., Raposo, S., Lima-Costa, M.E., Connolly, P., Glennon, B., Kieran, M., 2004. Focused beam reflectance measurement (FBRM) monitoring of particle size and morphology in suspension cultures of Morinda Citrifolia and Centaurea calcitrapa. Biotech. Lett. 25, 2023–2028. Johansson, J., Folestad, S., Abrahamsson, B., 2006. Novel Process Analytical Methodology to Establish Design Space and Real Time Prediction of Dissolution AAPS Workshop on Calleges for Dissolution Testing for the 21th Century, Arlington, VA, USA, May 1–3, 2006. Ju, R.T., Nixon, P.R., Patel, M.V., 1995. Drug release from hydrphilic matrices. 1. New scaling law for predicting polymer and drug release based on the polymer disentanglement concentration and the diffusion layer. J. Pharm. Sci. 84, 1455–1463. Kazarian, S.G., Van der Weerd, J., 2008. Simultaneous FTIR spectroscopic imaging and visible photography to monitor tablet dissolution and drug release. Pharm. Res. 25, 853–860. Konrad, R., Christ, A., Zessin, G., Cobet, U., 1998. The use of ultrasound and penetrometer to characterize the advancement of swelling and eroding fronts in HPMC matrices. Int. J. Pharm. 163, 123–131. Kougoulos, E., Jones, A.G., Jennings, K.H., Wood-Kaczmar, M.W., 2005. Use of focused beam reflectance measurement (FBRM) and process video imaging (PVI) in a

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modified mixed suspension mixed product removal (MSMPR) cooling crystallizer. J. Cryst. Growth 273, 529–534. Körner, A., 2006. Dissolution of polydisperse polymers in water. Ph.D. Thesis. Center for Chemistry and Chemical Engineering, Lund University, Lund, Sweden. Körner, A., Larsson, A., Piculell, L., Wittgren, B., 2005. Molecular Information on dissolution of polydisperse polymers: mixtures of long and short poly(ethylene oxide). J. Phys. Chem., 109. Lapidus, H., Lordi, N.G., 1968. Drug release from compressed hydrophilic matrices. J. Pharm. Sci. 57, 1292–1301. Peppas, A.N., Gurny, R., Doelker, E., Buri, P., 1980. Modelling of drug diffusion through swellable polymeric systems. J. Membr. Sci. 7. Rajabi-Siahboomi, A.R., Bowtell, R.W., Mansfield, P., Henderson, A., Davies, M.C., Melia, C.D., 1994. Structure and behaviour in hydrophilic matrix sustained release dosage forms. 2. NMR-imaging studies of dimensional changes in the gel layer and core of HPMC tablets undergoing hydration. J. Control. Release 31, 121–128. Richardson, J.C., Bowtell, R.W., Mäder, K., Melia, C., 2005. Pharmaceutical applications of magnetic resonance imaging (MRI). Adv. Drug Del. Rev. 57, 1191– 1209. Trotzig, C., 2006. Water diffusion and free volume in hydrophilic polymers. Ph.D. Thesis. Lund University, Lund, Sweden, p. 294. Xinhui, H., Cunningham, C.J., Winstead, D., 2007. Study growth kinetics in fluidized bed granulation with at-line FBRM. Int. J. Pharm. 347, 54–61.