A possible application of magnetic resonance imaging for pharmaceutical research

European Journal of Pharmaceutical Sciences 42 (2011) 354–364

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

A possible application of magnetic resonance imaging for pharmaceutical research Joanna Kowalczuk, Jadwiga Tritt-Goc ∗ Institute of Molecular Physics, Polish Academy of Sciences, M. Smoluchowskiego 17, 60-179 Poznan, Poland

a r t i c l e

i n f o

Article history: Received 26 August 2010 Received in revised form 16 December 2010 Accepted 23 December 2010 Available online 30 December 2010 Keywords: Magnetic resonance imaging (MRI) Hydration Swelling Relaxation Diffusion Hydroxypropyl methylcellulose

a b s t r a c t Magnetic resonance imaging (MRI) is a non-destructive and non-invasive method, the experiment can be conducted in situ and allows the studying of the sample and the different processes in vitro or in vivo. 1D, 2D or 3D imaging can be undertaken. MRI is nowadays most widely used in medicine as a clinical diagnostic tool, but has still seen limited application in the food and pharmaceutical sciences. The different imaging pulse sequences of MRI allow to image the processes that take place in a wide scale range from ms (dissolution of compact tablets) to hours (hydration of drug delivery systems) for mobile as well as for rigid spins, usually protons. The paper gives examples of MRI application of in vitro imaging of pharmaceutical dosage based on hydroxypropyl methylcellulose which have focused on water-penetration, diffusion, polymer swelling, and drug release, characterized with respect to other physical parameters such as pH and the molecular weight of polymer. Tetracycline hydrochloride was used as a model drug. NMR imaging of density distributions and fast kinetics of the dissolution behavior of compact tablets is presented for paracetamol tablets. © 2010 Elsevier B.V. All rights reserved.

1. Introduction In recent years different nuclear magnetic resonance (NMR) methods have been widely used in the pharmaceutical industry, among them NMR imaging generally known as magnetic resonance imaging (MRI) or magnetic resonance microscopy (MRM). The former refers to NMR imaging in macroscale, the latter denotes imaging at higher spatial resolution. The limiting case of imaging, where the relaxation times, diffusion coefficient or spectra are measured from one or in some cases a few volume elements (voxels) of a large sample, is called spatially resolved NMR. The idea of how to use NMR in order to obtain spatially resolved information about the studied sample came about in 1973 independently from two scientists: Lauterbur and Mansfield (Lauterbur, 1973; Mansfield and Grannell, 1973). They proposed to apply a time dependent linear gradient field onto the static magnetic field to relate the magnetic field to the spatial position. Since the nuclear magnetic resonance frequency (the Larmor frequency) is proportional to the magnetic field, there is also a linear relationship between the resonance frequency and the spatial position. It makes possible to produce 1D profile and 2D or 3D images with the spatial resolution order of tens of ␮m. The gradients are usually applied in

∗ Corresponding author. Tel.: +48 61 8695226; fax: +48 61 8684524. E-mail address: [email protected] (J. Tritt-Goc). 0928-0987/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2010.12.009

three perpendicular directions x, y and z, and called the frequency encoding Gx , the phase encoding Gy and the slice selection Gz gradients, respectively. In order to achieve the best resolution, in MRI experiments very often a slice of the sample is imaged, instead of the whole sample. The intensity of every point of the image is directly proportional to the spin density of the resonance nuclei (usually protons) in this point. Depending on the experimental conditions it is possible to measure the spin density (r), the spin–spin relaxation time T2 , the spin–lattice relaxation time T1 or the diffusion D weighted images. The imaging methods allow the collection of images taken in the function of time from the same sample. This fact removes the inherent sample to sample variations. The details of the theory of MRI are described in excellent books (Callaghan, 1991; Kimmich, 1997; Blümich, 2000). Magnetic resonance imaging is a non-destructive and noninvasive method, the experiment can be conducted in situ and what is more the method allows studying the sample and the different processes in vitro or in vivo. Therefore, MRI is nowadays most widely used in medicine as a clinical diagnostic tool and represents a breakthrough in medical diagnostics and research. The importance of NMR imaging in medicine was acknowledged by the Nobel Prize in medicine in 2003 which was awarded to Lauterbur and Mansfield for their pioneering contributions, which later led to the applications of magnetic resonance in medical imaging. Magnetic resonance imaging is also the stimuli for the pharmaceutical development which is recently undergoing explosive

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growth (Richardson et al., 2005; Nott, 2010). This method provides an excellent opportunity, in particular for controlled release or solid dispersion dosage forms, to follow and understand all important mechanisms that might contribute internally to the drug release process (Alderman, 1984; Conte et al., 1988; Bowtell et al., 1994; Davies and Melia, 1994; Rajabi-Siahboomi et al., 1994; Fyfe and Blazek, 1997; Barbieri et al., 1998; Snar et al., 1998; Fyfe and BlazekWelsh, 2000; Bajpai and Giri, 2002; Tritt-Goc and Pi´slewski, 2002; Tritt-Goc et al., 2003, 2005; Kowalczuk et al., 2004; AbrahmsenAlami et al., 2007; Dahlberg et al., 2007; Dahlberg, 2010). With the resolution of images better than (100 ␮m2 ) 1 H MRI microscopy can also be used to determine the porosity and compaction density within compacted tablets (Nebgen et al., 1995; Tritt-Goc and Pi´slewski, 2000). This is a significant advance for the pharmaceutical scientist, because in situ data on local homogeneities within tablets is difficult to obtain using other techniques. The MRI method is also used in the optimisation of compression coated regulated release systems (Fahie et al., 1998; Rajabi-Siahboomi et al., 1998) and can be used for the in situ study of the disintegration of compact tablets (Tritt-Goc and Kowalczuk, 2002; Djemai and Sinka, 2006; Körner, 2006). In contrast to the controlled released drugs where the MRI experiments are performed in the long-time scale (from hours to days), the disintegration of compact tablets is a fast process that lasts minutes but can be followed thanks to different methods of MRI. The application of MRI in pharmacy has shown that this method is a powerful tool for understanding key processes inside pharmaceutical dosage forms and plays an important role as a method to assist product development. The main goal of this paper is to show the examples of MRI experiments which can be useful in the pharmaceutical research and the parameters which can be measured. The paper presents the results obtained in our laboratory and is concentrated on MRI applications to the hydroxypropyl methylcellulose, the most successful carrier material for solid dispersions and controlled realized drugs. Some examples of the study of the compact tablets will also be given. We hope that the paper will stimulate the interest in MRI and enable people to start applying any of the presented MRI methods. 2. Methods and materials

Fig. 1. The simplified Single-Slice-Multi-Echo (SSME) pulse sequence. The 90◦ and 180◦ are the soft radio-frequency pulses and Gz , Gy , and Gx are the slice, phase and frequency encoding gradients, respectively.

T1 contrast can be eliminated from the images. In this equation T2 is called the spin–spin relaxation time. However, quantitative true T2 values cannot be calculated in conventional micro imaging experiments from a series of images with increasing echo time, because T2 is strongly affected by the self-diffusion effect (Brandl and Haase, 1994). This effect can be eliminated using a modified spin – echo pulse sequence, which was theoretically justified and confirmed in an appropriate experiment (Hsu et al., 1995). However, in the experiments described in this paper, a conventional spin – echo sequence was used. Therefore, the measured T2 values are the “effective T2 ” rather than the spin–spin relaxation time. The spatial distribution of the spin–spin relaxation time T2 and spin density  can be determined directly from the images (Tritt-Goc and Pi´slewski, 2002; Tajarobi et al., 2009). Through the replacement of 180◦ pulse by the Carr Purcell Meiboom Gill echo sequence, which generates a series of echoes instead of a single one (Meiboom and Gill, 1958) the so-called Multi-Slice-Multi-Echo (MSME) pulse sequence is generated. This pulse sequence allows the measurements of T2 weighted images. The data for the equivalent pixel in each of the images are fitted to the equation

 t 

2.1. The MRI methods

M(t) = M0 exp − Proton MRI experiments were performed on Bruker AVANCE 300 MHz WB spectrometer, equipped with a 7T vertical bore superconducting magnet and microimaging probehead with a 25, 15 or 10 mm coil and a maximum magnetic field gradient of 100 Gs/cm in the x, y and z directions. The most frequently used pulse sequence was Single-Slice-Multi-Echo (SSME) pulse sequence (Fig. 1) (Blümich, 2000). In this sequence the excitation radio-frequency (RF) pulse is soft and thereby selective. The slice selection field gradient Gz is linear and applied simultaneously with the RF pulse, which bandwidth is dependent on the gradient shape and duration. Thus, the slice thickness is determined by the bandwidth of the pulse and the strength of the gradient Gz . The phase Gy and frequency Gx encoding gradients provide spatial information. The intensity of the image signal is given by the following equation (Callaghan, 1991; Kimmich, 1997; Blümich, 2000):



 T  R

S =  1 − exp −

T1

 T  E

exp −

T2

(1)

where  is the spin density, T2 the spin–spin relaxation time, T1 the spin–lattice relaxation time, TE the echo time, and TR the repetition time. As seen in Eq. (1) the image intensity depends on T2 , T1 and . However, when the TR is sufficiently long (≥5T1 ) the

355

T2

(2)

where M(t) is the measured transverse magnetization, M0 is the equilibrium value of the magnetization (proportional to spin density ), and t is the echo time, which is varied during the experiment. The fitting of Eq. (2) to the experimental data provides the spatial distribution of the fitting parameters T2 and M0 (spin density) or so-called spin–spin and spin-density images, profiles or maps. The imaging experiments described above were used to characterize the swelling behavior of hydrophilic polymer matrix: hydroxypropyl methylcellulose (HPMC). The swelling experiment was initiated after adding an excess amount of the appropriate solvent to an initially dry tube containing the sample and kept in a solvent bath at studied temperature. At different hydration times, the solvent was removed from the tube, and the sample placed in the magnet of the NMR spectrometer for imaging. Such a procedure was repeated until the beginning of the dissolution of the HPMC samples was observed. The sample was laid along the direction of the main magnetic field and the NMR properties of the samples such as spin–spin relaxation time and spin density of the solvent were mapped in the function of time. The images were acquired with the repetition time TR of 3000 ms and echo time t was varied from 10 to 360 ms. The acquisition parameters were

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Fig. 2. The Pulse Gradient Spin Echo pulse sequence for measurements of diffusion coefficient D. 90◦ and 180◦ are the radio-frequency pulses forming the spin echo separated by gradient field pulses of magnitude G and duration ı.  is the gradient pulse interval called also the diffusing time. To determine D the echo signal intensity is measured as a function of G while other parameters are constant.

a field-of-view (FOV) of 1.5 mm × 1.5 mm digitized into 128 × 128 pixels with a slice thickness of 2 mm (i.e. each voxel equals 117 by 117 by 2 × 103 ␮m). The MRI measurements were performed at 37 ◦ C. Beside the experiments that allow the measurements of the spin density (r), the spin–spin T2 or the spin–lattice relaxation time T1 images there is also the experimental possibility to obtain the diffusion D weighted images. Pulse Gradient Spin Echo (PGSE) (Stejskal and Tanner, 1965; Mair et al., 1998; Walderhaug and Nyström, 1999; Dvinskikh et al., 2001; Topgaard et al., 2002) sequence presented in Fig. 2 is used to measure the diffusion coefficient D in the standard NMR experiments. When this pulse sequence is superimposed on the SSME pulse sequence presented in Fig. 1, the spatially resolved values of the diffusion coefficient are measured. The NMR diffusion measurements use the Hahn spin echo pulse sequence (/2––) with a pair of square-shaped gradient field pulses (separated by time ) of magnitude G and duration ı – the first applied between the two RF pulses and the other after the  pulse. The echo amplitude is attenuated by an amount dependent on the change in the spins position by the process of self-diffusion in the time interval . The attenuation of the echo signal due to the diffusion is described by the equation S(bi ) = S0 exp(−bi D)

(3)

bi =  2 Gi2 ı2

−

ı 3

thickness of 2 mm (i.e. each voxel equals 117 by 117 by 2 × 103 ␮m). The MRI measurements were performed at and 37 ◦ C. SSME and MSME pulse sequences are useless for imaging systems characterized by very short relaxation times, for example the distribution of the of polymer or drug within the dry solid dispersion system, or for imaging the physical processes like for example: the disintegration or the decomposition of tablets which occur on a very fast time scale. One of the methods suitable for imaging the distribution of rigid protons within the particular sample is Single Point Imaging (SPI), also called Constant Time Imaging (CTI) method (Gravina and Cory, 1994; Fang et al., 2001; Li et al., 2009). In SPI pulse sequence (Fig. 3) a single data point is collected at a fixed encoding time tp , after the RF pulse. The spatial dimension is phase-encoding by cycling the magnetic field gradient amplitude (G) along x, y or z direction. The RF pulse is applied while the phase-encoding gradient is on as is shown in Fig. 3. Thus the duration of the pulse should be short enough to cover the frequency range introduced by the gradient. Because there is no frequency-encoding gradient, the SPI images are free from distortions due to the magnetic field inhomogeneity, susceptibility variations and chemical shift. The signal intensity S in the image is proportional to the local proton density  according to

 t  p

with the attenuation factor bi equal:



Fig. 3. Illustration of Single Point Imaging (SPI) sequence in one dimension. RF is a broadband pulse exciting transverse magnetization which is phase encoded at time tp . A single point of the signal is acquired at each gradient value G.



S =  exp − (4)

In Eqs. (3) and (4) S(bi ) and S0 are echo signal intensities at t = 2 with and without the field gradient pulse being the strength G, respectively.  is the pulse interval,  the magnetogyric ratio of the proton, D is the diffusion coefficient and  is the gradient pulse interval, which is called the diffusing time. The echo signal intensity was measured as a function of G and the plot of ln S(bi ) against  2 G2 ı2 ( − ı/3), so called Stejskal–Tanner plot, gives a straight line with a slope of −D if the studied sample consists of a single component. This means that the D value can be determined from its slope by fitting Eq. (3) to the experimental points. When the PGSE pulse sequence is combined with the SSME pulse sequence the diffusion coefficients D is calculated pixel by pixel by fitting Eq. (3) to experimental points and as a result the map of the diffusion coefficient is obtained for the studied samples. The Stejskal–Tanner imaging sequence was used in our study to exploit the diffusion of the solvent into hydroxypropyl methylcellulose. The diffusion measurements were performed with the following constant values of parameters: ı = 2 ms,  = 10 ms, TR = 3000 ms, and the echo time TE = 19 ms. Only the G parameter was being incremented during the experiment from 0 to 100 Gs/cm. The acquisition parameters were a field-of-view (FOV) of 1.5 mm × 1.5 mm digitized into 128 × 128 pixels with a slice

T2



1 − exp(TR /T1 ) sin  1 − cos  exp(−T/T1 )

(5)

where TR is the repetition time,  is the flip angle of RF pulse and T1 and T2 are the spin–lattice and spin–spin relaxation times, respectively. The 1D pulse sequence presented in Fig. 3 can be easily expanded to 2D or 3D methods by applying the phase-encoding gradient in the second and/or third direction. In our work the SPI method was applied in order to obtain the distribution of protons within the paracetamol tablet. The 1D profile was acquired with tp = 105 ␮s and a resolution of 117 ␮m, at room temperature. The processes which take place very fast like the kinetics of the disintegration process of paracetamol in aqueous solution can be followed by the Snapshot FLASH (Fast Low Angle Shot) imaging pulse sequence shown in Fig. 4 (Haase et al., 1986; Deichmann et al., 1995; Rokitta et al., 1999). The technique uses excitation pulses with small flip angles ˛ of the order of 15◦ . NMR signal is detected in the form of a gradient echo generated by the reversal of the read gradient. The sequence is repeated n times recording n projections with different phase-encoding gradients. No waiting time is required between subsequent excitations. The FLASH technique has the following advantages: optimal signal to noise ratio, measuring time reduced about 100-fold, uses an extremely low power pulse. Additionally no loss of spatial resolution is observed. Snapshot FLASH imaging allows the fastest acquisition of images among

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the amount of non-active additives not specified by the pharmaceutical companies. 3. Results and discussion 3.1. MRI studies of the hydrophilic polymer matrix on the example of hydroxypropyl methylcellulose

Fig. 4. Timing diagram of the 2D Snapshot FLASH (Fast Low Angle Shot). The method uses excitation pulse ˛ with a small flip angle of the order of 15◦ . The scheme is repeated n times and the signal is recorded in the form of a gradient echo after time reversal by the read gradient Gx .

MRI methods. Because of a small excitation pulse it is possible to work with a repetition time TR which is very small in comparison to the spin–lattice relaxation time T1 . Thus, a high resolution image may be acquired in a very short time order of milliseconds. The FLASH pulse sequence was applied in this work to study in situ fast processes such as the dissolution of paracetamol tablets. We use the flip angle of 15◦ . Cross-section radial images were taken through the center of the tablet (2 mm thickness) with the resolution of 117 ␮m × 117 ␮m and were recorded within 452 ms. 2.2. Materials The subject of our MRI studies was hydroxypropyl methylcellulose, HPMC (pure and drug-containing) and paracetamol tablets. HPMC is the most commonly used polymer in the production of coated tablets, controlled release, and solid dispersion forms. Paracetamol, under different names, is most commonly and widely used as a pain reliever and fever reducing medicine. As a model drug, we used tetracycline hydrochloride (TETHCl), a broadspectrum antibiotic widely used in medicine. HPMC (with a molecular weight of 120,000 and 86,000) and tetracycline hydrochloride, TETHCl, were purchased as powders from Aldrich Co., Germany and used as supplied. The samples (tablets) for microimaging experiments had a cylindrical shape with 8 mm in diameter and 5 mm in lengths. They were prepared by compressing polymer powder or a homogeneous mixture of drug and polymer powder under a pressure of 90 MPa. In addition, for HPMC of 86,000 the sample was prepared by compressing a homogeneous mixture of the drug TETHCl and the polymer. Each of the samples was affixed to the base of the NMR glass tube by a silicone rubber compound adhesive. With the appropriate slice selection pulse gradient, 2 mm thick slices from the middle of the sample were selected for the image. The image slice was always well away from the area in contact with the glue. In order to simulate the swelling behavior of HPMC matrices in the condition of the gastrointestinal tract, as a hydrated medium we used the solvent with different pH (2, 7, and 12). The solvents penetrate the samples from all sites with the exception of the bottom. The hydration process started after immersing the HPMC tablet in the particular solvent at the temperature of 37 ◦ C. The paracetamol tablets under study, manufactured by various pharmaceutical companies named: A, B, C and D are commercially available on the Polish market. They are characterized by the same amount (500 mg) of 4-(N-acetyl) aminophenol but can differ as to

3.1.1. The gel layer formation The exposition of the hydrophilic HPMC matrix to water or another solvent causes the hydration of the matrix from the outer boundary towards the center of the sample. As a result a gel layer forms around the dry core of the polymer (Rajabi-Siahboomi et al., 1994; Fyfe and Blazek, 1997; Bettini et al., 2001; Kojima and Nakagami, 2002; Tritt-Goc and Pi´slewski, 2002; Tritt-Goc et al., 2003; Tritt-Goc and Kowalczuk, 2005; Kowalczuk et al., 2004; Dahlberg, 2010). Fig. 5 presents the selected 2D images of pure HPMC (d) and containing different amounts of TETHCl (a–c). The images were taken after different times of swelling (10, 20 and 60 min) for acidic solvent (pH = 2). The signal intensities on the images come only from the solvent protons within the gel layer of polymer. The polymer protons have a spin–spin relaxation time T2 too short to be observed in our experimental conditions. Hence, the white color on the images refers to the solvent molecules forming the gel layer of the polymer whereas the black color in the center of images indicates the anhydrates part of the sample (dry HPMC). Three features are easily seen from the images in Fig. 5: the regular growth of the gel layer, the decrease of the glassy core of the polymer, and the increase of the dimension of the samples. The border between the gel layer and the dry core of the polymer forms the diffusion or solvent penetration front. The distance between the diffusion front and the outer edge of the sample defines the thickness of the gel layer (r) which can be determined directly from the images. With increasing swelling time, the gel layer broadens and finally, after appropriate time, no part of the tablet remains dry. However, in our studies we performed the hydration experiment until the beginning of the dissolution of the tablets was observed and thus not until the full hydration of the sample. The same preparation method of the all studied HPMC samples avoided any influence of the manufacturing process on the matrix. On the basis of the images like that in Fig. 5 the quantitative characterization of the swelling can be attempted. First, we can estimate the amount of hydrated HPMC through the measurements of the gel layer thickness r. This quantity and its variation by the swelling time are shown in Fig. 6 for the HPMC sample with the molecular weight of 120,000 and solvent with different pH value (2, 7 and 12, respectively). During the hydration of the hydrophilic polymer two simultaneous processes take place: the diffusion of the solvent within the sample and the swelling of the polymer matrix in the opposite direction (Alderman, 1984; Sung et al., 1996). Therefore, on can write r = d + s, where d is the distance on which the diffusion front penetrates the glassy HPMC sample and s the swelling-size. The diffusion distance is calculated from the relation d = (n − m)/2 where n, is the diameter of the dry sample (before hydration) and m is the diameter of dry core at the particular hydration time t. Both contributions: d and s can also characterize the polymer swelling and can be evaluated on base of the experimental images and above relations. Their dependencies on the hydration time are of similar character with that presented in Fig. 6. In this figure the solid curves represent the best fitting of the equation r(t) = a + bt n

(6)

to the experimental points. The points represent the thickness of the gel layer measured at a particular hydration time. In Eq. (6) a and b are the constants, r is the gel layer thickness which

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Fig. 5. The 2D radial images of a 2 mm slice at the center of HPMC tablets contained 35% of TETHCl (a), 25% of TETHCl (b), 20% of TETHCl (c), and for pure HPMC (d). Images were taken at 37 ◦ C, in solvent with pH = 2 and after different times of swelling 10 min, 30 min, and 60 min, respectively. The acquisition parameters were a field-of-view (FOV) of 1.5 mm × 1.5 mm digitized into 128 × 128 pixels with a slice thickness of 2 mm (i.e. each voxel equals 117 by 117 by 2 × 103 ␮m).

Fig. 6. Thickness of the gel layers formed on the HPMC (120,000) tablets as a function of swelling time, evaluated from the images like that in Fig. 5. The solid lines represent the best fit of Eq. (6) to the experimental points with n value equal 1 for acidic (pH = 2) and 0.5 for neutral (pH = 7) and alkaline (pH = 12) solvent, respectively.

depends on hydration time t, and n is the exponent characterizing the swelling mechanism. The swelling process can be classified as diffusion controlled with n = 0.5 or swelling controlled with n = 1. Only for these two cases does the above equation become physically realistic. Other values of n indicate anomalous case of diffusion (Fyre et al., 1993; Ercken et al., 1996; Chin et al., 1999; Rinaki et al., 2003; Kowalczuk et al., 2004; Adriaensens et al., 2004; Tritt-Goc et al., 2005; Adriaensens et al., 2001). Parameters estimates derived from fitting Eq. (6) to the experimental points in Fig. 6 are shown in Table 1. The n value is equal 1 for acidic solvent indicated swelling controlled process. The value of n = 0.5 for neutral and alkaline solvents indicates that the swelling of HMPC is controlled by the diffusion. In the literature, the classification of the swelling process is usually based only on the value of the n parameter. However, according to Alfrey’s classification (Alfrey et al., 1966) the spatially resolved spin–spin relaxation times and spin densities of solvent molecules within the gel layer of the polymer together with the values of n

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Table 1 Parameters derived from fitting of Eq. (6) to the experimental results of the increase in the gel layer thickness, for the HPMC (120,000) and solvent with different pH, as a function of hydration time. pH

a

b

n

R

2 7 12

1.23 ± 0.28 0.75 ± 0.04 0.75 ± 0.12

0.02 ± 0.01 0.16 ± 0.01 0.17 ± 0.04

1.00 ± 0.19 0.51 ± 0.02 0.51 ± 0.04

0.994 0.999 0.999

should be taken into consideration to fully classify the mechanisms of the solvent diffusion into the polymer. In the case of diffusion controlled process the concentration of the solution in the gel layer of the polymer increases when going from the dry core of the polymer to the external edge of the layer, the profile of T2 relaxation time of the solution is constant throughout the gel layer, and the depth of a solvent penetration is proportional to the square root of the diffusion time (n = 0.5). In this case the diffusion of the solution is very slow in comparison with polymer relaxation. On the other hand the swelling controlled process is characterized by the profile of concentration which is constant in the gel layer, the T2 relaxation time which increases when going from the dry core of the polymer to the external edge of the layer, and the depth of a solvent penetration being proportional to the diffusion time (n = 1) (Thomas and Winde, 1982; Hui et al., 1987a,b). The diffusion of solvent is considerably quicker in comparison to the speed of polymer chain relaxation. 3.1.2. One dimensional solvent density and spin–spin relaxation profiles The MSME pulse sequence allows the obtaining of spatially resolved values of solvent density () and spin–spin relaxation (T2 ) within the gel layer of HPMC tablets. The corresponding 1D radial  and T2 profiles are shown in Figs. 7 and 8, respectively. The profiles are measured for the same HPMC samples as in Fig. 6 after 210 min of hydration time and only their left parts are presented. The profiles differed as to the shape. The  profile of concentration is constant in the gel layer for acidic solvent and shows a continuous decrease in the proton concentration from the most outer part of the gel layer toward the dry core of HPMC for the alkaline solvents. The differences for both solvents are also seen in the T2 profiles. The alkaline protons are characterized by constant value of the spin–spin relaxation time throughout the gel layer whereas a continuous decrease in the relaxation time is observed for acidic protons. The density and spin–spin relaxation profiles for the neutral solvent diffused into the hydroxypropyl methylcellulose show the behavior that is a mix of that found for acidic and alkaline solvents.

Fig. 7. MRI one dimensional signal intensity profiles of HPMC tablets taken after 210 min of hydration. The profiles (only left parts are presented) are for the same samples and solvents as in Fig. 6.

Fig. 8. MRI one dimensional spin–spin relaxation profiles of HPMC tablets taken after 210 min of hydration. The profiles (only left parts are presented) are for the same samples and solvents as in Figs. 6 and 7.

The shape of spin-density and spin–spin relaxation profiles of acidic and alkaline protons in the gel layer of the HPMC polymer confirmed the swelling mechanism to be swelling controlled for the former solvent and diffusion-controlled for the latter one (Berensen, 1977; Hui et al., 1987a,b; Argon et al., 1999; Qian and Taylor, 2000; Kosmidis et al., 2003). However, in the case of neutral solvent, judging only from the value of n (n = 0.51) obtained by fitting Eq. (6) to the proper experimental data showing the increase of the gel layer thickness in the function of hydration time – Fig. 6, the swelling mechanism was classified as diffusion controlled. The 1D profiles of  and T2 obtained for neutral water solvent clearly demonstrate that such a conclusion was incorrect and for neutral solvent the diffusion mechanism should be classified as an anomalous diffusion (Fick, 1855; Rogers et al., 1965; Lloyd et al., 1995; Ghi et al., 1997; Hopkinson et al., 1997, 2001; Vrentas and Vrentas, 1998; Sleep, 1998; Collins, 1998; Goodwin et al., 2000; Brazel and Peppas, 2000; Vesely, 2001; Sanopoulou and Stamatialis, 2001; Tritt-Goc and Pi´slewski, 2002; Buonocore et al., 2003). Our results proved that the MRI method is indeed the only one which allows the distinguishing of the abnormal solvent diffusion into the polymer. The spatially resolved relaxation data in Fig. 8 serves not only for the classification of the swelling mechanism, but can also provide information about the interactions of solvent molecules and the HPMC polymer. As can be seen from profiles the values of T2 taken about 0.25 mm from the most outer part of the gel layer differ very much depending on the solvent pH value. They are correspondingly equal to 150 ms, 98 ms and 43 ms for acidic, neutral and alkaline solvent. A single relaxation time was measured for all studied solvents which indicates the fast exchange process of the solvent protons at the studied temperature (37 ◦ C). Therefore, like in other polysaccharides gels, the spin–spin relaxation data for an acidic solvent have been interpreted in terms of fast exchange between the free and bound state of water (Smyth et al., 1988; Ganapathy et al., 2000). To explain the reduction in the T2 values observed for neutral and especially for alkaline solvents, we assumed in addition to fast exchange process also a chemical exchange between water protons and the hydroxyl groups of side chains of the polymer and the hydroxyl group of alkaline solvent (Hills et al., 1990; Roorda et al., 1990; Lewis et al., 1987; Barbieri et al., 1998). The chemical exchange relaxation process is the major contribution to the relaxation in an alkaline solvent, significantly reducing the relaxation value in comparison to ones measured for an acidic solvent. 3.1.3. One dimensional solvent diffusion profiles The Stejskal–Tanner imaging sequence (Stejskal and Tanner, 1965) was used to exploit the diffusion of water solvent into cylindrically shaped HPMC tablets. The diffusion gradients were

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Fig. 10. The mean diffusivity values for the alkaline (pH = 12) solvent penetrating the HPMC samples with molecular mass of 86,000 and 120,000. Fig. 9. MRI one dimensional diffusion profile of HPMC tablets (86,000 and 120,000) taken after 210 min of hydration. The profile was measured for alkaline solvent after 210 min of hydration and along the axial direction of the cylindrical sample. The acquisition parameters were a field-of-view (FOV) of 1.5 mm × 1.5 mm digitized into 128 × 128 pixels with a slice thickness of 2 mm (i.e. each voxel equals 117 by 117 by 2 × 103 ␮m).

applied in radial or axial directions, thus the solvent diffusion coefficient (more precisely mutual diffusion coefficient) was measured in these directions. Fig. 9 present the example of 1D profile (only the left side) of alkaline solvent diffusing within the gel layer of HPMC of molecular weight equal 86,000 and 120,000. The profile was measured after 210 min of hydration time along the axial directions. Of the two of HPMC polymers, the solvent diffusion within the gel layer of the HPMC with higher molecular mass (120,000) is faster than into the HPMC characterized by lower molecular mass (86,000). The same effect was also observed in the hydration process of both polymers. The hydrodynamics volume occupied by the hydrated polymer chains is larger in the polymer of higher molecular weight. Consequently, a greater swollen mass of the matrices is formed at this same time. The increase in the initial diameter of the samples, observed after 180 min of hydration, was equal to about 27% and 48% for HPMC with lower and higher molecular weight, respectively. In swollen polymer matrix there is higher motional freedom for the solvent molecules characterized by a higher diffusion coefficient. The obtained diffusion coefficients reflect the mobility of the translation motions of the solvent molecules in the gel layer of HPMC matrices and in opposite to the spin–spin relaxation times they are independent on the magnetic field. The HPMC matrix is inhomogeneous for the diffusing solvent molecules and to fully describe the diffusion phenomenon one needs to determine the full diffusion tensor. The diffusion tensor (3 × 3 matrix) is symmetric, only six elements are independent and therefore six measurements in non-linear directions are needed to estimate the tensor. After diagonalization of the tensor the eigenvalues (Dxx , Dyy , Dzz ) and eigenvectors are determined. Traditionally, in diffusion-weighted imaging, three gradient-directions are applied, which are sufficient to estimate the trace of the diffusion tensor or so-called mean diffusivity (Stejskal and Tanner, 1965; Hills et al., 1990; Griffiths et al., 1992; Basser et al., 1994; Ilyina and Daragan, 1994; Bjorling et al., 1995; Matsukawa and Ando, 1996; Cercignami and Horsfield, 2001). The mean diffusiv ¯ = (1/3) Dxx + Dyy + Dzz is a directionally averaged diffusion ity D coefficient that can be obtained by averaging the diffusion tensor measured in three orthogonal directions, without estimating the full tensor. In our experimental setup the cylindrical HPMC samples were fitted into the NMR probehead and than in the magnet with the main axis of the sample oriented along the z axis of the static magnetic field Bz . For cylindrically sample Dxx = Dyy and only two diffusion gradients Gz , and Gx , applied along x and z axes of the

frame connected with the sample were needed to determine the mean diffusivity within the gel layer. The directionally averaged diffusion coefficients obtained for the studied samples are presented in Fig. 10. The data provide information about the diffusion anisotropy in particular voxels of the gel layer of HPMC samples. On the base on the results describe previously, we determined the diffusion mechanism to be diffusion-controlled for the alkaline solvent. If so, Fick’s law of diffusion holds and the kinetics should follow a square-root law √ (7) d = 2NDt 1/2 where d is the diffusion distance, N the dimension in which the diffusion takes place, and t is the diffusion time. In our experiment t =  = 10 ms and N = 3. MRI can only measure diffusion along one direction at a time but the diffusion coefficients presented in Fig. 10 are the mean diffusivities values and thus described the diffusion in three directions. For the most outer voxels of the gel layers from Fig. 10, they are equal 1.727 × 10−9 m2 /s and 1.24 × 10−9 m2 /s and for HPMC of 120,000 and 86,000 molecular mass, respectively. After inserting these values into Eq. (7), one can estimate the diffusion distance of the alkaline solvent, within the gel layer. For HPMC with higher molecular weight the distance is about 1.01 × 10−9 m. The studied solvent diffusivity is of great importance because the solvent penetration rate determined the kinetics of the gel layer formation of the controlled release drug or solid dispersion, and therefore, significantly influenced drug realize and dissolution. MRI methods can be successively used to perform the study of solvent diffusion into the hydrophilic matrix. 3.1.4. Drug release experiments Hydroxypropyl methylcellulose is the polymer most frequently used as the carrier in the production of the controlled release drugs, coated tablets or solid dispersions. The experiments described previously demonstrated that HPMC swells when in contact with water solution and forms a gel layer. The kinetics of the gel layer formation is a key parameter that controls the drug release and decides about the success or failure of particular drugs. There are two basic possibilities of the drug release from hydrophilic polymers: through the dissolution of the polymer matrix or diffusion of the drug through the gel layer of the polymer (Alderman, 1984; Sung et al., 1996; Conte et al., 1988; Brazel and Peppas, 1999; Bettini et al., 2001; Roy and Rohera, 2002; Kojima and Nakagami, 2002). We studied the release of tetracycline hydrochloride (TETHCl) from HPMC sample with molecular weight of 86,000 immersed in the acidic (pH = 2) solvent at 37 ◦ C. The temperature and the solution medium were chosen to simulate the temperature of the human body and the acidic condition of the human stomach. The selected images generated in the radial plane after 10, 30, and 60 min of hydration are presented in Fig. 6. The influence of the

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Fig. 11. Thickness of the gel layers formed on the HPMC (86,000) matrix loaded with 35%, 25% and 20% of the model drug tetracycline hydrochloride as a function of swelling time, evaluated by imaging from Fig. 6. They were hydrated in the acidic (pH = 2) solvent at 37 ◦ C. The solid lines represent the best fit of Eq. (6) to the experimental points.

TETHCl on the swelling process of HPMC is easily seen. The sample with the highest amount of the drug (35%) exhibited the highest increase of the gel layer thickness as a function of hydration time in comparison with a matrix loaded with 25% and 20% of the drug or pure 100% HPMC. The hydration process of the HPMC samples was finished before the erosion of the sample. Therefore it is reasonable to assume that the release of the drug took place by its diffusion through the gel layer of the polymer. Visually the drug release was observed by the change of the color of the hydration solvent from white to yellow, which is the color of the dry TETHCl drug. The intensity of this color increased as a function of hydration time, which indicated the increase of the dissolved drug concentration in hydration solvent. The kinetics of the drug release was not studied directly but through the kinetics of the gel layer formation. The increase of the gel layer thickness in the function of hydration time for the HPMC samples loaded with the studied drug is shown in Fig. 11. The plots are a linear function of time which indicates that also for the HPMC samples loaded with different amounts of the drug and hydrated in acidic solvent the swelling mechanism is swelling controlled. If so, in Eq. (6) the parameter n = 1. This equation was fitted to the experimental points from Fig. 11 and the best fitting parameters a and v (v = b in Eq. (6)) are given in Table 2. In the dry HPMC sample the drug molecules are almost completely immobilized. Only these drug molecules which find themselves in the hydrated part of the matrix (in the gel layer) gain motional freedom and release (diffuse) to the outer solvent. The drug molecules mostly diffuse much faster than the polymer swells and therefore the drug release should follow the swelling front almost precisely. The fitting parameter v can be interpreted as a kinetic parameter characterizing the velocity of the swelling of HPMC matrix loaded with different amounts of tetracycline chloride and therefore the velocity of the drug release. The data from Table 2 shows that the velocity of the drug release from the HPMC matrix increases with the increase of the amount of the loaded drug. The values of v parameters from Table 2 together with this value obtained for pure Table 2 Values v for the velocity of the swelling of HPMC matrix loaded with different amounts of tetracycline chloride and therefore the velocity of the drug release. pH

TETHCL

a

v (×10−7 m/s)

Error (×10−8 )

R

2 2 2

20% 25% 35%

0.517 0.572 0.662

4.435 4.743 6.483

1.6 2.0 1.8

0.997 0.996 0.997

361

Fig. 12. The velocity of the tetracycline hydrochloride release from HPMC matrix described in Fig. 11 as a function of drug concentration. The release of the drug is the linear function of the drug concentration.

HPMC sample are presented as a function of drug concentration in Fig. 12. The data were fitted with the linear function y = a + kx with the fitting parameters k = 1.66 × 10−7 ; b = 0.13 × 10−7 . The good linear dependence between the velocity of the gel layer (the velocity of the drug release) and the drug concentration within the HPMC matrix is well judged by the R = 0.998. The knowledge gained from Fig. 12 can be very valuable in the production of tablets containing TETHCl in an HPMC matrix. With the proper amount of drug concentration we can modify the growth of the gel layer and thereby the drug release. In our experiments we did not follow directly the release of tetracycline hydrochloride from HPMC matrix but the direct measurements of the drug release into the liquid phase are possible through the MRI or NMR methods and excellent examples are given in literature (Dahlberg, 2010). 3.2. MRI studies of the compact tablets on the example of paracetamol tablet 3.2.1. Paracetamol disintegration kinetics Paracetamol tablets under different names are most widely used as pain relievers and fever reducing medicine. Therefore, the tablets should act as soon as possible and reduce the pain/fever in suffering patients. The dissolution of the drug is one of the major factors determining the effectiveness of paracetamol performance in the gastrointestinal tract of the human body. The kinetics of the dissolution process is very fast but can be followed in situ by one of the MRI method called Snapshot FLASH. The pulse sequence of this method is shown in Fig. 4 and was described early in the paper. In the human body the dissolution takes place in the acidic contents of the stomach and therefore the disintegration imaging experiments were performed in acidic solvent (pH = 2) and at body temperature of 37 ◦ C. The experimental setup of the paracetamol tablet in the NMR glass vial inserted into a magnet for imaging is presented in Fig. 13a. The tablet under study was hydrated in excess by the solvent and immediately put in the spectrometer for imaging. The total time of the single experiment was equal 425 ms and allowed the study of the disintegration process in real time, on one tablet. The examples of 2D images of one of the paracetamol tablets under study in the function of immersion time are presented in Fig. 14. The images were taken from a plane section through the center of tablet (see Fig. 13a) well away from the area in contact with the adhesive. White pixels represent the signal from the proton of the acidic solvent surrounding the tablet in the glass vial. The cross-section of the tablet under investigation is seen as black pixels. As seen

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Fig. 15. The disintegration profiles for all studied paracetamol tablets as a function of dissolution time. The profiles were calculated with the help of Eq. (8) and the cross-section area of the tablet free from the solution was directly measured from the images like that on Fig. 14.

S=

Fig. 13. The experimental setup of the paracetamol tablet in the NMR glass vial inserted into a static magnet for dissolution imaging (a) together with one dimensional proton density Single Point Image profile acquired for dry paracetamol tablet with the experimental setup as in a (b). The 1D profile was acquired with tp = 105 ␮s and a resolution of 117 ␮m.

from Fig. 14 the image area of the tablets decreases in the function of the immersion time of the tablets into the solvent, due to the disintegration process. Similar images were recorded for other paracetamol tablets commercially available on the Polish market and manufactured by different pharmaceutical companies (A, B, C and D). Based on the images we can assume that the penetration of the aqueous fluid into the paracetamol tablet is homogenous and if so, the simple parameters which characterized the disintegration process of the tablet can be defined through the following equation



1−

S S0



× 100%

(8)

where S is the disintegration part of the tablet in %, S0 is the surface of the cross-section of the tablet before the immersion in the water hydrochloric solution (measured for the dry tablet) and S is the cross-section area of the tablet free from the solution (directly measured from the images like that on Fig. 14). In Fig. 15 the disintegration profiles for all studied paracetamol tablets are presented. It is easily seen that under the same condition, the rates of the disintegration greatly differ. For tablet A the rate is almost eight times faster when compared with paracetamol tablet C. The solubility of the drug depends on the properties of drug itself (the particle size, molecular size, hydrophilicity) and on the medium in which it dissolves (pH value of the solvent). In the performed imaging experiment the solvent medium was the same for all tablets therefore we can conclude that the properties of the paracetamol are different which causes the observed variation in the disintegration rate. Our experiment shows that Snapshot FLASH method can be successfully used to give a visual representation of the fast disintegration process of paracetamol as well as multicomponent tablets. 3.2.2. One dimensional spin density profile of the tablet To check the homogeneity of the dry paracetamol tablets the Single Point Imaging method described in paragraph 2.1 was applied and an example of the 1D 1 H SPI profile of one of the stud-

Fig. 14. The 2D radial images of a 2 mm slice at the center of a paracetamol tablet (see Fig. 13a) under study in the function of immersion time in the acidic (pH = 2) solvent at body temperature of 37 ◦ C. White pixels represent the signal from the proton of the solvent surrounding the tablet in the glass whereas the black pixels in the center of images represent the tablet. The images were taken through the center of the tablet with the flip angle of 15◦ and resolution of 117 ␮m × 117 ␮m. They were recorded within 452 ms.

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ied paracetamols is presented in Fig. 13b. The profile was acquired in the presence of a gradient applied along the long axis of the tablet for the experimental set up as shown in Fig. 13a. The signal intensity at each point in the profiles is proportional to the protons in a plane perpendicular to the long axis of the tablet, at a point on this axis. The main source of the protons in the studied tablets is 4-(N-acetyl)aminophenol (C8 H9 NO2 ). The other protons of the non-active additives will influence the profile only in a limited way due to their low concentration. As seen in Fig. 13b the intensity of the profile is almost constant across the sample which indicates homogeneous distribution of C8 H9 NO2 protons within the paracetamol tablet. The SPI profiles measured for other paracetamol tablets have the same characteristic. The homogenous distribution of the protons of active compound is important for patients taking a smaller dosage (for example one-half) of the tablet. These results also indicate that the disintegration experiment of the tablet described in the previous paragraph will be independent of the position of the chosen slice. 4. Conclusion MRI imaging experiments are superior to many other techniques, both on a macroscopic and molecular level for analyzing the processes which govern the behavior of solid pharmaceutical formulation like controlled release drugs and that of solid dispersion. These methods allow the monitoring of all processes during tablet dissolution: liquid penetration, swelling, dissolution of components, and diffusion of drug molecules into liquid. Therefore, MRI is a powerful tool for understanding key processes inside pharmaceutical dosage forms and plays an important role as a method to assist product development. References Abrahmsen-Alami, S., Korne, 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. Adriaensens, P., Pollaris, A., Carleer, R., Vanderzande, D., Gelan, J., Litvinov, V.M., Tijssen, J., 2001. Quantitative magnetic resonance imaging study of water uptake by polyamide 4,6. Polymer 42, 7943–7952. Adriaensens, P., Pollaris, A., Rulkens, R., Litvinov, V.M., Gelan, J., 2004. Study of the water uptake of polyamide 46 based copolymers by magnetic resonance imaging relaxometry. Polymer 45, 2465–2473. Alderman, D.A., 1984. A review of cellulose ethers in hydrophilic matrices for oral controlled-release dosage forms. Int. J. Pharm. Tech. Mfr. 5, 1–9. Alfrey, T., Gurnee, E.F., Lloyd, W.G., 1966. Diffusion in glassy polymer. J. Polym. Sci. C12, 249–261. Argon, A.S., Cohen, R.E., Patel, A.C., 1999. A mechanistic model of case II diffusion of a diluent into a glassy polymer. Polymer 40, 6991–7012. Bajpai, A.K., Giri, A., 2002. Swelling dynamics of a macromolecular hydrophilic network and evaluation of its potential for controlled release of agrochemicals. React. Funct. Polym. 53, 125–141. Barbieri, R., Quaglia, M., Delfini, M., Brosio, E., 1998. Magnetic resonance imaging (MRI) of water diffusion in 2-hydroxyethyl methacrylate (HEMA) gels. Polymer 39, 1059–1066. Basser, P.J., Mattiello, J., le Bihan, D., 1994. Estimation of the effective self-diffusion tensor from NMR spin-echo. Biophys. J. 66, 259–267. Berensen, A.R., 1977. Diffusion and relaxation in glassy polymers powders. 1. Fickian diffusion of vinyl chloride in poly(vinylchloride). Polymer 18, 697–704. Bettini, R., Catellani, P.L., Santi, P., Massimo, G., Peppas, N.A., 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. Bjorling, M., Herslof-Bjorling, A., Stilbs, P., 1995. An NMR self-diffusion study of the interaction between sodium hyaluronate and tetradecyltrimethylammonium bromide. Macromolecules 28, 6970–6975. Blümich, B., 2000. NMR Imaging of Materials. Oxford Science Publications, New York. Bowtell, R.W., Sharp, J.C., Peters, A., Mansfield, P., Rajabi-Siahboomi, A.R., Brandl, M., Haase, A., 1994. Molecular diffusion in NMR microscopy. J. Magn. Reson. B 103, 162–167. Brandl, M., Haase, A., 1994. Molecular diffusion in NMR microscopy. J. Magn. Reson. B 103, 162–167. Brazel, C.S., Peppas, N.A., 1999. Mechanisms of solute and drug transport in relaxing, swellable, hydrophilic glassy polymers. Polymer 40, 3383–3398.

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