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Thursday, 28 February 2013 14:54

Investigating Drug Release During Dissolution With MRI

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Schematics of the dissolution imaging experimental set-up under pharmacopeial conditions, including the AV400 magnetic resonance spectrometer, USP-IV flow-through dissolution cell, UV-Vis spectrometer. Schematics of the dissolution imaging experimental set-up under pharmacopeial conditions, including the AV400 magnetic resonance spectrometer, USP-IV flow-through dissolution cell, UV-Vis spectrometer.

Magnetic Resonance Imaging

The use of MRI as a powerful imaging and characterization modality in pharmaceutical dissolution research is now well established [1]. The non-invasive and non-destructive nature of MRI enables the investigation of structural, chemical and dynamical processes in many optically opaque systems at the microscopic level. Spatial maps of water penetration, tablet swelling and dissolution, as well as the mobilization and distribution of drug products can now be quantified and visualized [2,3]. In addition, the hydrodynamics within a USP recommended flow-through dissolution apparatus can also be visualized by MRI [4]. Such comprehensive information is essential in pharmaceutical research for: (i) the correct interpretation of conventional drug dissolution profiles and (ii) the optimal design (QbD) of controlled release formulations.

MRI Principle

Magnetic resonance images of a sample are reconstructed from a nuclear magnetic resonance (NMR) signal, which is generated by certain nuclei (most commonly 1H) when subjected to a strong external magnetic field, B0,  (e.g. 9.4 Tesla) and subsequently  irradiated with radio frequency pulses. A spatially encoded NMR signal, i.e. an image, is first generated by the application of RF pulses and additional much smaller magnitude magnetic field gradients. The spatial image can then be obtained via Fourier transformation of the raw data.  Figure 1 depicts the set-up of a vertical MRI magnet and USP-IV dissolution cell.

By tailoring the timings of the radio frequency pulses and magnetic field gradients, the MR images can be weighted to show different information such as the chemical composition, spin-lattice relaxation time (T1), spin-spin relaxation time (T2), and molecular self-diffusion coefficient, as well as the velocity of flowing dissolution media within the dissolution apparatus.  

Structure and Dynamics of HPMC Swelling and Drug Dissolution - Quantitative information

The ‘quantitative’ nature of magnetic resonance is one of the defining beauties of MRI. The acquired signal, in theory, is proportional to the number of nuclei of interest in a particular sample. Thus MRI tells us ‘how much’ of a particular substance we have in a particular system [1-3,5]. For example, we can spatially map the concentration of water, or the API in a swollen gel layer (see Figure 2).    

In addition to ‘how much’, MRI data can be also be acquired and manipulated to give quantitative information regarding ‘how fast’ the molecules of interest move [1-3,5]. For example, of particular interest within the pharmaceutical research community is being able to: (i) quantify the rate of ingress of dissolution media into swellable matrices and (ii) quantify the rate of formation and expansion of gel layers (see Figure 2). 

Quantitative MRI provides unique insight into the change in tablet microstructure during dissolution.

Hence by using the comprehensive MRI based information of the tablet swelling process during dissolution, it is inturn possible to evaluate the polymer structure quantitatively. For example, we have found two distinct regimes in the ‘gel’ region, namely the ‘swollen glassy layer’ (SGL) and the ‘gel layer’, based on the correlation between the water concentration and T2 obtained by MRI (see Figures 3 and 4). The temporal evolution of each component can thus be monitored accordingly (see Figure 5). 

The movie shows how the in-vitro T2-relaxation time maps can be used to follow the evolution of the gel and swollen glassy layers with time and highlights the quite different behaviour of the formulations chosen here.


Video of temporal evolution of gel structure of HPMC tablets (o.d. 5 mm) during dissolution in a USP-IV dissolution cell under pharmacopeial conditions, visualized by the spin-spin relaxation map (T2 map). The formulations used are HPMC polymer of increasing molecular weights (K4M < K15M < K100M) loaded with 30%(w/w) model drug ibuprofen (IBU) .

Interpreting drug release profiles

The determination of the gel structure and the evolution of each component are essential pieces of information because the water ingress and polymer swelling directly affect the drug release process. In particular, the definition of swollen glassy layer and its separation from the gel layer are critical to aid our understanding of drug release, because the HPMC polymer chains start to relax in the SGL and create larger voids for the drug to diffuse through.

A case study is illustrated in Figure 6. Three grades of HPMC with different molecular weights (K100M > K15M > K4M) were compared as swelling excipients for the release of model drug ibuprofen (IBU). It is found that the release rate of IBU from K4M is the highest, while K15M and K100M have similar release profiles. Without the differentiation of the SGL from gel layer, the comparison of total gel region (SGL+ gel layer) shows that K4M has the largest swollen layer, which in theory results in the slowest release rate.  However this is contrary to the observed cumulative drug release profile. With the evaluation of a separate SGL and gel layer, it is clearly seen that the SGL of K4M disappears fastest, indicating the drug becomes fully hydrated in the shortest time. Despite the fact that the IBU from the K4M sample has the thickest gel layer to diffuse through, it still releases the fastest. Thus, in this case, the rate determining step for release of IBU from HPMC matrix is controlled by the rate of HPMC hydration.

Future work

The majority of current MRI research studies in the pharmaceutical community acquire signals from water molecules and very few studies have investigated directly the behaviour of the APIs, since the 1H signal from API is normally obscured by the huge 1H signal associated with the water based dissolution medium [2]. We are currently exploring the 2D imaging of the API using the signatory atoms it possesses. Preliminary results indicate that MRI shows great potential in revealing the distribution and evolution of APIs under in vitro pharmacopeial dissolution conditions. The combination of NMR and MRI techniques applied to API and dissolution media can bring together the imaging results of both species, which will certainly result in a more comprehensive understanding of the controlled release systems.

References

[1]  Mantle, M.D., 2011. Int J Pharm, 417(1), pp. 173-195, doi:10.1016/j.ijpharm.2010.11.035

[2]  Zhang, Q., Gladden, L.F., Avalle, P., Mantle, M.D., 2011, J Control Release, 156(3), pp. 345-354, doi:10.1016/j.jconrel.2011.08.039

[3]  Chen, YY., Hughes, L.P., Gladden, L.F., Mantle, M.D., 2010. J Pharm Sci, 99(8), pp. 3462-3472, doi:10.1002/jps.22110

[4]  Shiko, G., Gladden, L.F., Sederman, A.J., Connolly, P.C., Butler, J.M., 2010. J Pharm Sci, 100(3), pp. 976-991, doi:10.1002/jps.22343

[5]  Laity P.R., Mantle M.D., Gladden L.F., Cameron R.E., 2010. Eur J Pharm Biopharm, 74(1), pp. 109-119, doi:10.1016/j.ejpb.2009.06.014

PSSRC Facilities

The group of Professor Lynn Gladden and Dr Mick Mantle at the Magnetic Resonance Research Centre (MRRC), University of Cambridge. The MRRC acts as a focus for applications of magnetic resonance techniques in chemical engineering research in the UK. The main research interest is in understanding multi-component adsorption, diffusion and flow processes. These phenomena are particularly important in the controlled release of pharmaceuticals, one of the focus areas of the research at the MRRC. The centre has wide expertise in the study of diffusion processes into pharmaceutical matrices and coatings by magnetic resonance imaging (MRI). A number of research projects at the MRRC are in collaboration with major pharmaceutical companies.

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