nmr imaging investigations of drug delivery devices using a flow-through usp dissolution apparatus

Journal of Controlled Release 68 (2000) 73–83www.elsevier.com/ locate / jconrel

NMR imaging investigations of drug delivery devices using aflow-through USP dissolution apparatus

a , a a b b*C.A. Fyfe , H. Grondey , A.I. Blazek-Welsh , S.K. Chopra , B.J. FahieaDepartment of Chemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1

bPharmaceutical Sciences Division, Glaxo-Wellcome Inc., Mississauga, Ontario, Canada L5N 6L4

Received 20 July 1999; accepted 19 February 2000

Abstract

A system for performing NMR imaging experiments on drug delivery devices within a flow-through dissolution apparatus,USP Apparatus 4, has been developed. The system was used to image the physical changes that occur in solid dosage formsduring dissolution in the flow-through apparatus. Simultaneous cumulative drug release measurements were also made. TheNMR images obtained under these conditions and the drug release data provide a better understanding of the processesinvolved in the release of drugs from drug delivery systems based on diffusion, dissolution and osmosis mechanisms. 2000 Elsevier Science B.V. All rights reserved.

Keywords: Controlled release; Flow NMR imaging; USP Apparatus 4

1. Introduction ent drugs from this matrix [7]. In another study [8],the use of NMR imaging in detecting structural

In recent years, microscopic NMR imaging has changes which occur in a controlled release devicebeen used to study the controlled release of drugs during the dissolution process has also been demon-from hydrophilic polymer matrices. Although early strated. In that work, the dissolution medium was instudies were mainly qualitative in nature [1–4], these static state. However, the official drug release ratetechniques can yield considerable information on the measurements require dissolution medium in dy-release processes at the molecular level. Our current namic state. Therefore, the NMR images taken in theresearch is focussed on developing the application of previous study may not have truly represented theNMR spectroscopy and NMR imaging techniques to structural changes that may occur under officialthe study of controlled release drug delivery devices. dissolution conditions. Thus, in order to properlyWe have investigated and quantified the formation of integrate the imaging data with those from conven-hydrogel from hydroxypropyl methylcellulose tional release measurements it is important to per-(HPMC) [5,6] and have evaluated its role in the form the experiments under identical conditions. Indiffusion based hydrophilic matrices and more re- the present paper, we describe a setup based on thecently have studied the concurrent release of differ- Sotax flow-through dissolution system, USP Ap-

paratus 4, with which it is possible to obtain NMR*Corresponding author. images of controlled release devices immersed in

0168-3659/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S0168-3659( 00 )00237-6

74 C.A. Fyfe et al. / Journal of Controlled Release 68 (2000) 73 –83

dynamic dissolution medium. We also present NMR through the delivery devices during the dissolutionimages and drug release data on three different drug process. The 2563256 pixel images had a resolutiondelivery systems immersed in static dissolution of 100 mm and a slice thickness of 500 mm.medium and dynamic dissolution medium. The Sotax flow-through unit (USP Apparatus 4)

was used as the model for the cell used in ourimaging studies [10]. Due to the size constraints

2. Experimental within the imaging system, commercial versions ofthe flow-through apparatus could not be used be-

2.1. Equipment cause their outer diameters were larger than could beaccommodated by the r.f. coil. A version of the

The NMR imaging experiments were carried out flow-through cell which matched all the internalusing a Bruker MSL 400 NMR spectrometer with a dimensions of the Sotax flow cell but with reducedBruker microscopic imaging accessory. The prob- outer dimensions was fabricated to fit into the r.f.ehead incorporated a 26 mm radio frequency (r.f.) coil. Other modifications included the replacement ofcoil into which the flow cell was inserted and field metallic components with similarly designed plasticgradient strengths up to 12 G/cm were used for components since the metal components would havephase and frequency encoding in the experiments. A interacted with the strong magnetic field and dis-conventional spin-warp imaging sequence [9] was torted the NMR images. The modified flow cell isused to obtain two-dimensional images of ‘slices’ shown by itself in Fig. 1 and within the magnet in

Fig. 1. Schematic diagram of the flow-through dissolution apparatus used for the NMR imaging studies.

C.A. Fyfe et al. / Journal of Controlled Release 68 (2000) 73 –83 75

Fig. 2. The total volume of the cell and tubing was from Glaxo Wellcome Inc., Canada. Model con-45 ml. A calibrated Gilson Miniplus 3 was used to trolled dissolution tablets (800 mg, thickness 5.0pump the dissolution medium and measurements of mm, diameter 12.8 mm). were compressed from thethe total drug released during the dissolution process ranitidine-HCl mixture. A 2 mm hole was drilledwere made by UV–visible spectroscopy. through the tablet and filled with wax. Wax was also

applied to both the flat faces. The peripheral cylindri-2.2. Sample preparations cal face was left exposed so that it could come in

contact with the dissolution medium. The osmoticHydroxypropyl methylcellulose (HPMC, Dow tablets, Volmax Extended Release 8, were obtained

Methocel K4M) was obtained as a gift from UpJohn- from Glaxo Wellcome Inc. These tablets contained 8Pharmacia. Flat-faced HPMC tablets (120 mg, thick- mg of salbutamol (albuterol) sulfate. In the case ofness 1.7 mm, diameter 8.8 mm) were prepared by the HPMC experiments, the dissolution medium wasdirect compression using a rotary tablet press. A simulated gastric fluid. In the other cases, themixture of ranitidine-HCl (75%), lactose (12.5%), dissolution medium was simulated gastric fluid with-and hydroxypropyl cellulose (12.5%) was obtained out enzyme with 5 mM CuSO added as relaxation4

Fig. 2. Schematic diagram of the flow-through dissolution apparatus within the NMR imaging magnet.


agent. The ranitidine-HCl concentration in 900 ml of reproduced and the black circles in the lower part ofdissolution medium was measured from its UV the image are due to the glass beads used to produceabsorbance at 313 nm and the salbutamol sulfate a smooth flow of medium over the sample. Inconcentration in 200 ml of dissolution medium from subsequent images, approximately the same part ofits UV absorbance at 225 nm. the flow cell is imaged with the drug delivery device

either attached to a plastic support in the free watervolume above the beads or covered by the beads

3. Results and discussion themselves.

Fig. 3 shows the two-dimensional proton NMR 3.1. HPMC tablet swellingimage of a vertical slice taken through the center ofthe flow-through cell without any sample with In order to investigate possible effects of dissolu-simulated gastric fluid. The image is in gray scale tion medium flow on hydrogel swelling, a criticalwith white indicating the presence of water and black feature of diffusion controlled release, pure HPMCindicating the absence of water. The general features tablets were studied under both static and flowof the flow cell (Fig. 2) are clearly visible in the conditions. The resulting images are presented inimage. The exact shape of the interior of the cell is Fig. 4 where those on the left (a–d) were obtained

Fig. 3. NMR imaging of water within the Sotax flow-through apparatus (cf. Fig. 1). The 1-mm beads in the cone can be clearlydistinguished and the full width of the image is equivalent to 30 mm in the sample.


Fig. 4. Images of HPMC tablets within the flow-through apparatus at swelling times of (a, e) 1 h, (b, f) 5 h, (c, g) 13 h, and (d, h) 19 h. Theimages on the left (a–d) are under static conditions while the images on the right (e–h) were obtained under flow conditions of 8 ml /min.The full width of the image is equivalent to 16 mm in the sample. TE55 ms, TR51.7 s.

under static medium conditions and those on the top of the glass beads. The imaging conditions wereright (e–h) were recorded under continuous medium exactly the same in the two sets of experiments andflow conditions of 8 ml /min. the images can be compared directly both within and

In the images, the dark feature at the top is the between the two series with respect to their dimen-plastic support to which the tablet was glued. The sions and image intensities. Although it is possibleplastic support is not visible in the last two flow that fast medium flows could distort the imageimages as the gel has become detached and rests on intensities and produce artifacts [11], the rates of


Fig. 5. Images of dissolution tablets within the flow-through apparatus at (a, e, i) 0.5 h, (b, f, j) 3 h, (c, g, k) 6 h, and (d, h, l) 10.5 h. Images(a–d) were obtained under static conditions, images (e–h) and (i–l) were obtained with 4 and 16 ml/min flow, respectively. The full widthof the image is equivalent to 16 mm in the sample.


flow used in the present study are too slow to cause The drug release from these tablets was studied inany such effects. static dissolution medium and turbulent dissolution

In the imaging experiments, the TE and TR values medium. The images taken are presented in Fig. 5.(see caption) were selected to enhance the contribu- For the two experiments under flow conditions (4tion to the image from the true gel portion of the ml /min (e–h) and 16 ml /min (i–l)), the total drugswollen tablets, i.e. HPMC concentrations from 10 to release at various intervals was also measured. These25% w/w. Thus, regions in the center of the tablet data are shown in Fig. 6.which are still dry appear black, the swollen gel is The rates of erosion were higher for the tabletsbright and the surrounding water and ‘loose gel’ with that were in turbulent medium than for those thatlow HPMC concentrations are intermediate in in- were in static medium. However, there was verytensity. At short exposure times, only the outer layer little difference in the erosion rates of the tabletsof the tablet has formed gel, while at long exposure under the two flow rates studied. The drug releasetimes, the whole tablet is in the gel state. The black curves (Fig. 6) for the tablets under the two different‘spots’ in these later images are due to air bubbles flow rates are virtually identical and have the generaloriginating from the release of gas trapped in the profiles expected for this type of release device.tablet during the compression process, as reportedpreviously [6]. 3.3. Osmotic release tablets

From a comparison of the two series, the gelvolume of the tablet under flow conditions at each The flow setup was also used to investigate thetime point is less than under static conditions. This performance of a commercial osmotic release systemsuggests that there is a mechanical perturbation of containing salbutamol sulfate. The osmotic deliverythe gel by the medium flow which strips away the system consisted of an osmotically active core coatedoutermost very highly hydrated HPMC exposing the with a semipermeable membrane which had a laser-less hydrated HPMC more to the medium flow and drilled hole. The core contained salbutamol sulphate,erosion. In terms of drug release, this will tend to an osmotic agent, sodium chloride and a lubricatingincrease the release rate, particularly of larger mole- agent, magnesium stearate. As water penetrates thecules, such as triflupromazine-HCl, which are only tablet and dissolves the core, the osmotic pressurereleased when the HPMC concentration is very low within the tablet increases and drug solution is forced[7]. through the hole.

For this series of experiments, the tablet was3.2. Model controlled dissolution tablets

As described in Section 2, the model controlleddissolution tablets contained a dissolving matrixmixture composed of ranitidine-HCl, lactose andhydroxypropyl cellulose. The two flat surfaces werecoated with wax so that erosion and dissolutioncould take place from only the peripheral face of thetablet. The tablets also had a central supportingcolumn joining the coats on the two flat surfaces togive them structural integrity throughout the dissolu-tion process. The tablets were mounted horizontallyon a plastic support which appears as a dark object atthe top of the images. The central column is ob-served when the slice selected is exactly through the

Fig. 6. Cumulative release of ranitidine-HCl obtained during thecenter of the tablet, but is not seen if the slice is imaging experiments of Fig. 5. The release of drug from theslightly off center as in the last image of the 16 dissolution tablet is similar at both 4 ml /min (s) and 16 ml /minml /min series (image l). d) flow rates.


Fig. 7. Images of an elementary osmotic pump tablet obtained with medium flow of 8 ml /min at (a) 0.25 h, (b) 1 h, (c) 3 h, (d) 4 h, (e) 6 h,(f) 8 h, (g) 10 h, and (h) 12 h. The full width of the image is equivalent to 16 mm in the sample.


Fig. 8. Profiles of the water distribution through the osmotic pump tablet obtained from the images of Fig. 7 at (a) 0.25 h, (b) 1 h, (c) 3 h,(d) 4 h, (e) 6 h, (f) 8 h, (g) 10 h, and (h) 12 h. The arrows indicate the edges of the tablet. The spikes outside the tablet region are signalsfrom water between the glass beads used for positioning the tablet. This intensity was used as reference to normalize the signal from withinthe osmotic pump tablet.


covered by the glass beads to facilitate water pene- 4. Conclusionstration from the entire surface. The images in Fig. 7show a relatively fast increase in the volume of the NMR imaging within a flow-through dissolutiontablet in the first hour, indicating the build up of apparatus was demonstrated for a number of dosageosmotic pressure in the inner system. The core is still forms. The information obtained from the NMRdark so any water taken up at this stage must be images complements the drug release profiles ob-quite strongly bound and this immobilization makes tained in the USP approved method and would beit ‘transparent’ in the image as the experiment, as invaluable in the development of novel drug deliveryimplemented, only detects mobile materials. At systems by simultaneously providing direct infor-longer exposure times there is further hydration of mation on the nature of the molecular processesthe inner core from the outside of the tablet inwards involved.until after 8 h it is completely hydrated. Thesechanges can be seen more quantitatively in Fig. 8,which shows single rows through the center of the Acknowledgementsimages (presented with the same vertical scaling) atthe times indicated. The outer dimension of the tablet The authors thank the Natural Sciences and En-is indicated by the arrows at the top of the figure and gineering Research Council of Canada and Glaxothe spikes outside this region are not ‘noise’ but the Wellcome Inc., Canada, for funding the presentsignals from the volumes of water between the glass research. The support of the mechanical and electri-beads.. cal engineering units of the Department of Chemistry

During the dissolution process, the drug is forced of UBC is acknowledged, specifically Mr. Oskarthrough the single hole and the drug release profile Greiner for preparing the flow cell used for this(Fig. 9) shows the expected linear behaviour for this study.type of device. Note that although the maximumdrug release is reached at the 10 h time point, therebeing no further change after 20 h, Figs. 7h and 8h Referencesshow that water penetration into the osmotic pumptablet continued after this time. [1] A.R. Rajabi-Siahboomi, R.W. Bowtell, P. Mansfield, M.C.

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nmr imaging investigations of drug delivery devices using a flow-through usp dissolution apparatus

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