Research paper
Usage of radiopharmaceuticals in the development of pharmaceutical drug delivery systems: validation of [99mTc]DTPA and [99mTc]ECD

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Abstract

Tablets containing drugs of different lipophilicity, ranitidine and cinarizine, and placebo were prepared and their in vitro behaviour was studied by dissolution and disintegration tests. [99mTc]Diethylenetriamine-pentaacetic acid ([99mTc]DTPA) and [99mTc]ethyl cysteinate dimer ([99mTc]ECD) were used as tracers of the process. Both of them were added to tablets during wet granulation. Dissolution and disintegration profiles were assessed at different pH values (1, 4 and 7). Radioactivity was evaluated in filtered samples and scintigraphic studies were carried out in gamma camera. Stability in dissolution media was confirmed for both tracers under these conditions. Dissolution and disintegration velocity constants were calculated. [99mTc]DTPA proved to be an appropriate tracer for polar drugs such as ranitidine. Nevertheless, it was not a suitable tracer for lipophilic active drugs such as cinarizine. On the other hand, the most lipophilic tracer, [99mTc]ECD, exhibited the opposite behaviour. Scintigraphic studies of the disintegration process did not show significant differences between placebos and tablets containing active drugs. As disintegration is a physical process it does not discriminate between chemical differences in tablet formulations. Both methods complement each other because the dissolution process can be followed when a suitable radiotracer is chosen according to the physicochemical characteristics of the active drug.

Introduction

During the last 20 years, very important improvements have been achieved in pharmaceutical dosage formulation using radiopharmaceuticals as tracers [1], [2], [3], but only a few systematic studies have been performed to validate the methodology. Radiopharmaceuticals in nuclear medicine were primarily developed for diagnosis purposes and most of them were administered parenterally. In order to optimise the usage of radiopharmaceuticals in the development of pharmaceutical drug delivery systems, the behaviour of the tracers administered by routes other than the normal must be validated in different dissolution media and in the presence of pharmaceutical excipients [4], [5]. Our group has performed stability and in vitro studies of different radiopharmaceuticals with the aim of creating a database of tracers with known physicochemical properties to be used as model drugs in pharmaceutical dosage development [6], [7], [8], [9].

The objective of this study is to examine the way radiotracers model the release of drugs from tablet formulations and to validate the feasibility and limitations of two radiotracers with different physicochemical characteristics through basic in vitro studies. The possibility of developing a database of the physicochemical behaviour of radiotracers would allow selection of the most appropriate drug models when using scintigraphic techniques in the development of pharmaceutical dosage forms [10], [11], [12], [13], [14].

The characterised radiopharmaceuticals were [99mTc]diethylenetriamine-pentaacetic acid ([99mTc]DTPA) and [99mTc]ethyl cysteinate dimer ([99mTc]ECD) [15] which were incorporated into tablets during wet granulation. Tablets with drugs of different lipophilicity, ranitidine and cinarizine, and placebo were prepared as previously reported by our group [16]. Dissolution and disintegration profiles were assessed at different pH values (1, 4 and 7) [17], [18], [19].

Section snippets

Radiopharmaceuticals labelling

[99mTc]DTPA and [99mTc]ECD were obtained by labelling commercial kits with [99mTc]pertechnetate obtained from an Elumatic III generator (Schering CIS)®. Radiochemical purity tests were performed by chromatographic systems using Whatman No. 1/propanone and Whatman No. 1/NaCl 0.9% for [99mTc]DTPA complex. [99mTc]ECD radiochemical purity was studied by chromatography in Whatman No. 1/methanol 85% and HPLC (Shimadzu LC-10 AS) using a Partisphere C18 (Whatman) Column as stationary phase and the

Labelling process

Tracers [99mTc]DTPA and [99mTc]ECD were prepared with radiochemical purity higher than 99% [21].

Stability studies

No physicochemical change of the radiotracer was observed after 120 min incubation of [99mTc]DTPA with the dissolution media at pH 1, 4 and 7 and after the process of wetting and drying the components of the formulation.

The w/o coefficient for [99mTc]DTPA was 0.95 in the saline phase.

[99mTc]ECD during the granulation process showed no changes in radiochemical purity. When it was incubated in the

Discussion

According to the results [99mTc]DTPA is a suitable model for the dissolution of a polar drug such as ranitidine. This is supported by the fact that the dissolution velocity constants of both drug and tracer are of the same order at pH 7 (Table 1). It should be taken into account that according to USP XXV, the dissolution test for ranitidine should be performed at pH 7. Also disintegration studies showed similar profiles (Fig. 1, Fig. 2) as confirmed by scintigraphic studies. [99mTc]DTPA was a

Conclusions

Dissolution studies demonstrate differences in behaviour between similar formulations containing different drugs, presumably due to the physicochemical nature of the drugs themselves and interactions with the tracer. Scintigraphic studies of the disintegration process did not show significant differences between placebos and tablets containing active drugs. As disintegration is a physical process it does not discriminate between chemical differences in tablet formulations. This method does show

Acknowledgements

The authors thank TECHI S.A. for supplying radiopharmaceutical kits and Centro de Medicina Nuclear, Hospital de Clı́nicas for Nuclear Medicine equipment facilities.

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