Abstract
This investigation compared in vitro dissolution profiles from sodium iodide capsules with radioiodide thyroid uptake in patients with thyroid abnormalities, using sodium iodide capsules prepared with a formulation exhibiting complete release of radioiodide in vitro and a formulation exhibiting incomplete release. Methods: In vitro dissolution profiles for radioactive sodium iodide capsules with 2 different formulations were determined using the U.S. Pharmacopeia (USP) XXIV dissolution test. The 2 formulations studied in vitro were sodium phosphate dibasic powder with 1% magnesium stearate and calcium phosphate dibasic powder with 3% magnesium stearate. The thyroid uptake of radioiodide from capsules exhibiting complete release or incomplete release of radioiodide was determined in patients with thyroid disorders. Results: In the dissolution studies, by 20 min after initiation of the test, >95% of the radioactive iodide was released from capsules of sodium phosphate dibasic powder. The capsules of calcium phosphate dibasic powder reached 75% at 65 min, with no further release occurring thereafter. In the in vivo studies, the mean thyroid uptake at 1 h for sodium phosphate dibasic powder with 1% magnesium stearate (complete-release formulation) was 12.7%, compared with 9.3% for calcium phosphate dibasic powder with 3% magnesium stearate (incomplete-release formulation) (P < 0.05). At 24 h, the value was 56.6% for the complete-release formulation, compared with 50.3% for the incomplete-release formulation (P < 0.01, Wilcoxon signed rank test). At 1 h, the abdominal activity for the complete-release formulation was 3.4%, compared with 8.8% for the incomplete-release formulation (P < 0.01). At 24 h, the value was 0.4% for the complete-release formulation, compared with 1.0% for the incomplete-release formulation (P < 0.01). Conclusion: The data suggest that the incomplete dissolution profile observed in vitro may correlate with reduced bioavailability of radioiodide in vivo. The USP dissolution test can be applied to radioiodide sodium iodide capsules as a quality assurance procedure.
Radioactive sodium iodide is the drug of choice to aid in the diagnosis of hyperthyroidism and thyroid cancer and for therapy in patients with these conditions. The radioiodide capsule, because it provides a convenient and safe way to administer radioiodide, has been the preferred dosage form for patients (1). Variability in the bioavailability of radioiodide from a capsule can affect the outcome of a diagnostic study or a therapeutic application of the radiopharmaceutical.
Halpern et al. (2) found a reduction in percentage uptake of radioiodide in the thyroid when capsules, in comparison with the liquid dosage form, were used. According to Yu et al. (3), in vitro dissolution studies of 131I sodium iodide capsules obtained from 3 commercial vendors showed a marked reduction in radioiodine release from one vendor compared with the other vendors. Yu et al. suggested that the slower release of radioiodide from the capsules may result from the possible formation of an 131I magnesium stearate complex. The presence of magnesium stearate has been found to affect the release of active components from capsules and tablets (4,5). In a second in vitro study by Yu et al. (6), the dissolution profiles for 131I sodium iodide therapeutic capsules from the same 3 commercial vendors showed that 100% release of activity was attained within 35 min. Yu et al. (6) suggested that the rapid release of radioiodide from the therapeutic capsules resulted from the absence of magnesium stearate in the capsules.
In vitro dissolution profiles were found to be influenced by the diluent, type of lubricant, and concentration of lubricant used to prepare radioiodide capsules (7). Lee et al. (7) noted that increasing the concentration of magnesium stearate decreased the dissolution rates of radioiodide from capsules prepared with diluents such as sodium phosphate, calcium phosphate, or lactose.
A previous study (8) showed that the U.S. Pharmacopeia (USP) XXIV dissolution test (9) can detect differences in 131I release profiles for capsules prepared with formulations expected to produce poor release and formulations expected to produce good release in hyperthyroid cats. However, the relationship between in vitro dissolution profiles and radioiodide uptake in the thyroid of patients should be examined to ascertain the importance of formulation in thyroid function studies and treatment. If a correlation exists, in vitro dissolution studies may be useful for quality control in the pharmaceutical industry. If, indeed, a dosage formulation results in poor bioavailability of the radioiodide, then less radioactivity will be available for thyroid uptake for that formulation than for a formulation exhibiting good bioavailability. Diagnostic errors and potential dosing errors in the treatment of hyperthyroid patients can result.
This investigation compared USP XXIV in vitro dissolution profiles with radioiodide thyroid uptake in patients with thyroid disorders using sodium iodide capsules prepared with a formulation exhibiting a rapid and complete release of radioiodide in vitro and a formulation exhibiting a slow and incomplete release of radioiodide. The purpose of the study was to determine whether the in vitro release characteristics of radioiodide from capsules indicate the bioavailability of the radioiodide in vivo, leading to differences in thyroid uptake values that can adversely affect clinical decisions about patients.
MATERIALS AND METHODS
Patients
Radioiodine thyroid uptake was measured in 20 patients with various thyroid abnormalities or in a euthyroid state (16 women, 4 men; age range, 18–68 y). The clinical characteristics for the 20 patients are shown in Table 1. The marked increase in free thyroxine and decrease in thyroid-stimulating hormone that is exhibited in patients with thyroid disorders made it easier to show significant changes influenced by radioiodide capsule formulation that may not be seen in euthyroid patients. The diagnosis of thyroid abnormalities was based on the history, physical findings, a plasma free-thyroxine concentration exceeding the upper limit of the reference range (1.8 ng/dL), and a thyroid-stimulating hormone level less than the lower limit of the reference range (0.35 IU/L).
Detailed Patient Data
Preparation of Granulation and 131I Sodium Iodide Capsules
Granulations were prepared with either sodium phosphate dibasic powder or calcium phosphate dibasic powder (7). The preparation of 131I capsules was similar to that in our previous study (8). The desired weight of lubricant was added to the labeled granulation after drying, while the material was still contained in the glass container, which was then shaken for 15 min. To prepare the formulation exhibiting a rapid and complete release of radioiodide in vitro (formulation A), we added 1% magnesium stearate as a lubricant to the granulation of sodium phosphate dibasic powder after overnight drying. To prepare the formulation exhibiting a slow and incomplete release of radioiodide in vitro (formulation B), we added 3% magnesium stearate as a lubricant to the granulation of calcium phosphate dibasic powder.
Dissolution Test
Six capsules of the 2 formulations to be tested in patients were used for dissolution studies. Dissolution profiles were determined for every in vivo study. The dissolution studies were conducted according to the USP XXIV method (9). Briefly, each unit consisted of a 1,000-mL glass beaker and a motor-driven metallic shaft connected to a paddle blade. The stirring element was placed at the prescribed distance of 25 ± 2 mm from the bottom of the beaker and rotated at 50 rpm. The beaker, containing 900 mL distilled water, was maintained at 37°C ± 0.5°C. Each capsule was placed in a wire cage to prevent floating. Sampling (1 mL) was conducted at 5, 10, 15, 20, 30, 40, 50, 65, 80, 95, 110, 125, and 140 min after placement of the capsules in the beaker. A volume of distilled water equal to the sample was added to each beaker immediately after each sampling. Using the methodology of Yu et al. (3), the samples were counted in a γ-counter (Compac 120; Picker International, Northford, CT). An aliquot of an 131I reference standard solution was used to determine the counting efficiency of the γ-counter. Net sample counts were corrected for background, counting efficiency, radioactive decay, and volume factor. Data were expressed as the percentage of initial activity.
Radioiodine Uptake Measurements
Each patient was studied with the 2 formulations. After the study of the first formulation, 1 wk was allowed for decay of any residual radioactivity. Before the second study took place, the residual radioactivity in the thyroid and abdomen was measured. Individual patients were studied at different times. Medicine (propylthiouracil, methimazole, or thyroxine) was withheld 2 wk before the first and second studies. Each patient was administrated a 3.7-MBq (100 μCi) 131I capsule orally, and thyroidal and abdominal uptake were measured at 1 and 24 h with a detector (Thyrodyne Uptake System; Picker, Northford, CT). Four total counts of interest were measured: thyroid, right thigh (background), abdomen (probe detector placed against the upper 5 cm of umbilicus), and standard capsule in the thyroid phantom. Percentage uptake values were obtained using the counting data from the radioactive capsule count as 100%.
Statistical Analysis
The Wilcoxon signed rank test was used when a study was designed by paired measures and the percentage data did not meet the t test assumption. For in vivo data, the formulations at 1 and 24 h were compared statistically with the aid of the Wilcoxon signed rank test for nonparametric variables. P < 0.05 was considered statistically significant. Statistical calculations were performed using SPSS, version 9.0 (SPSS Inc., Chicago, IL), for Windows (Microsoft, Redmond, WA).
RESULTS
Dissolution Profiles
In vitro dissolution profiles for capsules of the 2 formulations used in radioiodide uptake studies were obtained for each patient. As may be observed in Figure 1, which is a typical profile of the dissolution studies, formulation influenced the 131I release profile in vitro. By 20 min, ≥95% of the activity was released from capsules prepared with the sodium phosphate dibasic powder with 1% magnesium stearate (formulation A). Formulation A was released almost immediately after the dissolution studies began. The capsule appeared to disintegrate and dissolve quickly.
Dissolution profiles for 131I sodium phosphate dibasic powder with 1% magnesium stearate (A) and calcium phosphate dibasic powder with 3% magnesium stearate (B).
Figure 1 shows that capsules made with calcium phosphate dibasic powder with 3% magnesium stearate (formulation B) released 46% of the 131I at 20 min. Approximately 75% of the activity was released at 65 min, and this percentage remained approximately the same until the end of the study (140 min). The capsule appeared to dissolve slowly in relation to that of formulation A. The contents of the capsules were seen to have dispersed in the bottom of the beaker and to have incompletely dissolved at the end of the study.
For capsules used in the thyroid uptake studies, ≥95% of the activity was released by 20 min for formulation A. Only 75% of the activity was released within 140 min for formulation B.
Radioiodide Activity
Thyroid Uptake.
The plasma free-thyroxine values for the study ranged from 0.9 to 9.8 ng/dL. Individual values are presented in Table 1. As may be seen in Table 2, at 1 h the mean thyroid uptake for formulation A was 12.7%, compared with 9.3% for formulation B. Furthermore, 16 of 20 patients exhibited a decreased thyroid uptake at 1 h for formulation B, in comparison with their thyroid uptake at 1 h for formulation A. In addition, at 24 h 16 of 20 patients had thyroid uptake for formulation B that was lower than that for formulation A. Moreover, Table 2 shows that the mean thyroid uptake for formulation A was 56.6% (SD, 27.7%), compared with 50.3% (SD, 26.5%) for formulation B, at 24 h. The same relationship was noted at 1 h (12.7% [SD, 18.5%] and 9.3% [SD, 13.1%] for formulations A and B, respectively). The Wilcoxon signed rank test showed a significant difference in radioiodide thyroid uptake between formulations A and B at 1 and 24 h (P < 0.05). It appears that the poor dissolution profile observed in vitro may correlate with a reduced bioavailability of the radioiodide in vivo.
Mean Percentage Radioiodide Uptake in Thyroid
Abdominal Activity.
Table 3 shows that at 1 h the mean abdominal activity for formulation A was 3.37% (SD, 2.88%), compared with 8.75% (SD, 5.06%) for formulation B. The same relationship was noted at 24 h (0.44% [SD, 0.15%] and 1.03% [SD, 0.63%] for formulations A and B, respectively). That the values in the abdominal areas were slightly but significantly higher for formulation B than for formulation A was confirmed statistically (Wilcoxon signed rank test, P < 0.05).
Mean Percentage Radioiodide Activity Present in Abdomen
DISCUSSION
The multiple t test showed statistically significant differences in the dissolution profile between the 2 formulations at all intervals (P < 0.05). The SDs for the percentage release values for formulation A were larger at early sampling intervals and much smaller later (Fig. 1) because of the inhomogeneity of 131I within the 900 mL of water at the time that 131I was rapidly released from the capsules. The small paddle blade does not circulate the 131I within the large volume as quickly as desired. However, this finding was normal and was typical of the outcome using the USP apparatus for dissolution. It is interesting that the SDs for values for formulation B were smaller at the early sampling intervals and thereafter. This pattern would be expected of a formulation that releases the radioactivity more slowly.
As Table 4 indicates, the time to reach 95% release of radioiodide from capsules containing formulation A in the current investigation was less than that from the diagnostic capsules of vendors B and C studied by Yu et al. (3). In addition, release from our formulation A was quicker than that from the therapeutic capsules of vendors B and C (6). However, except for the comparison with the diagnostic capsules of vendor B, the differences were not significant. Moreover, in a study of Lee et al. (7), the presence of 3% magnesium stearate in the sodium phosphate dibasic powder capsules resulted in a longer interval to attain 95% release of the radioiodide. In the current investigation, 3% magnesium stearate combined with calcium phosphate dibasic powder resulted in only a 74% release of radioiodide even after 140 min in the 900 mL of distilled water.
Comparisons of Time (Minutes) for 95% Release of Radioiodide from Capsules
In the in vivo studies of this investigation, the 24-h mean thyroid uptake for formulation A was 56.2% (SD, 27.7%), compared with 50.3% (SD, 26.5%) for formulation B. The difference was similar to the results reported for a study by Robertson et al. (10), in which the average thyroid uptake decreased 8% when the dosage form was changed from liquid to capsule. The problem observed in this study may exist for other orally administered compounds. A tritiated or 14C-labeled tracer can be used to determine the appearance time and peak serum levels of the drug when administered in liquid and capsule form. The time to attain 95% release of the radioiodide from capsules with formulation A was similar to that from capsules prepared for studies on cats (8). The dissolution profiles for formulation B were also similar to those found by Lee et al. (7). These results indicate that the USP dissolution test can indicate the influence of formulation or preparation on the release of radioiodide from capsules used in radioiodide thyroid uptake studies or for treatment of thyroid diseases.
CONCLUSION
The results of the in vivo study confirmed that the formulation factor was significant. The Wilcoxon signed rank test showed that statistically significant differences in mean radioiodide thyroid uptake existed between the 2 formulations at 1 h and 24 h after administration of the capsules. The USP dissolution test has merit for radioiodide capsules. Also, the resultant effects of formulation on diagnostic studies of radioiodide thyroid uptake should be considered.
Acknowledgments
This study was supported in part by grant DOH89-TD-1207 from Department of Health, Taiwan, and grant NSC89-NU-7-016-001 from the National Science Council.
Footnotes
Received Mar. 5, 2001; revision accepted Sep. 21, 2001.
For correspondence or reprints contact: Ming-Der Yu, PhD, Department of Nuclear Medicine, Tri-Service General Hospital, 325 Cheng-Kung Rd., Sec. 2, Taipei, Taiwan 114.
E-mail: mdyu{at}ndmctsgh.edu.tw
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